Sharon Worcester

Factor VIII expression was detected on liver biopsies at more than 2 years after a single infusion of adeno-associated virus (AAV) gene therapy for hemophilia A in two patients who were part of a recent phase 1/2 study and who participated in an optional liver biopsy substudy.

The persistent factor VIII (FVIII) expression seen in the two patients was consistent with the presence of circularized, full-length human FVIII-SQ DNA in the biopsy samples and was observed in one patients at week 201 after infusion with 6 x 10¹² vg/kg of the AAV serotype 5 human FVIII-SQ gene therapy(valoctocogene roxaparvovec) and in another at week 140 after infusion with 4×10¹³ vg/kg, Sylvia Fong, PhD, reported during the International Society of Thrombosis and Haemostasis virtual congress.

The first patient had no FVIII detected in the plasma at the time of biopsy. The second had 28.4% of normal FVIII activity detected at the time of biopsy, said Dr. Fong of BioMarin Pharmaceutical, noting that alanine aminotransferase levels were normal at the time of biopsy for both subjects.

“Valoctocogene roxaparvovec is currently being evaluated in a phase 3 clinical study,” Dr. Fong said. “Data from the phase 1/2 trial have demonstrated preliminary proof of concept that valoctocogene roxaparvovec treatment, in many cases, eliminated spontaneous bleeds and the need for prophylactic factor VIII replacement.

“In addition, an acceptable safety profile was observed.”

Data from that trial were presented at the World Federation of Hemophilia virtual summit in June.
 

Liver biopsy for factor VIII expression

The current exploratory liver biopsy substudy – the first-in-human liver biopsy study after gene therapy for hemophilia A – was open to all phase 1/2 study participants and was initiated in September 2019 with multiple aims, including improved understanding of the durability and variability of AAV gene therapy, she explained.

Histopathological examination revealed normal liver architecture with mild steatosis and no evidence of steatohepatitis or significant inflammation in either participant. In the 6×10¹² vg/kg– and 4×10¹³ vg/kg–treated participants, a dose-dependent increase was seen in the percentage of hepatocytes that stained positive for vector genomes (1.3% and 32%, respectively), she said.

“This was very exciting to see,” she said, referring to the 32% stain-positive rate in the patient who received the 4x10¹³ vg/kg dose. “Not only were we able to detect vector genomes more than 2 years post-dose, there seems to be quite a bit of signals in this patient sample.”

The findings were similar to those seen in preclinical nonhuman primate models, she noted.

Dose-dependent increases were also seen in quantities of circular full-length/ITR-fused vector genomes and in FVIII-SQ RNA vector genomes; liver hFVIII-SQ RNA levels were 7.67×10² copies/mcg and 6.77×10⁴ copies/µg in the 6×10¹² vg/kg–treated participant the 4×10¹³ vg/kg–treated participant, respectively.

The circularized genomes were present as monomers and concatemers in both participants, and “were presumably associated with long-term expression,” Dr. Fong said.

Both participants are clinically stable with no long-term hepatic issues, she said, noting that analyses of results from additional participants in the substudy will be shared as they become available.

To date, because of “precious small amounts” of tissue available from the biopsy samples, Dr. Fong said she and her colleagues had not looked for degradation of the vectors.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de recherche des Cordeliers, Paris, asked: “Is there a plan [to do so] or not, because I guess it’s a very important point,” to which Dr. Fong said that it is a possibility if adequate samples become available.

Dr. Fong is an employee of BioMarin Pharmaceuticals.

[email protected]

SOURCE: Fong S. 2020 ISTH Congress, Abstract OC 03.4.

Factor VIII expression was detected on liver biopsies at more than 2 years after a single infusion of adeno-associated virus (AAV) gene therapy for hemophilia A in two patients who were part of a recent phase 1/2 study and who participated in an optional liver biopsy substudy.

The persistent factor VIII (FVIII) expression seen in the two patients was consistent with the presence of circularized, full-length human FVIII-SQ DNA in the biopsy samples and was observed in one patients at week 201 after infusion with 6 x 10¹² vg/kg of the AAV serotype 5 human FVIII-SQ gene therapy(valoctocogene roxaparvovec) and in another at week 140 after infusion with 4×10¹³ vg/kg, Sylvia Fong, PhD, reported during the International Society of Thrombosis and Haemostasis virtual congress.

The first patient had no FVIII detected in the plasma at the time of biopsy. The second had 28.4% of normal FVIII activity detected at the time of biopsy, said Dr. Fong of BioMarin Pharmaceutical, noting that alanine aminotransferase levels were normal at the time of biopsy for both subjects.

“Valoctocogene roxaparvovec is currently being evaluated in a phase 3 clinical study,” Dr. Fong said. “Data from the phase 1/2 trial have demonstrated preliminary proof of concept that valoctocogene roxaparvovec treatment, in many cases, eliminated spontaneous bleeds and the need for prophylactic factor VIII replacement.

“In addition, an acceptable safety profile was observed.”

Data from that trial were presented at the World Federation of Hemophilia virtual summit in June.
 

Liver biopsy for factor VIII expression

The current exploratory liver biopsy substudy – the first-in-human liver biopsy study after gene therapy for hemophilia A – was open to all phase 1/2 study participants and was initiated in September 2019 with multiple aims, including improved understanding of the durability and variability of AAV gene therapy, she explained.

Histopathological examination revealed normal liver architecture with mild steatosis and no evidence of steatohepatitis or significant inflammation in either participant. In the 6×10¹² vg/kg– and 4×10¹³ vg/kg–treated participants, a dose-dependent increase was seen in the percentage of hepatocytes that stained positive for vector genomes (1.3% and 32%, respectively), she said.

“This was very exciting to see,” she said, referring to the 32% stain-positive rate in the patient who received the 4x10¹³ vg/kg dose. “Not only were we able to detect vector genomes more than 2 years post-dose, there seems to be quite a bit of signals in this patient sample.”

The findings were similar to those seen in preclinical nonhuman primate models, she noted.

Dose-dependent increases were also seen in quantities of circular full-length/ITR-fused vector genomes and in FVIII-SQ RNA vector genomes; liver hFVIII-SQ RNA levels were 7.67×10² copies/mcg and 6.77×10⁴ copies/µg in the 6×10¹² vg/kg–treated participant the 4×10¹³ vg/kg–treated participant, respectively.

The circularized genomes were present as monomers and concatemers in both participants, and “were presumably associated with long-term expression,” Dr. Fong said.

Both participants are clinically stable with no long-term hepatic issues, she said, noting that analyses of results from additional participants in the substudy will be shared as they become available.

To date, because of “precious small amounts” of tissue available from the biopsy samples, Dr. Fong said she and her colleagues had not looked for degradation of the vectors.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de recherche des Cordeliers, Paris, asked: “Is there a plan [to do so] or not, because I guess it’s a very important point,” to which Dr. Fong said that it is a possibility if adequate samples become available.

Dr. Fong is an employee of BioMarin Pharmaceuticals.

[email protected]

SOURCE: Fong S. 2020 ISTH Congress, Abstract OC 03.4.

Factor VIII expression was detected on liver biopsies at more than 2 years after a single infusion of adeno-associated virus (AAV) gene therapy for hemophilia A in two patients who were part of a recent phase 1/2 study and who participated in an optional liver biopsy substudy.

The persistent factor VIII (FVIII) expression seen in the two patients was consistent with the presence of circularized, full-length human FVIII-SQ DNA in the biopsy samples and was observed in one patients at week 201 after infusion with 6 x 10¹² vg/kg of the AAV serotype 5 human FVIII-SQ gene therapy(valoctocogene roxaparvovec) and in another at week 140 after infusion with 4×10¹³ vg/kg, Sylvia Fong, PhD, reported during the International Society of Thrombosis and Haemostasis virtual congress.

The first patient had no FVIII detected in the plasma at the time of biopsy. The second had 28.4% of normal FVIII activity detected at the time of biopsy, said Dr. Fong of BioMarin Pharmaceutical, noting that alanine aminotransferase levels were normal at the time of biopsy for both subjects.

“Valoctocogene roxaparvovec is currently being evaluated in a phase 3 clinical study,” Dr. Fong said. “Data from the phase 1/2 trial have demonstrated preliminary proof of concept that valoctocogene roxaparvovec treatment, in many cases, eliminated spontaneous bleeds and the need for prophylactic factor VIII replacement.

“In addition, an acceptable safety profile was observed.”

Data from that trial were presented at the World Federation of Hemophilia virtual summit in June.
 

Liver biopsy for factor VIII expression

The current exploratory liver biopsy substudy – the first-in-human liver biopsy study after gene therapy for hemophilia A – was open to all phase 1/2 study participants and was initiated in September 2019 with multiple aims, including improved understanding of the durability and variability of AAV gene therapy, she explained.

Histopathological examination revealed normal liver architecture with mild steatosis and no evidence of steatohepatitis or significant inflammation in either participant. In the 6×10¹² vg/kg– and 4×10¹³ vg/kg–treated participants, a dose-dependent increase was seen in the percentage of hepatocytes that stained positive for vector genomes (1.3% and 32%, respectively), she said.

“This was very exciting to see,” she said, referring to the 32% stain-positive rate in the patient who received the 4x10¹³ vg/kg dose. “Not only were we able to detect vector genomes more than 2 years post-dose, there seems to be quite a bit of signals in this patient sample.”

The findings were similar to those seen in preclinical nonhuman primate models, she noted.

Dose-dependent increases were also seen in quantities of circular full-length/ITR-fused vector genomes and in FVIII-SQ RNA vector genomes; liver hFVIII-SQ RNA levels were 7.67×10² copies/mcg and 6.77×10⁴ copies/µg in the 6×10¹² vg/kg–treated participant the 4×10¹³ vg/kg–treated participant, respectively.

The circularized genomes were present as monomers and concatemers in both participants, and “were presumably associated with long-term expression,” Dr. Fong said.

Both participants are clinically stable with no long-term hepatic issues, she said, noting that analyses of results from additional participants in the substudy will be shared as they become available.

To date, because of “precious small amounts” of tissue available from the biopsy samples, Dr. Fong said she and her colleagues had not looked for degradation of the vectors.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de recherche des Cordeliers, Paris, asked: “Is there a plan [to do so] or not, because I guess it’s a very important point,” to which Dr. Fong said that it is a possibility if adequate samples become available.

Dr. Fong is an employee of BioMarin Pharmaceuticals.

[email protected]

SOURCE: Fong S. 2020 ISTH Congress, Abstract OC 03.4.

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Artificial intelligence (AI)–based Gleason scores correlated with pathologists’ Gleason scores for predicting survival in patients with prostate cancer, according to a cohort-based analysis.

An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.

The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.

