AVAHO

VANCOUVER – Two multitarget stool tests in development compare favorably for colorectal cancer (CRC) screening in average-risk people, suggest two new studies.

In a blinded, prospective, cross-sectional study, researchers assessed a multitarget stool RNA test (mt-sRNA; Colosense, Geneoscopy) vs. colonoscopy for detection of advanced adenomas and CRC in average-risk individuals aged 45 years and older.

In a prospective, cross-sectional study, investigators evaluated the clinical performance of a next-generation multitarget stool DNA (mt-sDNA; Cologuard, Exact Sciences) and fecal hemoglobin assay for CRC screening in adults aged 40 years and older.

Both studies were presented at the ACG: American College of Gastroenterology 2023 Annual Scientific Meeting.
 

RNA as a biomarker

For CRC-PREVENT, which evaluated the mt-sRNA test, David Lieberman, MD, professor of medicine and former chief of the division of gastroenterology and hepatology at the Oregon Health & Science University, Portland, and colleagues recruited a diverse group of 8,289 adults undergoing colonoscopy at one of more than 3,800 endoscopy centers nationwide. Recruitment included outreach through social media, which could be used to improve future screening rates, Dr. Lieberman said.

The full study findings of CRC-PREVENT were also published online in the Journal of the American Medical Association.

Participants provided stool samples before colonoscopy. Colosense includes a commercially available fecal immunochemical test (FIT) and tests for eight different strands of RNA. The mt-sRNA test results were compared with the colonoscopy results.

The mt-sRNA test had 100% sensitivity for early, stage I cancers, which were detected in 12 patients. Advanced adenomas were detected with an overall sensitivity of 45%. When the advanced adenomas were ≥ 2 cm, sensitivity increased to 51%.

Specificity was 87% among patients with negative findings for hyperplastic polyps or lesions.

The mt-sRNA test showed significant improvements in sensitivity for CRC (94% vs. 77%; P = .029) and advanced adenomas (45% vs 29%; P < .001), when compared with the FIT results alone.

“This is the first large study to include the 45- to 49-year-old population, for whom screening is now recommended,” Dr. Lieberman told this news organization.

Results show a sensitivity of 100% for detecting CRC and 44% for advanced adenomas in this younger age group. That performance is “excellent,” said Dr. Lieberman.

Results also were reliable across all ages.

“The consistent performance across all age groups for whom screening is recommended is a key finding and was totally unknown” before this study, Dr. Lieberman said.

RNA-based testing may have an advantage over DNA biomarker tests, which can be prone to age-related DNA methylation changes, he added.
 

Detection by DNA

Thomas Imperiale, MD, distinguished professor of medicine at Indiana University, Indianapolis, and colleagues conducted the BLUE-C trial to validate the next-generation mt-sDNA test for CRC screening.

The mt-sDNA assay tests for three novel methylated DNA markers and fecal hemoglobin.

Dr. Imperiale and colleagues studied 20,176 adults (mean age, 63 years) scheduled for screening colonoscopy at one of 186 U.S. sites. Participants provided a stool sample for the mt-sDNA test and comparator FIT prior to colonoscopy preparation. They compared results to colonoscopy and FIT findings.

Colonoscopy revealed 98 people with CRC, 2,144 with advanced precancerous lesions, and 17,934 with no advanced neoplasia.

Sensitivity of the mt-sDNA test for detecting CRC was 93.9% (95% confidence interval, 87.1-97.7), advanced precancerous lesions was 43.4% (95% CI, 41.3-45.6), and advanced precancerous lesions with high-grade dysplasia was 74.6% (95% CI, 65.6-82.3).

Sensitivities of the mt-sDNA test for detecting CRC and advanced precancerous lesions were significantly higher than FIT (P < .0001).

In terms of specificity, the mt-sDNA test had a specificity of 90.6% (95% CI, 90.1-91.0) for the absence of advanced neoplasia. Specificity for non-neoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2-93.1).

