AVAHO

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

A version of this article first appeared on Medscape.com.

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Concurrent cisplatin should remain the standard treatment over cetuximab for patients with locoregionally advanced head and neck squamous cell carcinoma, according to a large comparative phase 3 trial.

Based on the results of an interim analysis of the ARTSCAN III clinical trial, the independent safety data monitoring committee recommended early closure of the study because the results of the study suggest that cetuximab may be inferior to cisplatin.

“This study supports previous retrospective and prospective studies that suggest that concurrent cisplatin with radiation is superior to regimens with concurrent cetuximab in locally advanced head and neck cancers,” commented Sachin Jhawar, MD, MSCI, assistant professor in the department of radiation oncology at Ohio State University Comprehensive Cancer Center, Columbus. “While the previous studies De-ESCALaTE HPV and RTOG 1016 were specific to HPV [human papillomavirus]-positive cancers, this study allowed non–virally mediated tumors, though the majority of cases were HPV related.”

The new study also used a lower-dose weekly regimen of cisplatin than the other two studies, noted Dr. Jhawar. Early trials used a cisplatin dose of 100 mg/m² every 3 weeks, but “the field is moving toward a dose of 40 mg/m² weekly, the dose use in the Swedish study. This study had an interesting second randomization of radiation dose-escalation for more advanced primary T stage tumors, but because the study ended early it is difficult to fully interpret those results.”

Swedish researchers, led by Maria Gebre-Medhin, MD, PhD, department of hematology, oncology, and radiation physics, Skåne University Hospital, Lund, Sweden, performed an open-label, randomized, controlled, phase 3 study of patients with locoregionally advanced head and neck squamous cell carcinoma. The patients received IV cetuximab 400 mg/m² 1 week before the start of radiation therapy followed by 250 mg/m² per week, or weekly IV cisplatin 40 mg/m² during radiation therapy.

The study results were published in the Journal of Clinical Oncology.

The study was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. The cumulative incidence of locoregional failures at 3 years was more than twice as high in the cetuximab group (23%), compared with the cisplatin group (9%; P = .0036). At 3 years, overall survival was higher in the cisplatin (88%) group than in the cetuximab group (78%), but the difference was not significant (P = .086). The cumulative incidence of distant failures did not differ between the treatment groups, and the toxicity burden was similar.

“Concurrent cisplatin led to improved locoregional control and event-free survival with a trend toward improved overall survival. The types of toxicity were different, as would be expected with the different drug mechanisms, but the rate of toxicity was not,” said Dr. Dr. Jhawar. “Interestingly, the benefit of cisplatin seemed to be limited to patients with p16-positive oropharyngeal cancer. There was clinical equipoise in the p16-negative oropharyngeal cancer group and in the non–oropharyngeal cancer group. The numbers were small, but this is intriguing and suggests that there is more work to be done in this group of patients to tease out if we can escalate or use alternative therapy.”

Cisplatin has been repeatedly proven to be superior in selected populations. The next steps, said Dr. Jhawar, include defining “optimal regimens in cisplatin-ineligible populations based on age, performance status, kidney function, hearing loss, neuropathy, and HIV/AIDS; improvements with new targeted therapies and immunotherapies; and deescalation of systemic and/or radiation regimens in the best outcome groups, such as low-risk HPV-positive patients. And we are going to see more personalized medicine with genetic testing of tumors.”

When patients are ineligible for cisplatin, no optimal regimens have been defined as yet. At Ohio State, Dr. Jhawar and colleagues use carboplatin therapy.

For practicing oncologists, Dr. Jhawar said the bottom line is “patients who are eligible should receive concurrent cisplatin therapy for locoregionally advanced head and neck cancer.”

The ARTSCAN III study was funded by the Swedish Cancer Society and the Mrs. Berta Kamprad Cancer Foundation. One of the study’s coauthors reported a leadership role in ScandiDos. The other authors reported they had no conflicts. Dr. Jhawar reported he had no conflicts of interest.