The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.

The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.

Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).

In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”

Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.

“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.

Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).

Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.

In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).

“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.

Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.

“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”

Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.

[email protected]

SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.

Artificial intelligence (AI)–based Gleason scores correlated with pathologists’ Gleason scores for predicting survival in patients with prostate cancer, according to a cohort-based analysis.

An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.

The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.

The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.

The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.

Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).

In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”

Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.

“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.

Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).

Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.

In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).

“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.

Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.

“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”

Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.

[email protected]

SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.

Artificial intelligence (AI)–based Gleason scores correlated with pathologists’ Gleason scores for predicting survival in patients with prostate cancer, according to a cohort-based analysis.

An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.

The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.

The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.

The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.

Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).

In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”

Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.

“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.

Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).

Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.

In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).

“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.

Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.

“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”

Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.

[email protected]

SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.

Lipophilic statin use is associated with reduced mortality risk in women with ovarian cancer, findings from a large observational study suggest.

The study included 10,062 patients with epithelial ovarian cancer enrolled in the Finnish national cancer registry. There were 2,621 patients who were prescribed statins between 1995 and 2015, and 80% of them used lipophilic statins.

When compared with no statin use, any statin use was associated with a 40% reduction in ovarian cancer mortality (weighted hazard ratio, 0.60), and any use of lipophilic statins was associated with a 43% reduction in ovarian cancer mortality (wHR, 0.57).

Kala Visvanathan, MD, of Johns Hopkins University in Baltimore, and colleagues reported these findings in a poster at the AACR virtual meeting II.

Reductions in ovarian cancer mortality were observed in women who took simvastatin or atorvastatin (wHRs 0.24 and 0.20, respectively), the researchers found.

Lipophilic statin use also was associated with a reduction in ovarian cancer mortality across disease subtypes, although the magnitude of reduction varied. The hazard ratios were 0.60 for high-grade serous ovarian cancer, 0.50 for endometrioid ovarian cancer, 0.20 for clear cell ovarian cancer, 0.30 for mucinous ovarian cancer, and 0.27 for borderline disease.

Survival benefits were evident both in patients who started statins prior to their ovarian cancer diagnosis and in those who started statins after diagnosis.

Never-statin users had a median age of 62 years at baseline, and ever-statin users had a median age of 67 years. The median follow-up was 3.6 years and 5.5 years, respectively.

Data from the registry were linked to prescription claims, and a series of analyses were conducted to examine the association between pre- and postdiagnostic statin use and mortality. The findings were adjusted for age at diagnosis, stage, ovarian cancer subtype, treatments, year of diagnosis, and chronic disease medications. Adherence to statins was greater than 90%.
 

Implications and next steps

The idea of using statins for the treatment of ovarian cancer is appealing because of the promising survival data as well as the broad access, low cost, and tolerability of statins, Dr. Visvanathan said in a statement. About 28% of U.S. adults over age 40 routinely take statins for cholesterol control, and statins are widely used in other countries, she said.

“Our results support research to evaluate the repurposing of therapies that are well tolerated and inexpensive in order to help reduce the global cancer burden,” Dr. Visvanathan and colleagues wrote in their poster.

“Our results provide evidence in support of the evaluation of lipophilic statins, particularly atorvastatin and/or simvastatin, for the treatment of [epithelial ovarian cancer] in conjunction with existing therapies,” the researchers wrote. They added that these statins should be “evaluated in randomized clinical trials that include correlative endpoints.”

Further, the researchers argued that “the results are biologically plausible based on known mechanisms associated with statin use and highlight the fact that statins may be effective to treat more than one disease/outcome (i.e., high cholesterol, EOC [epithelial ovarian cancer], breast cancer).”

The results of this study are intriguing, according to James Yarmolinsky, MSc, of the University of Bristol, England. Mr. Yarmolinsky is the lead author of a case-control study that showed an association between genetically proxied 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition and lower odds of developing epithelial ovarian cancer (JAMA. 2020;323[7]:646-655).

Mr. Yarmolinsky and colleagues found that HMG-CoA reductase inhibition equivalent to a 38.7-mg/dL reduction in low-density lipoprotein cholesterol was significantly associated with lower odds of epithelial ovarian cancer in the general population (odds ratio, 0.60) and among BRCA1/2 mutation carriers (hazard ratio, 0.69). The findings raised questions about whether a similar association would be seen with medications such as statins that inhibit HMG-CoA reductase.

“These findings linking statin use to lower ovarian cancer mortality are really interesting given our own research suggesting that these drugs may also lower women’s risk of developing this disease in the first place,” Mr. Yarmolinsky said.

“The survival rate for ovarian cancer remains the lowest among all gynecological cancers in the United States, so use of these medications in either a preventive or therapeutic context could offer an important approach for reducing disease burden,” he added. “If the findings reported by Visvanathan and colleagues can be shown to replicate in other large population-based studies, testing the efficacy of statins in a randomized clinical trial could provide definitive evidence of whether these medications lower ovarian cancer mortality.”

The Department of Defense and the Breast Cancer Research Foundation funded the current study. Dr. Visvanathan and Mr. Yarmolinsky reported no disclosures.

[email protected]

SOURCE: Visvanathan K et al. AACR 2020, Abstract 5782.

Lipophilic statin use is associated with reduced mortality risk in women with ovarian cancer, findings from a large observational study suggest.

The study included 10,062 patients with epithelial ovarian cancer enrolled in the Finnish national cancer registry. There were 2,621 patients who were prescribed statins between 1995 and 2015, and 80% of them used lipophilic statins.

When compared with no statin use, any statin use was associated with a 40% reduction in ovarian cancer mortality (weighted hazard ratio, 0.60), and any use of lipophilic statins was associated with a 43% reduction in ovarian cancer mortality (wHR, 0.57).

Kala Visvanathan, MD, of Johns Hopkins University in Baltimore, and colleagues reported these findings in a poster at the AACR virtual meeting II.

Reductions in ovarian cancer mortality were observed in women who took simvastatin or atorvastatin (wHRs 0.24 and 0.20, respectively), the researchers found.

Lipophilic statin use also was associated with a reduction in ovarian cancer mortality across disease subtypes, although the magnitude of reduction varied. The hazard ratios were 0.60 for high-grade serous ovarian cancer, 0.50 for endometrioid ovarian cancer, 0.20 for clear cell ovarian cancer, 0.30 for mucinous ovarian cancer, and 0.27 for borderline disease.

Survival benefits were evident both in patients who started statins prior to their ovarian cancer diagnosis and in those who started statins after diagnosis.

Never-statin users had a median age of 62 years at baseline, and ever-statin users had a median age of 67 years. The median follow-up was 3.6 years and 5.5 years, respectively.

Data from the registry were linked to prescription claims, and a series of analyses were conducted to examine the association between pre- and postdiagnostic statin use and mortality. The findings were adjusted for age at diagnosis, stage, ovarian cancer subtype, treatments, year of diagnosis, and chronic disease medications. Adherence to statins was greater than 90%.
 

Implications and next steps

The idea of using statins for the treatment of ovarian cancer is appealing because of the promising survival data as well as the broad access, low cost, and tolerability of statins, Dr. Visvanathan said in a statement. About 28% of U.S. adults over age 40 routinely take statins for cholesterol control, and statins are widely used in other countries, she said.

“Our results support research to evaluate the repurposing of therapies that are well tolerated and inexpensive in order to help reduce the global cancer burden,” Dr. Visvanathan and colleagues wrote in their poster.

“Our results provide evidence in support of the evaluation of lipophilic statins, particularly atorvastatin and/or simvastatin, for the treatment of [epithelial ovarian cancer] in conjunction with existing therapies,” the researchers wrote. They added that these statins should be “evaluated in randomized clinical trials that include correlative endpoints.”

Further, the researchers argued that “the results are biologically plausible based on known mechanisms associated with statin use and highlight the fact that statins may be effective to treat more than one disease/outcome (i.e., high cholesterol, EOC [epithelial ovarian cancer], breast cancer).”

The results of this study are intriguing, according to James Yarmolinsky, MSc, of the University of Bristol, England. Mr. Yarmolinsky is the lead author of a case-control study that showed an association between genetically proxied 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition and lower odds of developing epithelial ovarian cancer (JAMA. 2020;323[7]:646-655).

Mr. Yarmolinsky and colleagues found that HMG-CoA reductase inhibition equivalent to a 38.7-mg/dL reduction in low-density lipoprotein cholesterol was significantly associated with lower odds of epithelial ovarian cancer in the general population (odds ratio, 0.60) and among BRCA1/2 mutation carriers (hazard ratio, 0.69). The findings raised questions about whether a similar association would be seen with medications such as statins that inhibit HMG-CoA reductase.

“These findings linking statin use to lower ovarian cancer mortality are really interesting given our own research suggesting that these drugs may also lower women’s risk of developing this disease in the first place,” Mr. Yarmolinsky said.

“The survival rate for ovarian cancer remains the lowest among all gynecological cancers in the United States, so use of these medications in either a preventive or therapeutic context could offer an important approach for reducing disease burden,” he added. “If the findings reported by Visvanathan and colleagues can be shown to replicate in other large population-based studies, testing the efficacy of statins in a randomized clinical trial could provide definitive evidence of whether these medications lower ovarian cancer mortality.”

The Department of Defense and the Breast Cancer Research Foundation funded the current study. Dr. Visvanathan and Mr. Yarmolinsky reported no disclosures.

[email protected]

SOURCE: Visvanathan K et al. AACR 2020, Abstract 5782.

Lipophilic statin use is associated with reduced mortality risk in women with ovarian cancer, findings from a large observational study suggest.

The study included 10,062 patients with epithelial ovarian cancer enrolled in the Finnish national cancer registry. There were 2,621 patients who were prescribed statins between 1995 and 2015, and 80% of them used lipophilic statins.

When compared with no statin use, any statin use was associated with a 40% reduction in ovarian cancer mortality (weighted hazard ratio, 0.60), and any use of lipophilic statins was associated with a 43% reduction in ovarian cancer mortality (wHR, 0.57).

Kala Visvanathan, MD, of Johns Hopkins University in Baltimore, and colleagues reported these findings in a poster at the AACR virtual meeting II.

Reductions in ovarian cancer mortality were observed in women who took simvastatin or atorvastatin (wHRs 0.24 and 0.20, respectively), the researchers found.

Lipophilic statin use also was associated with a reduction in ovarian cancer mortality across disease subtypes, although the magnitude of reduction varied. The hazard ratios were 0.60 for high-grade serous ovarian cancer, 0.50 for endometrioid ovarian cancer, 0.20 for clear cell ovarian cancer, 0.30 for mucinous ovarian cancer, and 0.27 for borderline disease.