The mt-sDNA test demonstrated high specificity and high CRC and advanced precancerous lesion sensitivity. The test outperformed FIT for these factors on sensitivity but not specificity, the authors noted.

Improved specificity was a goal of developing this next-generation assay. The BLUE-C trial demonstrated a 30% improvement in specificity that “will decrease the number of unnecessary colonoscopies performed for false-positive results,” said Dr. Imperiale.

“I was pleased to see the robust results support this new battery of markers,” Dr. Imperiale added. Improvements associated with this next-generation test could “help further reduce the incidence of and mortality from colorectal cancer.”
 

Tests to provide more noninvasive options

Both are “important studies” that look at a large, average-risk screening population in the United States, said Aasma Shaukat, MD, MPH, who was not affiliated with the research. “Both show high sensitivity for detecting CRC and decent specificity for advanced adenomas.”

While we will have to wait for the full publications, U.S. Food and Drug Administration approvals, and insurance coverage, gastroenterologists can expect to see these tests in clinical use in the near future, added Dr. Shaukat, professor of medicine and population health at NYU Langone Health, New York, and lead author of the ACG 2021 Colorectal Cancer Screening Guidelines.

These tests provide more noninvasive options for CRC screening and are more accurate, which hopefully will translate into increased screening and a reduced burden of CRC, she said.

“We are always looking for ways to increase colon cancer screening uptake,” said Brooks Cash, MD, professor and chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston, who also was not affiliated with the research.

Certainly, the multitarget stool DNA is not a new concept with Cologuard, but it is a new assay, Dr. Cash said.

“It’s significantly different than their previous version, and they were able to show improved sensitivity as well as specificity, which has been one of the concerns,” he said.

The multitarget stool RNA test “shows very similar results,” Dr. Cash added. “Their predicate is that it’s slightly different and actually may return very good sensitivity for older patients, where you don’t have the same methylation issues with the DNA.”

“It will be interesting to see how they play out,” he added.

“The critical part to all of these tests is that if a patient has a positive test, they need to get a colonoscopy. That doesn’t always happen,” Dr. Cash said. “We have to make sure that there’s appropriate education for not only patients but also providers, many of whom will not be gastroenterologists.”

Geneoscopy funded the CRC-PREVENT trial. Exact Sciences funded the BLUE-C trial. Dr. Lieberman is an advisor or review panel member for Geneoscopy. Dr. Imperiale receives grant or research support from Exact Sciences. Dr. Shaukat reports no relevant financial relationships. Dr. Cash is on the advisory board for Exact Sciences.

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

VANCOUVER – Two multitarget stool tests in development compare favorably for colorectal cancer (CRC) screening in average-risk people, suggest two new studies.

In a blinded, prospective, cross-sectional study, researchers assessed a multitarget stool RNA test (mt-sRNA; Colosense, Geneoscopy) vs. colonoscopy for detection of advanced adenomas and CRC in average-risk individuals aged 45 years and older.

In a prospective, cross-sectional study, investigators evaluated the clinical performance of a next-generation multitarget stool DNA (mt-sDNA; Cologuard, Exact Sciences) and fecal hemoglobin assay for CRC screening in adults aged 40 years and older.

Both studies were presented at the ACG: American College of Gastroenterology 2023 Annual Scientific Meeting.
 

RNA as a biomarker

For CRC-PREVENT, which evaluated the mt-sRNA test, David Lieberman, MD, professor of medicine and former chief of the division of gastroenterology and hepatology at the Oregon Health & Science University, Portland, and colleagues recruited a diverse group of 8,289 adults undergoing colonoscopy at one of more than 3,800 endoscopy centers nationwide. Recruitment included outreach through social media, which could be used to improve future screening rates, Dr. Lieberman said.

The full study findings of CRC-PREVENT were also published online in the Journal of the American Medical Association.

Participants provided stool samples before colonoscopy. Colosense includes a commercially available fecal immunochemical test (FIT) and tests for eight different strands of RNA. The mt-sRNA test results were compared with the colonoscopy results.