 

Concurrent cisplatin should remain the standard treatment over cetuximab for patients with locoregionally advanced head and neck squamous cell carcinoma, according to a large comparative phase 3 trial.

Based on the results of an interim analysis of the ARTSCAN III clinical trial, the independent safety data monitoring committee recommended early closure of the study because the results of the study suggest that cetuximab may be inferior to cisplatin.

“This study supports previous retrospective and prospective studies that suggest that concurrent cisplatin with radiation is superior to regimens with concurrent cetuximab in locally advanced head and neck cancers,” commented Sachin Jhawar, MD, MSCI, assistant professor in the department of radiation oncology at Ohio State University Comprehensive Cancer Center, Columbus. “While the previous studies De-ESCALaTE HPV and RTOG 1016 were specific to HPV [human papillomavirus]-positive cancers, this study allowed non–virally mediated tumors, though the majority of cases were HPV related.”

The new study also used a lower-dose weekly regimen of cisplatin than the other two studies, noted Dr. Jhawar. Early trials used a cisplatin dose of 100 mg/m² every 3 weeks, but “the field is moving toward a dose of 40 mg/m² weekly, the dose use in the Swedish study. This study had an interesting second randomization of radiation dose-escalation for more advanced primary T stage tumors, but because the study ended early it is difficult to fully interpret those results.”

Swedish researchers, led by Maria Gebre-Medhin, MD, PhD, department of hematology, oncology, and radiation physics, Skåne University Hospital, Lund, Sweden, performed an open-label, randomized, controlled, phase 3 study of patients with locoregionally advanced head and neck squamous cell carcinoma. The patients received IV cetuximab 400 mg/m² 1 week before the start of radiation therapy followed by 250 mg/m² per week, or weekly IV cisplatin 40 mg/m² during radiation therapy.

The study results were published in the Journal of Clinical Oncology.

The study was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. The cumulative incidence of locoregional failures at 3 years was more than twice as high in the cetuximab group (23%), compared with the cisplatin group (9%; P = .0036). At 3 years, overall survival was higher in the cisplatin (88%) group than in the cetuximab group (78%), but the difference was not significant (P = .086). The cumulative incidence of distant failures did not differ between the treatment groups, and the toxicity burden was similar.

“Concurrent cisplatin led to improved locoregional control and event-free survival with a trend toward improved overall survival. The types of toxicity were different, as would be expected with the different drug mechanisms, but the rate of toxicity was not,” said Dr. Dr. Jhawar. “Interestingly, the benefit of cisplatin seemed to be limited to patients with p16-positive oropharyngeal cancer. There was clinical equipoise in the p16-negative oropharyngeal cancer group and in the non–oropharyngeal cancer group. The numbers were small, but this is intriguing and suggests that there is more work to be done in this group of patients to tease out if we can escalate or use alternative therapy.”

Cisplatin has been repeatedly proven to be superior in selected populations. The next steps, said Dr. Jhawar, include defining “optimal regimens in cisplatin-ineligible populations based on age, performance status, kidney function, hearing loss, neuropathy, and HIV/AIDS; improvements with new targeted therapies and immunotherapies; and deescalation of systemic and/or radiation regimens in the best outcome groups, such as low-risk HPV-positive patients. And we are going to see more personalized medicine with genetic testing of tumors.”

When patients are ineligible for cisplatin, no optimal regimens have been defined as yet. At Ohio State, Dr. Jhawar and colleagues use carboplatin therapy.

For practicing oncologists, Dr. Jhawar said the bottom line is “patients who are eligible should receive concurrent cisplatin therapy for locoregionally advanced head and neck cancer.”

The ARTSCAN III study was funded by the Swedish Cancer Society and the Mrs. Berta Kamprad Cancer Foundation. One of the study’s coauthors reported a leadership role in ScandiDos. The other authors reported they had no conflicts. Dr. Jhawar reported he had no conflicts of interest.