Survival benefits were evident both in patients who started statins prior to their ovarian cancer diagnosis and in those who started statins after diagnosis.

Never-statin users had a median age of 62 years at baseline, and ever-statin users had a median age of 67 years. The median follow-up was 3.6 years and 5.5 years, respectively.

Data from the registry were linked to prescription claims, and a series of analyses were conducted to examine the association between pre- and postdiagnostic statin use and mortality. The findings were adjusted for age at diagnosis, stage, ovarian cancer subtype, treatments, year of diagnosis, and chronic disease medications. Adherence to statins was greater than 90%.
 

Implications and next steps

The idea of using statins for the treatment of ovarian cancer is appealing because of the promising survival data as well as the broad access, low cost, and tolerability of statins, Dr. Visvanathan said in a statement. About 28% of U.S. adults over age 40 routinely take statins for cholesterol control, and statins are widely used in other countries, she said.

“Our results support research to evaluate the repurposing of therapies that are well tolerated and inexpensive in order to help reduce the global cancer burden,” Dr. Visvanathan and colleagues wrote in their poster.

“Our results provide evidence in support of the evaluation of lipophilic statins, particularly atorvastatin and/or simvastatin, for the treatment of [epithelial ovarian cancer] in conjunction with existing therapies,” the researchers wrote. They added that these statins should be “evaluated in randomized clinical trials that include correlative endpoints.”

Further, the researchers argued that “the results are biologically plausible based on known mechanisms associated with statin use and highlight the fact that statins may be effective to treat more than one disease/outcome (i.e., high cholesterol, EOC [epithelial ovarian cancer], breast cancer).”

The results of this study are intriguing, according to James Yarmolinsky, MSc, of the University of Bristol, England. Mr. Yarmolinsky is the lead author of a case-control study that showed an association between genetically proxied 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition and lower odds of developing epithelial ovarian cancer (JAMA. 2020;323[7]:646-655).

Mr. Yarmolinsky and colleagues found that HMG-CoA reductase inhibition equivalent to a 38.7-mg/dL reduction in low-density lipoprotein cholesterol was significantly associated with lower odds of epithelial ovarian cancer in the general population (odds ratio, 0.60) and among BRCA1/2 mutation carriers (hazard ratio, 0.69). The findings raised questions about whether a similar association would be seen with medications such as statins that inhibit HMG-CoA reductase.

“These findings linking statin use to lower ovarian cancer mortality are really interesting given our own research suggesting that these drugs may also lower women’s risk of developing this disease in the first place,” Mr. Yarmolinsky said.

“The survival rate for ovarian cancer remains the lowest among all gynecological cancers in the United States, so use of these medications in either a preventive or therapeutic context could offer an important approach for reducing disease burden,” he added. “If the findings reported by Visvanathan and colleagues can be shown to replicate in other large population-based studies, testing the efficacy of statins in a randomized clinical trial could provide definitive evidence of whether these medications lower ovarian cancer mortality.”

The Department of Defense and the Breast Cancer Research Foundation funded the current study. Dr. Visvanathan and Mr. Yarmolinsky reported no disclosures.

[email protected]

SOURCE: Visvanathan K et al. AACR 2020, Abstract 5782.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.


 

Tumor marker utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

“Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive,” she added.
 

Rationale and next steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

“GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes,” Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

“CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse,” Dr. Fonseca said. “But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects.”

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

“Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations,” Dr. Fonseca said, adding that this can contribute to patients’ and parents’ anxiety and to increased overall health care costs and resource utilization.

Recent Children’s Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

“We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided,” she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

“Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients,” Dr. Fonseca said. “Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed.”

Dr. Fonseca and colleagues are “currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance,” she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

[email protected]

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.


 

Tumor marker utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

“Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive,” she added.
 

Rationale and next steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

“GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes,” Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

“CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse,” Dr. Fonseca said. “But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects.”

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

“Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations,” Dr. Fonseca said, adding that this can contribute to patients’ and parents’ anxiety and to increased overall health care costs and resource utilization.

Recent Children’s Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

“We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided,” she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

“Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients,” Dr. Fonseca said. “Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed.”

Dr. Fonseca and colleagues are “currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance,” she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

[email protected]

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.


 

Tumor marker utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

“Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive,” she added.
 

Rationale and next steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

“GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes,” Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

“CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse,” Dr. Fonseca said. “But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects.”

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

“Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations,” Dr. Fonseca said, adding that this can contribute to patients’ and parents’ anxiety and to increased overall health care costs and resource utilization.

Recent Children’s Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

“We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided,” she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

“Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients,” Dr. Fonseca said. “Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed.”

Dr. Fonseca and colleagues are “currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance,” she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

[email protected]

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

Sequential chemoradiation may improve disease-free survival (DFS) among patients with early-stage cervical cancer who have undergone radical hysterectomy, the phase 3 STARS trial suggests.

In the study’s intent-to-treat (ITT) population, the 3-year DFS rate was significantly higher among patients who received sequential chemoradiation than among patients who received concurrent chemoradiation or radiation alone.

“After an adjustment for baseline presence of lymph node metastasis, we found that sequential chemoradiation decreased, by 40% to 50%, the recurrence risk, compared with the other two groups,” said investigator He Huang, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China.

Dr. Huang presented these findings as part of the American Society of Clinical Oncology virtual scientific program.
 

Study rationale and details

“As we know, early-stage cervical cancer can be cured after treatment,” Dr. Huang said. “However, the risk of recurrence remains higher among patients with high-risk factors, including lymph node metastases, positive surgical margins, and parametrial invasion. Postoperative adjuvant radiation and chemotherapy may result in favorable survival for patients with high-risk factors.”

Although the efficacy of concurrent radiation with single-agent cisplatin has been demonstrated in primary treatment for local advanced cervical cancer, it has not been assessed as adjuvant treatment for early-stage cervical cancer in a randomized, controlled trial, Dr. Huang explained.

“Another question is whether patients with intermediate-risk factors could benefit from the concurrent chemotherapy [with] radiation,” he said. “So far, we don’t have enough evidence.”

To gain some insight, Dr. Huang and colleagues initiated the STARS trial. The trial enrolled patients with stage IB1-IIA2 cervical cancer and at least one adverse risk factor after radical hysterectomy. Patients had a median age of 48 years, and most had stage IB1 or IIA1 disease.

The patients were randomized 1:1:1 to receive radiation alone, concurrent chemoradiation, or sequential chemoradiation.

All patients received pelvic radiation at 45-50 Gy. Patients in the concurrent chemoradiation arm also received five doses of weekly cisplatin at 30-40 mg/m².

Patients in the sequential chemoradiation arm received 60-75 mg/m² of weekly cisplatin plus 135-175 mg/m² of paclitaxel in 21-day cycles, with two cycles given before and two cycles given after radiotherapy.

The treatment groups were comparable with respect to histologic subtypes, lymphovascular invasion rates, parametrial or surgical margin involvement, deep stromal involvement, tumor grade, minimally invasive surgery rates, and neoadjuvant chemotherapy, Dr. Huang said. He added, however, that lymph node metastasis was lowest in the radiation-only arm.
 

DFS results

In the ITT population, patients who received sequential chemoradiation had significantly better DFS compared with patients in the other treatment arms. The ITT population included 353 patients in the sequential chemoradiation arm, 345 patients in the concurrent chemoradiation arm, and 350 patients in the radiation-only arm.

The 3-year DFS rates were 90% in patients randomized to sequential chemoradiation, 85% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (hazard ratios, 0.52 for sequential chemoradiation vs. radiation alone and 0.65 for sequential vs. concurrent chemoradiation; P = .03).

Subgroup analyses showed a DFS benefit with sequential chemoradiation versus radiation alone across histology types, tumor grades, and tumor size, Dr. Huang noted.

In the per-protocol population, sequential chemoradiation was associated with better DFS when compared with radiation alone. However, there were no significant differences between the sequential and concurrent chemoradiation arms or the concurrent chemoradiation and radiation-only arms.

The per-protocol population included 235 patients in the sequential chemoradiation arm, 190 patients in the concurrent chemoradiation arm, and 324 patients in the radiation-only arm.

In the per-protocol population, the 3-year DFS rates were 91% in patients randomized to sequential chemoradiation, 86% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (HRs, 0.47 for sequential vs. radiation alone and 0.67 for sequential vs. concurrent; P = .026).

In the overall population, DFS was superior among patients with intermediate-risk versus high-risk factors. The 3-year DFS rates were 90% and 74%, respectively (P < .05).
 

Overall survival and safety

As for overall survival (OS), sequential chemoradiation showed a trend toward improvement at 5 years, compared with the other treatment groups. However, the differences were not statistically significant in either the ITT or per-protocol populations.

In the ITT population, the 5-year OS was 92% in the sequential chemoradiation arm, 89% in the concurrent chemoradiation arm, and 88% in the radiation-only arm. In the per-protocol population, the 5-year OS rates were 93%, 90%, and 88%, respectively.

Patients with intermediate-risk factors had a more favorable OS. The 5-year OS rate was 93% in patients with intermediate-risk factors and 81% in patients with high-risk factors (P < .05).

Dr. Huang noted that patients in the radiation-only arm experienced fewer grade 3-4 adverse events than the other patients. Less neutropenia, nausea, and vomiting were observed in the radiation-only arm.

There was more grade 3-4 nausea and vomiting in the concurrent chemoradiation arm than in the sequential chemoradiation arm.

However, Dr. Huang noted that “adding chemotherapy to radiation did not impact the patients’ quality of life in the long-term compared with radiation alone.

“In this study, sequential chemoradiation resulted in a better disease-free survival and a lower risk of cancer death for cervical cancer patients with adverse pathological factors,” he said. “We believe that sequential chemoradiation could be an optimal option for post-operative adjuvant treatment.”

This study was sponsored by Sun Yat-sen University in collaboration with Guangdong Provincial People’s Hospital, First Affiliated Hospital/Sun Yat-Sen University, Shenzhen People’s Hospital, and Cancer Hospital of Guangxi Medical University. Dr. Huang reported receiving honoraria, travel, accommodations, and expenses from AstraZeneca.

[email protected]

SOURCE: Huang H et al. ASCO 2020, Abstract 6007.

Sequential chemoradiation may improve disease-free survival (DFS) among patients with early-stage cervical cancer who have undergone radical hysterectomy, the phase 3 STARS trial suggests.

In the study’s intent-to-treat (ITT) population, the 3-year DFS rate was significantly higher among patients who received sequential chemoradiation than among patients who received concurrent chemoradiation or radiation alone.

“After an adjustment for baseline presence of lymph node metastasis, we found that sequential chemoradiation decreased, by 40% to 50%, the recurrence risk, compared with the other two groups,” said investigator He Huang, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China.