The mt-sRNA test had 100% sensitivity for early, stage I cancers, which were detected in 12 patients. Advanced adenomas were detected with an overall sensitivity of 45%. When the advanced adenomas were ≥ 2 cm, sensitivity increased to 51%.

Specificity was 87% among patients with negative findings for hyperplastic polyps or lesions.

The mt-sRNA test showed significant improvements in sensitivity for CRC (94% vs. 77%; P = .029) and advanced adenomas (45% vs 29%; P < .001), when compared with the FIT results alone.

“This is the first large study to include the 45- to 49-year-old population, for whom screening is now recommended,” Dr. Lieberman told this news organization.

Results show a sensitivity of 100% for detecting CRC and 44% for advanced adenomas in this younger age group. That performance is “excellent,” said Dr. Lieberman.

Results also were reliable across all ages.

“The consistent performance across all age groups for whom screening is recommended is a key finding and was totally unknown” before this study, Dr. Lieberman said.

RNA-based testing may have an advantage over DNA biomarker tests, which can be prone to age-related DNA methylation changes, he added.
 

Detection by DNA

Thomas Imperiale, MD, distinguished professor of medicine at Indiana University, Indianapolis, and colleagues conducted the BLUE-C trial to validate the next-generation mt-sDNA test for CRC screening.

The mt-sDNA assay tests for three novel methylated DNA markers and fecal hemoglobin.

Dr. Imperiale and colleagues studied 20,176 adults (mean age, 63 years) scheduled for screening colonoscopy at one of 186 U.S. sites. Participants provided a stool sample for the mt-sDNA test and comparator FIT prior to colonoscopy preparation. They compared results to colonoscopy and FIT findings.

Colonoscopy revealed 98 people with CRC, 2,144 with advanced precancerous lesions, and 17,934 with no advanced neoplasia.

Sensitivity of the mt-sDNA test for detecting CRC was 93.9% (95% confidence interval, 87.1-97.7), advanced precancerous lesions was 43.4% (95% CI, 41.3-45.6), and advanced precancerous lesions with high-grade dysplasia was 74.6% (95% CI, 65.6-82.3).

Sensitivities of the mt-sDNA test for detecting CRC and advanced precancerous lesions were significantly higher than FIT (P < .0001).

In terms of specificity, the mt-sDNA test had a specificity of 90.6% (95% CI, 90.1-91.0) for the absence of advanced neoplasia. Specificity for non-neoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2-93.1).

The mt-sDNA test demonstrated high specificity and high CRC and advanced precancerous lesion sensitivity. The test outperformed FIT for these factors on sensitivity but not specificity, the authors noted.

Improved specificity was a goal of developing this next-generation assay. The BLUE-C trial demonstrated a 30% improvement in specificity that “will decrease the number of unnecessary colonoscopies performed for false-positive results,” said Dr. Imperiale.

“I was pleased to see the robust results support this new battery of markers,” Dr. Imperiale added. Improvements associated with this next-generation test could “help further reduce the incidence of and mortality from colorectal cancer.”
 

Tests to provide more noninvasive options

Both are “important studies” that look at a large, average-risk screening population in the United States, said Aasma Shaukat, MD, MPH, who was not affiliated with the research. “Both show high sensitivity for detecting CRC and decent specificity for advanced adenomas.”

While we will have to wait for the full publications, U.S. Food and Drug Administration approvals, and insurance coverage, gastroenterologists can expect to see these tests in clinical use in the near future, added Dr. Shaukat, professor of medicine and population health at NYU Langone Health, New York, and lead author of the ACG 2021 Colorectal Cancer Screening Guidelines.

These tests provide more noninvasive options for CRC screening and are more accurate, which hopefully will translate into increased screening and a reduced burden of CRC, she said.

“We are always looking for ways to increase colon cancer screening uptake,” said Brooks Cash, MD, professor and chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston, who also was not affiliated with the research.

Certainly, the multitarget stool DNA is not a new concept with Cologuard, but it is a new assay, Dr. Cash said.