 

Concurrent cisplatin should remain the standard treatment over cetuximab for patients with locoregionally advanced head and neck squamous cell carcinoma, according to a large comparative phase 3 trial.

Based on the results of an interim analysis of the ARTSCAN III clinical trial, the independent safety data monitoring committee recommended early closure of the study because the results of the study suggest that cetuximab may be inferior to cisplatin.

“This study supports previous retrospective and prospective studies that suggest that concurrent cisplatin with radiation is superior to regimens with concurrent cetuximab in locally advanced head and neck cancers,” commented Sachin Jhawar, MD, MSCI, assistant professor in the department of radiation oncology at Ohio State University Comprehensive Cancer Center, Columbus. “While the previous studies De-ESCALaTE HPV and RTOG 1016 were specific to HPV [human papillomavirus]-positive cancers, this study allowed non–virally mediated tumors, though the majority of cases were HPV related.”

The new study also used a lower-dose weekly regimen of cisplatin than the other two studies, noted Dr. Jhawar. Early trials used a cisplatin dose of 100 mg/m² every 3 weeks, but “the field is moving toward a dose of 40 mg/m² weekly, the dose use in the Swedish study. This study had an interesting second randomization of radiation dose-escalation for more advanced primary T stage tumors, but because the study ended early it is difficult to fully interpret those results.”

Swedish researchers, led by Maria Gebre-Medhin, MD, PhD, department of hematology, oncology, and radiation physics, Skåne University Hospital, Lund, Sweden, performed an open-label, randomized, controlled, phase 3 study of patients with locoregionally advanced head and neck squamous cell carcinoma. The patients received IV cetuximab 400 mg/m² 1 week before the start of radiation therapy followed by 250 mg/m² per week, or weekly IV cisplatin 40 mg/m² during radiation therapy.

The study results were published in the Journal of Clinical Oncology.

The study was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. The cumulative incidence of locoregional failures at 3 years was more than twice as high in the cetuximab group (23%), compared with the cisplatin group (9%; P = .0036). At 3 years, overall survival was higher in the cisplatin (88%) group than in the cetuximab group (78%), but the difference was not significant (P = .086). The cumulative incidence of distant failures did not differ between the treatment groups, and the toxicity burden was similar.

“Concurrent cisplatin led to improved locoregional control and event-free survival with a trend toward improved overall survival. The types of toxicity were different, as would be expected with the different drug mechanisms, but the rate of toxicity was not,” said Dr. Dr. Jhawar. “Interestingly, the benefit of cisplatin seemed to be limited to patients with p16-positive oropharyngeal cancer. There was clinical equipoise in the p16-negative oropharyngeal cancer group and in the non–oropharyngeal cancer group. The numbers were small, but this is intriguing and suggests that there is more work to be done in this group of patients to tease out if we can escalate or use alternative therapy.”

Cisplatin has been repeatedly proven to be superior in selected populations. The next steps, said Dr. Jhawar, include defining “optimal regimens in cisplatin-ineligible populations based on age, performance status, kidney function, hearing loss, neuropathy, and HIV/AIDS; improvements with new targeted therapies and immunotherapies; and deescalation of systemic and/or radiation regimens in the best outcome groups, such as low-risk HPV-positive patients. And we are going to see more personalized medicine with genetic testing of tumors.”

When patients are ineligible for cisplatin, no optimal regimens have been defined as yet. At Ohio State, Dr. Jhawar and colleagues use carboplatin therapy.

For practicing oncologists, Dr. Jhawar said the bottom line is “patients who are eligible should receive concurrent cisplatin therapy for locoregionally advanced head and neck cancer.”

The ARTSCAN III study was funded by the Swedish Cancer Society and the Mrs. Berta Kamprad Cancer Foundation. One of the study’s coauthors reported a leadership role in ScandiDos. The other authors reported they had no conflicts. Dr. Jhawar reported he had no conflicts of interest.




 

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.