Dr. Huang presented these findings as part of the American Society of Clinical Oncology virtual scientific program.
 

Study rationale and details

“As we know, early-stage cervical cancer can be cured after treatment,” Dr. Huang said. “However, the risk of recurrence remains higher among patients with high-risk factors, including lymph node metastases, positive surgical margins, and parametrial invasion. Postoperative adjuvant radiation and chemotherapy may result in favorable survival for patients with high-risk factors.”

Although the efficacy of concurrent radiation with single-agent cisplatin has been demonstrated in primary treatment for local advanced cervical cancer, it has not been assessed as adjuvant treatment for early-stage cervical cancer in a randomized, controlled trial, Dr. Huang explained.

“Another question is whether patients with intermediate-risk factors could benefit from the concurrent chemotherapy [with] radiation,” he said. “So far, we don’t have enough evidence.”

To gain some insight, Dr. Huang and colleagues initiated the STARS trial. The trial enrolled patients with stage IB1-IIA2 cervical cancer and at least one adverse risk factor after radical hysterectomy. Patients had a median age of 48 years, and most had stage IB1 or IIA1 disease.

The patients were randomized 1:1:1 to receive radiation alone, concurrent chemoradiation, or sequential chemoradiation.

All patients received pelvic radiation at 45-50 Gy. Patients in the concurrent chemoradiation arm also received five doses of weekly cisplatin at 30-40 mg/m².

Patients in the sequential chemoradiation arm received 60-75 mg/m² of weekly cisplatin plus 135-175 mg/m² of paclitaxel in 21-day cycles, with two cycles given before and two cycles given after radiotherapy.

The treatment groups were comparable with respect to histologic subtypes, lymphovascular invasion rates, parametrial or surgical margin involvement, deep stromal involvement, tumor grade, minimally invasive surgery rates, and neoadjuvant chemotherapy, Dr. Huang said. He added, however, that lymph node metastasis was lowest in the radiation-only arm.
 

DFS results

In the ITT population, patients who received sequential chemoradiation had significantly better DFS compared with patients in the other treatment arms. The ITT population included 353 patients in the sequential chemoradiation arm, 345 patients in the concurrent chemoradiation arm, and 350 patients in the radiation-only arm.

The 3-year DFS rates were 90% in patients randomized to sequential chemoradiation, 85% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (hazard ratios, 0.52 for sequential chemoradiation vs. radiation alone and 0.65 for sequential vs. concurrent chemoradiation; P = .03).

Subgroup analyses showed a DFS benefit with sequential chemoradiation versus radiation alone across histology types, tumor grades, and tumor size, Dr. Huang noted.

In the per-protocol population, sequential chemoradiation was associated with better DFS when compared with radiation alone. However, there were no significant differences between the sequential and concurrent chemoradiation arms or the concurrent chemoradiation and radiation-only arms.

The per-protocol population included 235 patients in the sequential chemoradiation arm, 190 patients in the concurrent chemoradiation arm, and 324 patients in the radiation-only arm.

In the per-protocol population, the 3-year DFS rates were 91% in patients randomized to sequential chemoradiation, 86% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (HRs, 0.47 for sequential vs. radiation alone and 0.67 for sequential vs. concurrent; P = .026).

In the overall population, DFS was superior among patients with intermediate-risk versus high-risk factors. The 3-year DFS rates were 90% and 74%, respectively (P < .05).
 

Overall survival and safety

As for overall survival (OS), sequential chemoradiation showed a trend toward improvement at 5 years, compared with the other treatment groups. However, the differences were not statistically significant in either the ITT or per-protocol populations.

In the ITT population, the 5-year OS was 92% in the sequential chemoradiation arm, 89% in the concurrent chemoradiation arm, and 88% in the radiation-only arm. In the per-protocol population, the 5-year OS rates were 93%, 90%, and 88%, respectively.

Patients with intermediate-risk factors had a more favorable OS. The 5-year OS rate was 93% in patients with intermediate-risk factors and 81% in patients with high-risk factors (P < .05).

Dr. Huang noted that patients in the radiation-only arm experienced fewer grade 3-4 adverse events than the other patients. Less neutropenia, nausea, and vomiting were observed in the radiation-only arm.

There was more grade 3-4 nausea and vomiting in the concurrent chemoradiation arm than in the sequential chemoradiation arm.

However, Dr. Huang noted that “adding chemotherapy to radiation did not impact the patients’ quality of life in the long-term compared with radiation alone.

“In this study, sequential chemoradiation resulted in a better disease-free survival and a lower risk of cancer death for cervical cancer patients with adverse pathological factors,” he said. “We believe that sequential chemoradiation could be an optimal option for post-operative adjuvant treatment.”

This study was sponsored by Sun Yat-sen University in collaboration with Guangdong Provincial People’s Hospital, First Affiliated Hospital/Sun Yat-Sen University, Shenzhen People’s Hospital, and Cancer Hospital of Guangxi Medical University. Dr. Huang reported receiving honoraria, travel, accommodations, and expenses from AstraZeneca.

[email protected]

SOURCE: Huang H et al. ASCO 2020, Abstract 6007.

Sequential chemoradiation may improve disease-free survival (DFS) among patients with early-stage cervical cancer who have undergone radical hysterectomy, the phase 3 STARS trial suggests.

In the study’s intent-to-treat (ITT) population, the 3-year DFS rate was significantly higher among patients who received sequential chemoradiation than among patients who received concurrent chemoradiation or radiation alone.

“After an adjustment for baseline presence of lymph node metastasis, we found that sequential chemoradiation decreased, by 40% to 50%, the recurrence risk, compared with the other two groups,” said investigator He Huang, MD, of Sun Yat-Sen University Cancer Center in Guangzhou, China.

Dr. Huang presented these findings as part of the American Society of Clinical Oncology virtual scientific program.
 

Study rationale and details

“As we know, early-stage cervical cancer can be cured after treatment,” Dr. Huang said. “However, the risk of recurrence remains higher among patients with high-risk factors, including lymph node metastases, positive surgical margins, and parametrial invasion. Postoperative adjuvant radiation and chemotherapy may result in favorable survival for patients with high-risk factors.”

Although the efficacy of concurrent radiation with single-agent cisplatin has been demonstrated in primary treatment for local advanced cervical cancer, it has not been assessed as adjuvant treatment for early-stage cervical cancer in a randomized, controlled trial, Dr. Huang explained.

“Another question is whether patients with intermediate-risk factors could benefit from the concurrent chemotherapy [with] radiation,” he said. “So far, we don’t have enough evidence.”

To gain some insight, Dr. Huang and colleagues initiated the STARS trial. The trial enrolled patients with stage IB1-IIA2 cervical cancer and at least one adverse risk factor after radical hysterectomy. Patients had a median age of 48 years, and most had stage IB1 or IIA1 disease.

The patients were randomized 1:1:1 to receive radiation alone, concurrent chemoradiation, or sequential chemoradiation.

All patients received pelvic radiation at 45-50 Gy. Patients in the concurrent chemoradiation arm also received five doses of weekly cisplatin at 30-40 mg/m².

Patients in the sequential chemoradiation arm received 60-75 mg/m² of weekly cisplatin plus 135-175 mg/m² of paclitaxel in 21-day cycles, with two cycles given before and two cycles given after radiotherapy.

The treatment groups were comparable with respect to histologic subtypes, lymphovascular invasion rates, parametrial or surgical margin involvement, deep stromal involvement, tumor grade, minimally invasive surgery rates, and neoadjuvant chemotherapy, Dr. Huang said. He added, however, that lymph node metastasis was lowest in the radiation-only arm.
 

DFS results

In the ITT population, patients who received sequential chemoradiation had significantly better DFS compared with patients in the other treatment arms. The ITT population included 353 patients in the sequential chemoradiation arm, 345 patients in the concurrent chemoradiation arm, and 350 patients in the radiation-only arm.

The 3-year DFS rates were 90% in patients randomized to sequential chemoradiation, 85% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (hazard ratios, 0.52 for sequential chemoradiation vs. radiation alone and 0.65 for sequential vs. concurrent chemoradiation; P = .03).

Subgroup analyses showed a DFS benefit with sequential chemoradiation versus radiation alone across histology types, tumor grades, and tumor size, Dr. Huang noted.

In the per-protocol population, sequential chemoradiation was associated with better DFS when compared with radiation alone. However, there were no significant differences between the sequential and concurrent chemoradiation arms or the concurrent chemoradiation and radiation-only arms.

The per-protocol population included 235 patients in the sequential chemoradiation arm, 190 patients in the concurrent chemoradiation arm, and 324 patients in the radiation-only arm.

In the per-protocol population, the 3-year DFS rates were 91% in patients randomized to sequential chemoradiation, 86% in patients randomized to concurrent chemoradiation, and 82% in patients randomized to radiation alone (HRs, 0.47 for sequential vs. radiation alone and 0.67 for sequential vs. concurrent; P = .026).

In the overall population, DFS was superior among patients with intermediate-risk versus high-risk factors. The 3-year DFS rates were 90% and 74%, respectively (P < .05).
 

Overall survival and safety

As for overall survival (OS), sequential chemoradiation showed a trend toward improvement at 5 years, compared with the other treatment groups. However, the differences were not statistically significant in either the ITT or per-protocol populations.

In the ITT population, the 5-year OS was 92% in the sequential chemoradiation arm, 89% in the concurrent chemoradiation arm, and 88% in the radiation-only arm. In the per-protocol population, the 5-year OS rates were 93%, 90%, and 88%, respectively.

Patients with intermediate-risk factors had a more favorable OS. The 5-year OS rate was 93% in patients with intermediate-risk factors and 81% in patients with high-risk factors (P < .05).

Dr. Huang noted that patients in the radiation-only arm experienced fewer grade 3-4 adverse events than the other patients. Less neutropenia, nausea, and vomiting were observed in the radiation-only arm.

There was more grade 3-4 nausea and vomiting in the concurrent chemoradiation arm than in the sequential chemoradiation arm.

However, Dr. Huang noted that “adding chemotherapy to radiation did not impact the patients’ quality of life in the long-term compared with radiation alone.

“In this study, sequential chemoradiation resulted in a better disease-free survival and a lower risk of cancer death for cervical cancer patients with adverse pathological factors,” he said. “We believe that sequential chemoradiation could be an optimal option for post-operative adjuvant treatment.”

This study was sponsored by Sun Yat-sen University in collaboration with Guangdong Provincial People’s Hospital, First Affiliated Hospital/Sun Yat-Sen University, Shenzhen People’s Hospital, and Cancer Hospital of Guangxi Medical University. Dr. Huang reported receiving honoraria, travel, accommodations, and expenses from AstraZeneca.