“It’s significantly different than their previous version, and they were able to show improved sensitivity as well as specificity, which has been one of the concerns,” he said.

The multitarget stool RNA test “shows very similar results,” Dr. Cash added. “Their predicate is that it’s slightly different and actually may return very good sensitivity for older patients, where you don’t have the same methylation issues with the DNA.”

“It will be interesting to see how they play out,” he added.

“The critical part to all of these tests is that if a patient has a positive test, they need to get a colonoscopy. That doesn’t always happen,” Dr. Cash said. “We have to make sure that there’s appropriate education for not only patients but also providers, many of whom will not be gastroenterologists.”

Geneoscopy funded the CRC-PREVENT trial. Exact Sciences funded the BLUE-C trial. Dr. Lieberman is an advisor or review panel member for Geneoscopy. Dr. Imperiale receives grant or research support from Exact Sciences. Dr. Shaukat reports no relevant financial relationships. Dr. Cash is on the advisory board for Exact Sciences.

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

VANCOUVER – Two multitarget stool tests in development compare favorably for colorectal cancer (CRC) screening in average-risk people, suggest two new studies.

In a blinded, prospective, cross-sectional study, researchers assessed a multitarget stool RNA test (mt-sRNA; Colosense, Geneoscopy) vs. colonoscopy for detection of advanced adenomas and CRC in average-risk individuals aged 45 years and older.

In a prospective, cross-sectional study, investigators evaluated the clinical performance of a next-generation multitarget stool DNA (mt-sDNA; Cologuard, Exact Sciences) and fecal hemoglobin assay for CRC screening in adults aged 40 years and older.

Both studies were presented at the ACG: American College of Gastroenterology 2023 Annual Scientific Meeting.
 

RNA as a biomarker

For CRC-PREVENT, which evaluated the mt-sRNA test, David Lieberman, MD, professor of medicine and former chief of the division of gastroenterology and hepatology at the Oregon Health & Science University, Portland, and colleagues recruited a diverse group of 8,289 adults undergoing colonoscopy at one of more than 3,800 endoscopy centers nationwide. Recruitment included outreach through social media, which could be used to improve future screening rates, Dr. Lieberman said.

The full study findings of CRC-PREVENT were also published online in the Journal of the American Medical Association.

Participants provided stool samples before colonoscopy. Colosense includes a commercially available fecal immunochemical test (FIT) and tests for eight different strands of RNA. The mt-sRNA test results were compared with the colonoscopy results.

The mt-sRNA test had 100% sensitivity for early, stage I cancers, which were detected in 12 patients. Advanced adenomas were detected with an overall sensitivity of 45%. When the advanced adenomas were ≥ 2 cm, sensitivity increased to 51%.

Specificity was 87% among patients with negative findings for hyperplastic polyps or lesions.

The mt-sRNA test showed significant improvements in sensitivity for CRC (94% vs. 77%; P = .029) and advanced adenomas (45% vs 29%; P < .001), when compared with the FIT results alone.

“This is the first large study to include the 45- to 49-year-old population, for whom screening is now recommended,” Dr. Lieberman told this news organization.

Results show a sensitivity of 100% for detecting CRC and 44% for advanced adenomas in this younger age group. That performance is “excellent,” said Dr. Lieberman.

Results also were reliable across all ages.

“The consistent performance across all age groups for whom screening is recommended is a key finding and was totally unknown” before this study, Dr. Lieberman said.

RNA-based testing may have an advantage over DNA biomarker tests, which can be prone to age-related DNA methylation changes, he added.
 

Detection by DNA

Thomas Imperiale, MD, distinguished professor of medicine at Indiana University, Indianapolis, and colleagues conducted the BLUE-C trial to validate the next-generation mt-sDNA test for CRC screening.

The mt-sDNA assay tests for three novel methylated DNA markers and fecal hemoglobin.

Dr. Imperiale and colleagues studied 20,176 adults (mean age, 63 years) scheduled for screening colonoscopy at one of 186 U.S. sites. Participants provided a stool sample for the mt-sDNA test and comparator FIT prior to colonoscopy preparation. They compared results to colonoscopy and FIT findings.

Colonoscopy revealed 98 people with CRC, 2,144 with advanced precancerous lesions, and 17,934 with no advanced neoplasia.

Sensitivity of the mt-sDNA test for detecting CRC was 93.9% (95% confidence interval, 87.1-97.7), advanced precancerous lesions was 43.4% (95% CI, 41.3-45.6), and advanced precancerous lesions with high-grade dysplasia was 74.6% (95% CI, 65.6-82.3).

Sensitivities of the mt-sDNA test for detecting CRC and advanced precancerous lesions were significantly higher than FIT (P < .0001).

In terms of specificity, the mt-sDNA test had a specificity of 90.6% (95% CI, 90.1-91.0) for the absence of advanced neoplasia. Specificity for non-neoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2-93.1).

The mt-sDNA test demonstrated high specificity and high CRC and advanced precancerous lesion sensitivity. The test outperformed FIT for these factors on sensitivity but not specificity, the authors noted.

Improved specificity was a goal of developing this next-generation assay. The BLUE-C trial demonstrated a 30% improvement in specificity that “will decrease the number of unnecessary colonoscopies performed for false-positive results,” said Dr. Imperiale.

“I was pleased to see the robust results support this new battery of markers,” Dr. Imperiale added. Improvements associated with this next-generation test could “help further reduce the incidence of and mortality from colorectal cancer.”
 

Tests to provide more noninvasive options

Both are “important studies” that look at a large, average-risk screening population in the United States, said Aasma Shaukat, MD, MPH, who was not affiliated with the research. “Both show high sensitivity for detecting CRC and decent specificity for advanced adenomas.”

While we will have to wait for the full publications, U.S. Food and Drug Administration approvals, and insurance coverage, gastroenterologists can expect to see these tests in clinical use in the near future, added Dr. Shaukat, professor of medicine and population health at NYU Langone Health, New York, and lead author of the ACG 2021 Colorectal Cancer Screening Guidelines.

These tests provide more noninvasive options for CRC screening and are more accurate, which hopefully will translate into increased screening and a reduced burden of CRC, she said.

“We are always looking for ways to increase colon cancer screening uptake,” said Brooks Cash, MD, professor and chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston, who also was not affiliated with the research.

Certainly, the multitarget stool DNA is not a new concept with Cologuard, but it is a new assay, Dr. Cash said.

“It’s significantly different than their previous version, and they were able to show improved sensitivity as well as specificity, which has been one of the concerns,” he said.

The multitarget stool RNA test “shows very similar results,” Dr. Cash added. “Their predicate is that it’s slightly different and actually may return very good sensitivity for older patients, where you don’t have the same methylation issues with the DNA.”

“It will be interesting to see how they play out,” he added.

“The critical part to all of these tests is that if a patient has a positive test, they need to get a colonoscopy. That doesn’t always happen,” Dr. Cash said. “We have to make sure that there’s appropriate education for not only patients but also providers, many of whom will not be gastroenterologists.”

Geneoscopy funded the CRC-PREVENT trial. Exact Sciences funded the BLUE-C trial. Dr. Lieberman is an advisor or review panel member for Geneoscopy. Dr. Imperiale receives grant or research support from Exact Sciences. Dr. Shaukat reports no relevant financial relationships. Dr. Cash is on the advisory board for Exact Sciences.

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

NEW YORK – Peripheral T-cell lymphomas (PTCL) make up only about 10% of non-Hodgkin lymphomas, yet this disease presents a vexing problem. The majority of patients relapse, but efforts to develop new therapies are stymied by the rarity and genetic varieties of the condition.