[email protected]

SOURCE: Huang H et al. ASCO 2020, Abstract 6007.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

[email protected]

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

This is the second of a two-part article on the role of racism and bias in the U.S. maternal mortality crisis and part of an ongoing Ob.Gyn. News feature series on the crisis. Part one of the story explored existing data, societal factors, and patient experiences related to structural racism, overt racism, and implicit bias as factors contributing to racial disparities in maternal outcomes. Here we explore potential solutions for addressing the inequities as proposed by thought leaders and key stakeholders.



The emerging racial disparities in COVID-19 incidence and outcomes in the United States are on a collision course with long-standing racial disparities in U.S. maternal care and mortality.

Maternal health advocates are bracing for the impact, but in the spotlight that the pandemic is training on the inequities and the health system changes taking shape in its wake, some also see hope for a shift in at least one important driver of the racial health disparities: access to care.

Non-Hispanic black women are at least three times more likely than Hispanic women and non-Hispanic white women to experience pregnancy-related death, and indigenous women are more than twice as likely, according to the latest data from the Centers for Disease Control and Prevention’s National Center for Health Statistics. The added strain COVID-19 is putting on the system stands to further limit the access to care that many pregnant women of color experience and to exacerbate racial disparities, panelists agreed during a recent National Maternal Health Patient Centered Outcomes Research Network webinar entitled “The Impact of COVID-19 on Black, Brown, and Native Pregnant People.”

“The saying is that ‘the virus doesn’t discriminate,’ but it understands our biases, right? So, the virus takes advantage of the weaknesses in our system,” said panelist Joia A. Crear-Perry, MD, an ob.gyn. and founder and president of the National Birth Equity Collaborative (NBEC), a New Orleans–based research, training, and advocacy organization working to optimize black maternal and infant health.
 

Hope for solutions from the ashes of a pandemic

The weaknesses in the system that Dr. Crear-Perry spoke of are in many ways a product of structural racism as described in a conceptual report in The Lancet, titled “America: Equity and Equality in Health,” which dug into the entrenched and tangled historical roots of racist sociological and political factors that formed a foundation for health inequity over time.

Today, people of color remain more likely to be excluded from access to health insurance and adequate health care. The authors defined structural racism as “the totality of ways in which societies foster racial discrimination through mutually reinforcing systems of housing, education, employment, earnings, benefits, credit, media, health care, and criminal justice.” Today, largely as a result of these “reinforcing systems,” people of color remain more likely to be excluded from access to health insurance and adequate health care. At the same time, and for the same reasons, they are more likely to work in the service industry, be essential workers, and use mass transit, each of which increases the risk of exposure to COVID-19, Dr. Crear-Perry explained.

“It’s important for us to know that, for maternal mortality, it’s the same thing that happens,” she said. That means the focus on COVID-19–related disparities helps magnify and elevate the conversation regarding similar disparities in maternal outcomes.

It also means that some of the care delivery solutions embraced and facilitated amid the pandemic, such as extension of Medicaid coverage for up to a year after giving birth and broader use and insurance coverage of telemedicine, could finally gain traction; those are solutions long-sought by advocates like Dr. Crear-Perry and others as a means for alleviating racial disparities in maternal outcomes and addressing the maternal mortality crisis.

Therein lies the hope, she explained in an interview. “Some of the policies that we know would have been helpful prior to COVID-19 now are being seen as really important.”
 

Solution: Extending coverage

During a May 7 virtual Congressional hearing on “America’s Two Public Health Crises: The Impact of COVID-19 on Racial Inequities and Maternal Mortality in the U.S.,” cosponsored by the American College of Obstetricians and Gynecologists, the March of Dimes, and the NBEC, Dr. Crear-Perry further explained the importance of extended coverage and care access.

Asked what Congress could do immediately to “ensure that the pandemic does not compound the nation’s maternal mortality crisis, including unacceptable rates among black women,” she didn’t hesitate.

“Well, it would be amazing if we could get Medicaid extended for 12 months post delivery,” she said. “As you can imagine right now, we have moms who are birthing in hospitals where they have to worry about, 2 months later, not having coverage for themselves.”

If that mom is exposed to COVID-19 and has no insurance coverage and a newborn at home, the likelihood that she will call a provider if she develops symptoms is low, Dr. Crear-Perry said. “This is a great opportunity for us to really rethink some of those policies that we know are barriers, that we have created for people to be able to thrive after they have a baby and during child birth.”

Current policies are centered around an arbitrary cutoff of about 6 weeks for postpartum care, but the CDC reports that a third of all postpartum deaths occur between 1 week and 12 months after birth.

“We need our policies to reflect the current knowledge and the science,” she said. “Just like babies have automatic insurance coverage for a year later, mothers should have the same.”

Medicaid finances nearly half of all births in the United States, according to a 2019 Kaiser Family Foundation brief, which explained that federal law requires Medicaid coverage for only 60 days post partum for women who are eligible. Decisions regarding coverage after 60 days are determined by individual states; those that expanded Medicaid under the Affordable Care Act typically allow extended coverage – but only with reapplication at 60 days.

Many women in nonexpansion states become uninsured after pregnancy-related coverage ends, as do some in expansion states for whom reapplying is a hurdle too high to clear with a newborn baby to care for at home, Dr. Crear-Perry said.

Addressing these coverage gaps is key to improving access, and it is a core component of the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March by Rep. Lauren Underwood (D-Ill.), Rep. Alma Adams (D-N.C.), Sen. Kamala Harris (D-Calif.), and members of the Black Maternal Health Caucus to “fill gaps in existing legislation to comprehensively address every dimension of the Black maternal health crisis in America.”

One bill in the package addresses extended coverage with a goal to “promote innovative payment models to incentivize high-quality maternity care and continuity of health insurance coverage from pregnancy through labor and delivery and up to 1 year post partum.” Another focuses on promoting alternative ways to access care, such as through telemedicine.

Solution: Expanding care access

“There is a need for the democratization of care,” Dr. Crear-Perry said. “There is a need for people to have more ways to get care. This idea that the only way you can get prenatal care is you have to come to me at my office, has been a burden for working people for a long, long time.”

The COVID-19 pandemic necessitates increased use of telemedicine, but building blocks to allow patients to use it effectively must be put in place, she said. That means expanding broadband access, providing patients with blood pressure cuffs and other tools for use remotely, and expanding reimbursement to include not just video, but also phone calls.

Heart Safe Motherhood, a University of Pennsylvania text-based intervention developed to address postpartum hypertension – a leading cause of maternal morbidity and mortality, and at the start of the program, the leading cause of 7-day readmissions among obstetric patients, demonstrated the value of such approaches to care.

The program involves remote blood pressure monitoring using a digital monitor provided to at-risk patients at discharge. Text-based monitoring reminders encourage patients to check their blood pressure twice daily for the first 7 days.

“In our randomized, controlled trial, we saw our ability to meet ACOG guidelines on postpartum blood monitoring leap from 0% to 82%, compared to in-person office visits and 7-day readmissions from hypertension drop from 3% to 0%,” an update at the program website states.

ACOG

Rebekah Gee, MD, an ob.gyn. and director of the Louisiana State University Health System in New Orleans, also noted the importance of finding ways to deliver care “that are outside the traditional norm.

“Telemedicine, home visiting ... I think there are a wide variety of ways,” she said, noting that these kind of approaches not only help circumvent roadblocks to care, such as lack of transportation, but also can feel more personal and approachable for some women.
 

Solution: Measuring, investing, diversifying, respecting

The aims of other bills in the Momnibus Act also mirror several solutions proposed by maternal health advocates interviewed for this article. Among them are:

• Development of improved data collection processes and quality measures to better understand the factors that contribute to the crisis overall and among special populations, and to inform solutions for addressing them.
• Investments in social determinants of health that influence maternal health outcomes, like housing, transportation, and nutrition.
• Commitment to the growth and diversification of the perinatal workforce to ensure that every mom receives maternity care and support from people she can trust to provide quality care and treat her with respect.

The latter is one that Dr. Gee, Dr. Crear-Perry, and others particularly emphasized.

“We need patient advocates like doulas, midwives and others who are better listeners and better able to advocate for patients,” Dr. Gee said. This would better allow for women’s desires in the childbirth experience to be addressed appropriately, she said, adding that this is something that “frankly, a lot of doctors do not have the time to do.”

That’s why the efforts to address maternal mortality have to focus on the health care system, not just on doctors’ behavior with respect to bias, she said.

Dr. Gee also said there is a need for culturally appropriate literacy and numeracy communications “that respect how people seek and understand information.” This varies by population, which is why it’s important to provide the same approach to care “no matter what the patient looks like,” while also understanding that different patients communicate in different ways.

A 2019 study published in Social Science & Medicine underscored how communication differences can affect outcomes; using a national sample of women who gave birth in U.S. hospitals, the authors found that those who had declined care for themselves or their infant during their childbirth hospitalization were more likely to report receiving poor treatment based on race or ethnicity. They concluded that, in the context of childbirth care, women – particularly black women – pay a penalty for what is perceived as uncooperative behavior.

This is another area where doulas and other patient advocates can help, Dr. Gee said.

Doulas have long been an integral part of the birthing process for many women, particularly women of color, and evidence suggests the supportive care they provide helps to improve outcomes. In fact, several states – including Oregon, Minnesota, and New York, among others – have expanded or have proposed expanding Medicaid coverage to include doula services for pregnant beneficiaries, a move cheered by doula associations and other maternal health advocates.

In many ways, it’s about “respectful maternity care,” which is something Dr. Crear-Perry has been working to promote through the NBEC in partnership with ACOG and the Robert Wood Johnson Foundation. It’s also something the World Health Organization has promoted by establishing global standards for such care.

“We’re hoping to socialize that as a norm in United States ... to really see what it would look like to value what birthing people want and to see them as partners in their birth,” she said.

However, the 2019 Giving Voice to Mothers study demonstrating consistently higher rates of mistreatment during obstetrical care for women of color than for comparable white women shows that the United States is falling short of those standards. The national study of 2,700 women examined how race, ethnicity, and place of birth interact with the experience of receiving maternity care in the United States, and showed that 1 in 6 experienced one or more types of mistreatment – with consistently higher rates among women of color, even after adjusting for interactions between race and other maternal characteristics, Saraswathi Veda, MD, of the Birth Place Lab and professor of midwifery at the University of British Columbia, Vancouver, and colleagues reported in Reproductive Health.
 

Solution: Listening, learning, reflecting, partnering

Timoria McQueen Saba, birth trauma survivor and maternal health advocate, has described experiencing instances of mistreatment throughout her obstetric care, and like Dr. Crear-Perry, she said trust and collaboration in care is imperative for improving outcomes.