University of Nebraska Medical Center

“Over the past 5 years, researchers have gotten a clearer picture of the different subtypes of peripheral T-cell lymphomas, and with this knowledge we are trying to identify potential targets of new treatments. Despite some progress, the need for these new treatments is still acute, due to the disease’s many subtypes and the difficulty of enrolling sufficient numbers of patients in clinical trials,” said Julie M. Vose, MD, MBA, of the University of Nebraska Medical Center, Omaha, speaking at the Lymphoma, Leukemia and Myeloma Congress 2023, in New York. Before her presentation at this year’s conference, Dr. Vose was awarded the SASS-ARENA Foundation’s John Ultmann Award for Major Contributions to Lymphoma Research.

Dr. Vose noted that only one subtype of PTCL, ALK+ ALCL, responds well to frontline treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Patients with the ALK+ ALCL signature treated with CHOP have a 5-year overall survival (OS) rate of 70%-90%, but this group only makes up about 6% of PTCL cases in North America, she added.

One of the most promising breakthroughs in treatment has been the addition of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) to chemotherapy with CHP (cyclophosphamide, doxorubicin, prednisone), Dr. Vose said. Results from the ECHELON-2 trial indicate that CD30+ PTCL patients have improved performance with R-CHP, compared with CHOP; 5-year progression free survival (PFS) rates were 51.4% with R+CHP versus 43.0% with CHOP, and 5-year overall survival rates were 70.1% versus 61.0%, respectively.

“ALCL is one of the most prevalent PTCL subtypes and accounts for about 24% of all PTCL; the current standard-of-care for induction treatment in these patients is BV-CHP,” said Jia Ruan, MD, PhD, of Weill Cornell Medicine in New York. Dr. Ruan explained the limitation of adding BV-CHP, saying “We don’t have as effective biological targeted therapies in other subtypes of T-cell lymphoma, such as PTCL NOS [not-other specified] or angioimmunoblastic T-cell lymphoma.”

There is evidence that autologous stem cell transplant (ACST) can increase PFS and OS in newly diagnosed patients with angioimmunoblastic T-cell lymphoma (AITL), but not in patients with other types of newly diagnosed PTCL. The estimated 2-year OS and PFS for patients with AITL who received ASCT + chemotherapy were 93.3% and 68.8 respectively versus 52.9% and 41.2 in the non-ASCT group. This news is promising, yet Dr. Vose presented statistics indicating that AITL PTCL has been estimated to account for less than 19% of PTCL cases.

Despite the improvements in PFS and OS in a few subtypes for frontline PTCL, 60% of patients with non-ALCL PTCL will relapse, and relapsed/ refractory (R/R) PTCL patients have a median PFS of 9.6 months. Several studies have shown some promise for improving outcomes in R/R PTCL patients, such as the phase-II PRIMO study of duvelisib (a dual PI3K-delta,gamma inhibitor), in which there was an overall response rate of 50% and a complete response rate of 32%. Despite these modest gains, the prognosis for most PTCL patients remains poor. Dr. Vose concluded her presentation by reiterating the need for new agents and for further research. She emphasized that studies will need to be collaborative and international to enroll sufficient patients.

Dr Ruan drew a similar conclusion, noting “We need to increase clinical, translational and basic research on a collaborative scale, so that we can advance bench-to-bedside discovery and bring new treatment to patients quickly.”

Dr. Vose disclosed research funding from Epizyme, GenMab, Kite, Novartis, and Lilly. Dr. Ruan disclosed clinical research trial support from BMS and Daiichi Sankyo.
 

NEW YORK – Peripheral T-cell lymphomas (PTCL) make up only about 10% of non-Hodgkin lymphomas, yet this disease presents a vexing problem. The majority of patients relapse, but efforts to develop new therapies are stymied by the rarity and genetic varieties of the condition.

University of Nebraska Medical Center

“Over the past 5 years, researchers have gotten a clearer picture of the different subtypes of peripheral T-cell lymphomas, and with this knowledge we are trying to identify potential targets of new treatments. Despite some progress, the need for these new treatments is still acute, due to the disease’s many subtypes and the difficulty of enrolling sufficient numbers of patients in clinical trials,” said Julie M. Vose, MD, MBA, of the University of Nebraska Medical Center, Omaha, speaking at the Lymphoma, Leukemia and Myeloma Congress 2023, in New York. Before her presentation at this year’s conference, Dr. Vose was awarded the SASS-ARENA Foundation’s John Ultmann Award for Major Contributions to Lymphoma Research.