“I think the most important thing you can do is really consider a patient a partner in the care you give them,” she said during a panel discussion at the 2019 ACOG annual meeting. “You’re not experts in their lived experience ... center a patient’s voice or the voice of a patient’s family. Incorporate that into your learning.”

During a virtual workshop held May 19-20 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Judette Louis, MD, chair of the department of obstetrics and gynecology at the University of South Florida, Tampa, and president of the Society of Maternal-Fetal Medicine, provided practical guidance for addressing racism and implicit bias in practice and in research to reduce disparities in outcomes.

In an interview, she summarized her key points, reiterating solutions proposed by Dr. Gee and Dr. Crear-Perry and addressed in the Momnibus Act, and also offering a few others:

First, put aside the notion that disparities are genetically driven. For a variety of reasons, that just doesn’t make sense. For one thing, not all blacks are African American.

“My family is from the Caribbean,” she said. “Is it really conceivable that we’re all so similar?”

Look also at the disparities among Native Americans, she said. “How can you take 500 distinct tribes that live across a wide geographic area and lump them into one group and assume that they are similar?”

The problem is racism, not race. “When you keep saying ‘it’s about race, it’s about race, it’s about race’ – that sends a message to the person who is of that race that there is something inherently broken about [them],” she said.

Recognize that the roots of the problem run deep. Learn about and support efforts to address the underlying structural factors that contribute to the problem, Dr. Louis emphasized, and recognize your own bias. “We all have it. The key is to recognize [biases] and mitigate them when taking care of patients.”

That’s easier said than done, at least judging by one survey of maternal-fetal medicine specialists in which 84% of respondents agreed that disparities impact practice, but only 29% agreed their own personal biases affect how they care for patients, she noted.

Tools are available to help individuals identify implicit bias, and training programs for health care providers can help, as well, she said. Implicit bias tests and training programs that help to identify and address bias and racism on individual and organizational levels are increasingly available through academic centers, health systems, and advocacy organizations.

Hope for solutions: Progress and promise

Like Dr. Crear-Perry, Dr. Louis sees hope for reducing disparities and improving maternal outcomes.

In another survey of SMFM members to identify the practice issues most important to them, racial disparities ranked in the top three.

“It says a lot that our [maternal-fetal medicine specialists] really see this as a problem and they want it fixed,” she said. “And I think it says that a lot of people need to work on this, not just us.”

Indeed, many are engaged in that work. Veronica Gillispie, MD, medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, has been instrumental in recent initiatives to improve maternal outcomes in Louisiana, and she too said she feels optimistic.

“I am hopeful and I do see signs of hope,” she said in an interview.

Teams that she works with and trains seem invested, institutions are increasingly implementing faculty training on racism and bias, and Oschner Health, where Dr. Gillispie practices as an ob.gyn., appointed its first chief diversity officer in February.

Medical students she works with are attuned to the issues of racism, bias, and disparities, and they show a desire to enact change, she said. “They already get it, and they are working to make it better.”

Dr. Crear-Perry also predicts practice-changing results from studies looking at the delivery of obstetrical care and the role of supportive care, and she pointed out another aspect of the COVID-19 crisis that provides an important lesson for health care providers who care for birthing people: the scarcity of personal protective equipment amid the pandemic.

“My friends who are ob.gyns., who are now not getting access to the things they need to stay safe to practice medicine and who are feeling very marginalized at this moment, feeling not valued – that’s how birthing people [of color] feel,” she said. “I’m hoping that builds a sense of empathy.

”I’m hoping at the end of this crisis, that those ob.gyns. will think of patients as allies in fighting for more access to health for everybody and for more resources to do their work,” Dr. Crear-Perry said. “We’re all in this together.”

[email protected]

This is the second of a two-part article on the role of racism and bias in the U.S. maternal mortality crisis and part of an ongoing Ob.Gyn. News feature series on the crisis. Part one of the story explored existing data, societal factors, and patient experiences related to structural racism, overt racism, and implicit bias as factors contributing to racial disparities in maternal outcomes. Here we explore potential solutions for addressing the inequities as proposed by thought leaders and key stakeholders.



The emerging racial disparities in COVID-19 incidence and outcomes in the United States are on a collision course with long-standing racial disparities in U.S. maternal care and mortality.

Maternal health advocates are bracing for the impact, but in the spotlight that the pandemic is training on the inequities and the health system changes taking shape in its wake, some also see hope for a shift in at least one important driver of the racial health disparities: access to care.

Non-Hispanic black women are at least three times more likely than Hispanic women and non-Hispanic white women to experience pregnancy-related death, and indigenous women are more than twice as likely, according to the latest data from the Centers for Disease Control and Prevention’s National Center for Health Statistics. The added strain COVID-19 is putting on the system stands to further limit the access to care that many pregnant women of color experience and to exacerbate racial disparities, panelists agreed during a recent National Maternal Health Patient Centered Outcomes Research Network webinar entitled “The Impact of COVID-19 on Black, Brown, and Native Pregnant People.”

“The saying is that ‘the virus doesn’t discriminate,’ but it understands our biases, right? So, the virus takes advantage of the weaknesses in our system,” said panelist Joia A. Crear-Perry, MD, an ob.gyn. and founder and president of the National Birth Equity Collaborative (NBEC), a New Orleans–based research, training, and advocacy organization working to optimize black maternal and infant health.
 

Hope for solutions from the ashes of a pandemic

The weaknesses in the system that Dr. Crear-Perry spoke of are in many ways a product of structural racism as described in a conceptual report in The Lancet, titled “America: Equity and Equality in Health,” which dug into the entrenched and tangled historical roots of racist sociological and political factors that formed a foundation for health inequity over time.

Today, people of color remain more likely to be excluded from access to health insurance and adequate health care. The authors defined structural racism as “the totality of ways in which societies foster racial discrimination through mutually reinforcing systems of housing, education, employment, earnings, benefits, credit, media, health care, and criminal justice.” Today, largely as a result of these “reinforcing systems,” people of color remain more likely to be excluded from access to health insurance and adequate health care. At the same time, and for the same reasons, they are more likely to work in the service industry, be essential workers, and use mass transit, each of which increases the risk of exposure to COVID-19, Dr. Crear-Perry explained.

“It’s important for us to know that, for maternal mortality, it’s the same thing that happens,” she said. That means the focus on COVID-19–related disparities helps magnify and elevate the conversation regarding similar disparities in maternal outcomes.

It also means that some of the care delivery solutions embraced and facilitated amid the pandemic, such as extension of Medicaid coverage for up to a year after giving birth and broader use and insurance coverage of telemedicine, could finally gain traction; those are solutions long-sought by advocates like Dr. Crear-Perry and others as a means for alleviating racial disparities in maternal outcomes and addressing the maternal mortality crisis.

Therein lies the hope, she explained in an interview. “Some of the policies that we know would have been helpful prior to COVID-19 now are being seen as really important.”
 

Solution: Extending coverage

During a May 7 virtual Congressional hearing on “America’s Two Public Health Crises: The Impact of COVID-19 on Racial Inequities and Maternal Mortality in the U.S.,” cosponsored by the American College of Obstetricians and Gynecologists, the March of Dimes, and the NBEC, Dr. Crear-Perry further explained the importance of extended coverage and care access.

Asked what Congress could do immediately to “ensure that the pandemic does not compound the nation’s maternal mortality crisis, including unacceptable rates among black women,” she didn’t hesitate.

“Well, it would be amazing if we could get Medicaid extended for 12 months post delivery,” she said. “As you can imagine right now, we have moms who are birthing in hospitals where they have to worry about, 2 months later, not having coverage for themselves.”

If that mom is exposed to COVID-19 and has no insurance coverage and a newborn at home, the likelihood that she will call a provider if she develops symptoms is low, Dr. Crear-Perry said. “This is a great opportunity for us to really rethink some of those policies that we know are barriers, that we have created for people to be able to thrive after they have a baby and during child birth.”

Current policies are centered around an arbitrary cutoff of about 6 weeks for postpartum care, but the CDC reports that a third of all postpartum deaths occur between 1 week and 12 months after birth.

“We need our policies to reflect the current knowledge and the science,” she said. “Just like babies have automatic insurance coverage for a year later, mothers should have the same.”

Medicaid finances nearly half of all births in the United States, according to a 2019 Kaiser Family Foundation brief, which explained that federal law requires Medicaid coverage for only 60 days post partum for women who are eligible. Decisions regarding coverage after 60 days are determined by individual states; those that expanded Medicaid under the Affordable Care Act typically allow extended coverage – but only with reapplication at 60 days.

Many women in nonexpansion states become uninsured after pregnancy-related coverage ends, as do some in expansion states for whom reapplying is a hurdle too high to clear with a newborn baby to care for at home, Dr. Crear-Perry said.

Addressing these coverage gaps is key to improving access, and it is a core component of the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March by Rep. Lauren Underwood (D-Ill.), Rep. Alma Adams (D-N.C.), Sen. Kamala Harris (D-Calif.), and members of the Black Maternal Health Caucus to “fill gaps in existing legislation to comprehensively address every dimension of the Black maternal health crisis in America.”

One bill in the package addresses extended coverage with a goal to “promote innovative payment models to incentivize high-quality maternity care and continuity of health insurance coverage from pregnancy through labor and delivery and up to 1 year post partum.” Another focuses on promoting alternative ways to access care, such as through telemedicine.

Solution: Expanding care access

“There is a need for the democratization of care,” Dr. Crear-Perry said. “There is a need for people to have more ways to get care. This idea that the only way you can get prenatal care is you have to come to me at my office, has been a burden for working people for a long, long time.”

The COVID-19 pandemic necessitates increased use of telemedicine, but building blocks to allow patients to use it effectively must be put in place, she said. That means expanding broadband access, providing patients with blood pressure cuffs and other tools for use remotely, and expanding reimbursement to include not just video, but also phone calls.

Heart Safe Motherhood, a University of Pennsylvania text-based intervention developed to address postpartum hypertension – a leading cause of maternal morbidity and mortality, and at the start of the program, the leading cause of 7-day readmissions among obstetric patients, demonstrated the value of such approaches to care.

The program involves remote blood pressure monitoring using a digital monitor provided to at-risk patients at discharge. Text-based monitoring reminders encourage patients to check their blood pressure twice daily for the first 7 days.

“In our randomized, controlled trial, we saw our ability to meet ACOG guidelines on postpartum blood monitoring leap from 0% to 82%, compared to in-person office visits and 7-day readmissions from hypertension drop from 3% to 0%,” an update at the program website states.

ACOG

Rebekah Gee, MD, an ob.gyn. and director of the Louisiana State University Health System in New Orleans, also noted the importance of finding ways to deliver care “that are outside the traditional norm.

“Telemedicine, home visiting ... I think there are a wide variety of ways,” she said, noting that these kind of approaches not only help circumvent roadblocks to care, such as lack of transportation, but also can feel more personal and approachable for some women.
 

Solution: Measuring, investing, diversifying, respecting

The aims of other bills in the Momnibus Act also mirror several solutions proposed by maternal health advocates interviewed for this article. Among them are:

• Development of improved data collection processes and quality measures to better understand the factors that contribute to the crisis overall and among special populations, and to inform solutions for addressing them.
• Investments in social determinants of health that influence maternal health outcomes, like housing, transportation, and nutrition.
• Commitment to the growth and diversification of the perinatal workforce to ensure that every mom receives maternity care and support from people she can trust to provide quality care and treat her with respect.

The latter is one that Dr. Gee, Dr. Crear-Perry, and others particularly emphasized.

“We need patient advocates like doulas, midwives and others who are better listeners and better able to advocate for patients,” Dr. Gee said. This would better allow for women’s desires in the childbirth experience to be addressed appropriately, she said, adding that this is something that “frankly, a lot of doctors do not have the time to do.”

That’s why the efforts to address maternal mortality have to focus on the health care system, not just on doctors’ behavior with respect to bias, she said.

Dr. Gee also said there is a need for culturally appropriate literacy and numeracy communications “that respect how people seek and understand information.” This varies by population, which is why it’s important to provide the same approach to care “no matter what the patient looks like,” while also understanding that different patients communicate in different ways.

A 2019 study published in Social Science & Medicine underscored how communication differences can affect outcomes; using a national sample of women who gave birth in U.S. hospitals, the authors found that those who had declined care for themselves or their infant during their childbirth hospitalization were more likely to report receiving poor treatment based on race or ethnicity. They concluded that, in the context of childbirth care, women – particularly black women – pay a penalty for what is perceived as uncooperative behavior.

This is another area where doulas and other patient advocates can help, Dr. Gee said.

Doulas have long been an integral part of the birthing process for many women, particularly women of color, and evidence suggests the supportive care they provide helps to improve outcomes. In fact, several states – including Oregon, Minnesota, and New York, among others – have expanded or have proposed expanding Medicaid coverage to include doula services for pregnant beneficiaries, a move cheered by doula associations and other maternal health advocates.

In many ways, it’s about “respectful maternity care,” which is something Dr. Crear-Perry has been working to promote through the NBEC in partnership with ACOG and the Robert Wood Johnson Foundation. It’s also something the World Health Organization has promoted by establishing global standards for such care.

“We’re hoping to socialize that as a norm in United States ... to really see what it would look like to value what birthing people want and to see them as partners in their birth,” she said.

However, the 2019 Giving Voice to Mothers study demonstrating consistently higher rates of mistreatment during obstetrical care for women of color than for comparable white women shows that the United States is falling short of those standards. The national study of 2,700 women examined how race, ethnicity, and place of birth interact with the experience of receiving maternity care in the United States, and showed that 1 in 6 experienced one or more types of mistreatment – with consistently higher rates among women of color, even after adjusting for interactions between race and other maternal characteristics, Saraswathi Veda, MD, of the Birth Place Lab and professor of midwifery at the University of British Columbia, Vancouver, and colleagues reported in Reproductive Health.
 

Solution: Listening, learning, reflecting, partnering

Timoria McQueen Saba, birth trauma survivor and maternal health advocate, has described experiencing instances of mistreatment throughout her obstetric care, and like Dr. Crear-Perry, she said trust and collaboration in care is imperative for improving outcomes.

“I think the most important thing you can do is really consider a patient a partner in the care you give them,” she said during a panel discussion at the 2019 ACOG annual meeting. “You’re not experts in their lived experience ... center a patient’s voice or the voice of a patient’s family. Incorporate that into your learning.”

During a virtual workshop held May 19-20 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Judette Louis, MD, chair of the department of obstetrics and gynecology at the University of South Florida, Tampa, and president of the Society of Maternal-Fetal Medicine, provided practical guidance for addressing racism and implicit bias in practice and in research to reduce disparities in outcomes.

In an interview, she summarized her key points, reiterating solutions proposed by Dr. Gee and Dr. Crear-Perry and addressed in the Momnibus Act, and also offering a few others:

First, put aside the notion that disparities are genetically driven. For a variety of reasons, that just doesn’t make sense. For one thing, not all blacks are African American.

“My family is from the Caribbean,” she said. “Is it really conceivable that we’re all so similar?”

Look also at the disparities among Native Americans, she said. “How can you take 500 distinct tribes that live across a wide geographic area and lump them into one group and assume that they are similar?”

The problem is racism, not race. “When you keep saying ‘it’s about race, it’s about race, it’s about race’ – that sends a message to the person who is of that race that there is something inherently broken about [them],” she said.

Recognize that the roots of the problem run deep. Learn about and support efforts to address the underlying structural factors that contribute to the problem, Dr. Louis emphasized, and recognize your own bias. “We all have it. The key is to recognize [biases] and mitigate them when taking care of patients.”

That’s easier said than done, at least judging by one survey of maternal-fetal medicine specialists in which 84% of respondents agreed that disparities impact practice, but only 29% agreed their own personal biases affect how they care for patients, she noted.

Tools are available to help individuals identify implicit bias, and training programs for health care providers can help, as well, she said. Implicit bias tests and training programs that help to identify and address bias and racism on individual and organizational levels are increasingly available through academic centers, health systems, and advocacy organizations.

Hope for solutions: Progress and promise

Like Dr. Crear-Perry, Dr. Louis sees hope for reducing disparities and improving maternal outcomes.

In another survey of SMFM members to identify the practice issues most important to them, racial disparities ranked in the top three.

“It says a lot that our [maternal-fetal medicine specialists] really see this as a problem and they want it fixed,” she said. “And I think it says that a lot of people need to work on this, not just us.”

Indeed, many are engaged in that work. Veronica Gillispie, MD, medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, has been instrumental in recent initiatives to improve maternal outcomes in Louisiana, and she too said she feels optimistic.

“I am hopeful and I do see signs of hope,” she said in an interview.

Teams that she works with and trains seem invested, institutions are increasingly implementing faculty training on racism and bias, and Oschner Health, where Dr. Gillispie practices as an ob.gyn., appointed its first chief diversity officer in February.

Medical students she works with are attuned to the issues of racism, bias, and disparities, and they show a desire to enact change, she said. “They already get it, and they are working to make it better.”

Dr. Crear-Perry also predicts practice-changing results from studies looking at the delivery of obstetrical care and the role of supportive care, and she pointed out another aspect of the COVID-19 crisis that provides an important lesson for health care providers who care for birthing people: the scarcity of personal protective equipment amid the pandemic.

“My friends who are ob.gyns., who are now not getting access to the things they need to stay safe to practice medicine and who are feeling very marginalized at this moment, feeling not valued – that’s how birthing people [of color] feel,” she said. “I’m hoping that builds a sense of empathy.

”I’m hoping at the end of this crisis, that those ob.gyns. will think of patients as allies in fighting for more access to health for everybody and for more resources to do their work,” Dr. Crear-Perry said. “We’re all in this together.”

[email protected]

This is the second of a two-part article on the role of racism and bias in the U.S. maternal mortality crisis and part of an ongoing Ob.Gyn. News feature series on the crisis. Part one of the story explored existing data, societal factors, and patient experiences related to structural racism, overt racism, and implicit bias as factors contributing to racial disparities in maternal outcomes. Here we explore potential solutions for addressing the inequities as proposed by thought leaders and key stakeholders.



The emerging racial disparities in COVID-19 incidence and outcomes in the United States are on a collision course with long-standing racial disparities in U.S. maternal care and mortality.

Maternal health advocates are bracing for the impact, but in the spotlight that the pandemic is training on the inequities and the health system changes taking shape in its wake, some also see hope for a shift in at least one important driver of the racial health disparities: access to care.

Non-Hispanic black women are at least three times more likely than Hispanic women and non-Hispanic white women to experience pregnancy-related death, and indigenous women are more than twice as likely, according to the latest data from the Centers for Disease Control and Prevention’s National Center for Health Statistics. The added strain COVID-19 is putting on the system stands to further limit the access to care that many pregnant women of color experience and to exacerbate racial disparities, panelists agreed during a recent National Maternal Health Patient Centered Outcomes Research Network webinar entitled “The Impact of COVID-19 on Black, Brown, and Native Pregnant People.”

“The saying is that ‘the virus doesn’t discriminate,’ but it understands our biases, right? So, the virus takes advantage of the weaknesses in our system,” said panelist Joia A. Crear-Perry, MD, an ob.gyn. and founder and president of the National Birth Equity Collaborative (NBEC), a New Orleans–based research, training, and advocacy organization working to optimize black maternal and infant health.
 

Hope for solutions from the ashes of a pandemic

The weaknesses in the system that Dr. Crear-Perry spoke of are in many ways a product of structural racism as described in a conceptual report in The Lancet, titled “America: Equity and Equality in Health,” which dug into the entrenched and tangled historical roots of racist sociological and political factors that formed a foundation for health inequity over time.

Today, people of color remain more likely to be excluded from access to health insurance and adequate health care. The authors defined structural racism as “the totality of ways in which societies foster racial discrimination through mutually reinforcing systems of housing, education, employment, earnings, benefits, credit, media, health care, and criminal justice.” Today, largely as a result of these “reinforcing systems,” people of color remain more likely to be excluded from access to health insurance and adequate health care. At the same time, and for the same reasons, they are more likely to work in the service industry, be essential workers, and use mass transit, each of which increases the risk of exposure to COVID-19, Dr. Crear-Perry explained.

“It’s important for us to know that, for maternal mortality, it’s the same thing that happens,” she said. That means the focus on COVID-19–related disparities helps magnify and elevate the conversation regarding similar disparities in maternal outcomes.

It also means that some of the care delivery solutions embraced and facilitated amid the pandemic, such as extension of Medicaid coverage for up to a year after giving birth and broader use and insurance coverage of telemedicine, could finally gain traction; those are solutions long-sought by advocates like Dr. Crear-Perry and others as a means for alleviating racial disparities in maternal outcomes and addressing the maternal mortality crisis.

Therein lies the hope, she explained in an interview. “Some of the policies that we know would have been helpful prior to COVID-19 now are being seen as really important.”
 

Solution: Extending coverage

During a May 7 virtual Congressional hearing on “America’s Two Public Health Crises: The Impact of COVID-19 on Racial Inequities and Maternal Mortality in the U.S.,” cosponsored by the American College of Obstetricians and Gynecologists, the March of Dimes, and the NBEC, Dr. Crear-Perry further explained the importance of extended coverage and care access.

Asked what Congress could do immediately to “ensure that the pandemic does not compound the nation’s maternal mortality crisis, including unacceptable rates among black women,” she didn’t hesitate.

“Well, it would be amazing if we could get Medicaid extended for 12 months post delivery,” she said. “As you can imagine right now, we have moms who are birthing in hospitals where they have to worry about, 2 months later, not having coverage for themselves.”

If that mom is exposed to COVID-19 and has no insurance coverage and a newborn at home, the likelihood that she will call a provider if she develops symptoms is low, Dr. Crear-Perry said. “This is a great opportunity for us to really rethink some of those policies that we know are barriers, that we have created for people to be able to thrive after they have a baby and during child birth.”

Current policies are centered around an arbitrary cutoff of about 6 weeks for postpartum care, but the CDC reports that a third of all postpartum deaths occur between 1 week and 12 months after birth.

“We need our policies to reflect the current knowledge and the science,” she said. “Just like babies have automatic insurance coverage for a year later, mothers should have the same.”

Medicaid finances nearly half of all births in the United States, according to a 2019 Kaiser Family Foundation brief, which explained that federal law requires Medicaid coverage for only 60 days post partum for women who are eligible. Decisions regarding coverage after 60 days are determined by individual states; those that expanded Medicaid under the Affordable Care Act typically allow extended coverage – but only with reapplication at 60 days.

Many women in nonexpansion states become uninsured after pregnancy-related coverage ends, as do some in expansion states for whom reapplying is a hurdle too high to clear with a newborn baby to care for at home, Dr. Crear-Perry said.

Addressing these coverage gaps is key to improving access, and it is a core component of the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March by Rep. Lauren Underwood (D-Ill.), Rep. Alma Adams (D-N.C.), Sen. Kamala Harris (D-Calif.), and members of the Black Maternal Health Caucus to “fill gaps in existing legislation to comprehensively address every dimension of the Black maternal health crisis in America.”

One bill in the package addresses extended coverage with a goal to “promote innovative payment models to incentivize high-quality maternity care and continuity of health insurance coverage from pregnancy through labor and delivery and up to 1 year post partum.” Another focuses on promoting alternative ways to access care, such as through telemedicine.

Solution: Expanding care access

“There is a need for the democratization of care,” Dr. Crear-Perry said. “There is a need for people to have more ways to get care. This idea that the only way you can get prenatal care is you have to come to me at my office, has been a burden for working people for a long, long time.”

The COVID-19 pandemic necessitates increased use of telemedicine, but building blocks to allow patients to use it effectively must be put in place, she said. That means expanding broadband access, providing patients with blood pressure cuffs and other tools for use remotely, and expanding reimbursement to include not just video, but also phone calls.

Heart Safe Motherhood, a University of Pennsylvania text-based intervention developed to address postpartum hypertension – a leading cause of maternal morbidity and mortality, and at the start of the program, the leading cause of 7-day readmissions among obstetric patients, demonstrated the value of such approaches to care.

The program involves remote blood pressure monitoring using a digital monitor provided to at-risk patients at discharge. Text-based monitoring reminders encourage patients to check their blood pressure twice daily for the first 7 days.

“In our randomized, controlled trial, we saw our ability to meet ACOG guidelines on postpartum blood monitoring leap from 0% to 82%, compared to in-person office visits and 7-day readmissions from hypertension drop from 3% to 0%,” an update at the program website states.

ACOG

Rebekah Gee, MD, an ob.gyn. and director of the Louisiana State University Health System in New Orleans, also noted the importance of finding ways to deliver care “that are outside the traditional norm.

“Telemedicine, home visiting ... I think there are a wide variety of ways,” she said, noting that these kind of approaches not only help circumvent roadblocks to care, such as lack of transportation, but also can feel more personal and approachable for some women.
 

Solution: Measuring, investing, diversifying, respecting

The aims of other bills in the Momnibus Act also mirror several solutions proposed by maternal health advocates interviewed for this article. Among them are:

• Development of improved data collection processes and quality measures to better understand the factors that contribute to the crisis overall and among special populations, and to inform solutions for addressing them.
• Investments in social determinants of health that influence maternal health outcomes, like housing, transportation, and nutrition.
• Commitment to the growth and diversification of the perinatal workforce to ensure that every mom receives maternity care and support from people she can trust to provide quality care and treat her with respect.

The latter is one that Dr. Gee, Dr. Crear-Perry, and others particularly emphasized.

“We need patient advocates like doulas, midwives and others who are better listeners and better able to advocate for patients,” Dr. Gee said. This would better allow for women’s desires in the childbirth experience to be addressed appropriately, she said, adding that this is something that “frankly, a lot of doctors do not have the time to do.”

That’s why the efforts to address maternal mortality have to focus on the health care system, not just on doctors’ behavior with respect to bias, she said.

Dr. Gee also said there is a need for culturally appropriate literacy and numeracy communications “that respect how people seek and understand information.” This varies by population, which is why it’s important to provide the same approach to care “no matter what the patient looks like,” while also understanding that different patients communicate in different ways.

A 2019 study published in Social Science & Medicine underscored how communication differences can affect outcomes; using a national sample of women who gave birth in U.S. hospitals, the authors found that those who had declined care for themselves or their infant during their childbirth hospitalization were more likely to report receiving poor treatment based on race or ethnicity. They concluded that, in the context of childbirth care, women – particularly black women – pay a penalty for what is perceived as uncooperative behavior.

This is another area where doulas and other patient advocates can help, Dr. Gee said.

Doulas have long been an integral part of the birthing process for many women, particularly women of color, and evidence suggests the supportive care they provide helps to improve outcomes. In fact, several states – including Oregon, Minnesota, and New York, among others – have expanded or have proposed expanding Medicaid coverage to include doula services for pregnant beneficiaries, a move cheered by doula associations and other maternal health advocates.

In many ways, it’s about “respectful maternity care,” which is something Dr. Crear-Perry has been working to promote through the NBEC in partnership with ACOG and the Robert Wood Johnson Foundation. It’s also something the World Health Organization has promoted by establishing global standards for such care.

“We’re hoping to socialize that as a norm in United States ... to really see what it would look like to value what birthing people want and to see them as partners in their birth,” she said.

However, the 2019 Giving Voice to Mothers study demonstrating consistently higher rates of mistreatment during obstetrical care for women of color than for comparable white women shows that the United States is falling short of those standards. The national study of 2,700 women examined how race, ethnicity, and place of birth interact with the experience of receiving maternity care in the United States, and showed that 1 in 6 experienced one or more types of mistreatment – with consistently higher rates among women of color, even after adjusting for interactions between race and other maternal characteristics, Saraswathi Veda, MD, of the Birth Place Lab and professor of midwifery at the University of British Columbia, Vancouver, and colleagues reported in Reproductive Health.
 

Solution: Listening, learning, reflecting, partnering

Timoria McQueen Saba, birth trauma survivor and maternal health advocate, has described experiencing instances of mistreatment throughout her obstetric care, and like Dr. Crear-Perry, she said trust and collaboration in care is imperative for improving outcomes.

“I think the most important thing you can do is really consider a patient a partner in the care you give them,” she said during a panel discussion at the 2019 ACOG annual meeting. “You’re not experts in their lived experience ... center a patient’s voice or the voice of a patient’s family. Incorporate that into your learning.”

During a virtual workshop held May 19-20 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Judette Louis, MD, chair of the department of obstetrics and gynecology at the University of South Florida, Tampa, and president of the Society of Maternal-Fetal Medicine, provided practical guidance for addressing racism and implicit bias in practice and in research to reduce disparities in outcomes.

In an interview, she summarized her key points, reiterating solutions proposed by Dr. Gee and Dr. Crear-Perry and addressed in the Momnibus Act, and also offering a few others:

First, put aside the notion that disparities are genetically driven. For a variety of reasons, that just doesn’t make sense. For one thing, not all blacks are African American.

“My family is from the Caribbean,” she said. “Is it really conceivable that we’re all so similar?”

Look also at the disparities among Native Americans, she said. “How can you take 500 distinct tribes that live across a wide geographic area and lump them into one group and assume that they are similar?”

The problem is racism, not race. “When you keep saying ‘it’s about race, it’s about race, it’s about race’ – that sends a message to the person who is of that race that there is something inherently broken about [them],” she said.

Recognize that the roots of the problem run deep. Learn about and support efforts to address the underlying structural factors that contribute to the problem, Dr. Louis emphasized, and recognize your own bias. “We all have it. The key is to recognize [biases] and mitigate them when taking care of patients.”

That’s easier said than done, at least judging by one survey of maternal-fetal medicine specialists in which 84% of respondents agreed that disparities impact practice, but only 29% agreed their own personal biases affect how they care for patients, she noted.

Tools are available to help individuals identify implicit bias, and training programs for health care providers can help, as well, she said. Implicit bias tests and training programs that help to identify and address bias and racism on individual and organizational levels are increasingly available through academic centers, health systems, and advocacy organizations.

Hope for solutions: Progress and promise

Like Dr. Crear-Perry, Dr. Louis sees hope for reducing disparities and improving maternal outcomes.

In another survey of SMFM members to identify the practice issues most important to them, racial disparities ranked in the top three.

“It says a lot that our [maternal-fetal medicine specialists] really see this as a problem and they want it fixed,” she said. “And I think it says that a lot of people need to work on this, not just us.”

Indeed, many are engaged in that work. Veronica Gillispie, MD, medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, has been instrumental in recent initiatives to improve maternal outcomes in Louisiana, and she too said she feels optimistic.

“I am hopeful and I do see signs of hope,” she said in an interview.

Teams that she works with and trains seem invested, institutions are increasingly implementing faculty training on racism and bias, and Oschner Health, where Dr. Gillispie practices as an ob.gyn., appointed its first chief diversity officer in February.

Medical students she works with are attuned to the issues of racism, bias, and disparities, and they show a desire to enact change, she said. “They already get it, and they are working to make it better.”

Dr. Crear-Perry also predicts practice-changing results from studies looking at the delivery of obstetrical care and the role of supportive care, and she pointed out another aspect of the COVID-19 crisis that provides an important lesson for health care providers who care for birthing people: the scarcity of personal protective equipment amid the pandemic.

“My friends who are ob.gyns., who are now not getting access to the things they need to stay safe to practice medicine and who are feeling very marginalized at this moment, feeling not valued – that’s how birthing people [of color] feel,” she said. “I’m hoping that builds a sense of empathy.

”I’m hoping at the end of this crisis, that those ob.gyns. will think of patients as allies in fighting for more access to health for everybody and for more resources to do their work,” Dr. Crear-Perry said. “We’re all in this together.”

[email protected]