Dr. Vose noted that only one subtype of PTCL, ALK+ ALCL, responds well to frontline treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Patients with the ALK+ ALCL signature treated with CHOP have a 5-year overall survival (OS) rate of 70%-90%, but this group only makes up about 6% of PTCL cases in North America, she added.

One of the most promising breakthroughs in treatment has been the addition of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) to chemotherapy with CHP (cyclophosphamide, doxorubicin, prednisone), Dr. Vose said. Results from the ECHELON-2 trial indicate that CD30+ PTCL patients have improved performance with R-CHP, compared with CHOP; 5-year progression free survival (PFS) rates were 51.4% with R+CHP versus 43.0% with CHOP, and 5-year overall survival rates were 70.1% versus 61.0%, respectively.

“ALCL is one of the most prevalent PTCL subtypes and accounts for about 24% of all PTCL; the current standard-of-care for induction treatment in these patients is BV-CHP,” said Jia Ruan, MD, PhD, of Weill Cornell Medicine in New York. Dr. Ruan explained the limitation of adding BV-CHP, saying “We don’t have as effective biological targeted therapies in other subtypes of T-cell lymphoma, such as PTCL NOS [not-other specified] or angioimmunoblastic T-cell lymphoma.”

There is evidence that autologous stem cell transplant (ACST) can increase PFS and OS in newly diagnosed patients with angioimmunoblastic T-cell lymphoma (AITL), but not in patients with other types of newly diagnosed PTCL. The estimated 2-year OS and PFS for patients with AITL who received ASCT + chemotherapy were 93.3% and 68.8 respectively versus 52.9% and 41.2 in the non-ASCT group. This news is promising, yet Dr. Vose presented statistics indicating that AITL PTCL has been estimated to account for less than 19% of PTCL cases.

Despite the improvements in PFS and OS in a few subtypes for frontline PTCL, 60% of patients with non-ALCL PTCL will relapse, and relapsed/ refractory (R/R) PTCL patients have a median PFS of 9.6 months. Several studies have shown some promise for improving outcomes in R/R PTCL patients, such as the phase-II PRIMO study of duvelisib (a dual PI3K-delta,gamma inhibitor), in which there was an overall response rate of 50% and a complete response rate of 32%. Despite these modest gains, the prognosis for most PTCL patients remains poor. Dr. Vose concluded her presentation by reiterating the need for new agents and for further research. She emphasized that studies will need to be collaborative and international to enroll sufficient patients.

Dr Ruan drew a similar conclusion, noting “We need to increase clinical, translational and basic research on a collaborative scale, so that we can advance bench-to-bedside discovery and bring new treatment to patients quickly.”

Dr. Vose disclosed research funding from Epizyme, GenMab, Kite, Novartis, and Lilly. Dr. Ruan disclosed clinical research trial support from BMS and Daiichi Sankyo.
 

NEW YORK – Peripheral T-cell lymphomas (PTCL) make up only about 10% of non-Hodgkin lymphomas, yet this disease presents a vexing problem. The majority of patients relapse, but efforts to develop new therapies are stymied by the rarity and genetic varieties of the condition.

University of Nebraska Medical Center

“Over the past 5 years, researchers have gotten a clearer picture of the different subtypes of peripheral T-cell lymphomas, and with this knowledge we are trying to identify potential targets of new treatments. Despite some progress, the need for these new treatments is still acute, due to the disease’s many subtypes and the difficulty of enrolling sufficient numbers of patients in clinical trials,” said Julie M. Vose, MD, MBA, of the University of Nebraska Medical Center, Omaha, speaking at the Lymphoma, Leukemia and Myeloma Congress 2023, in New York. Before her presentation at this year’s conference, Dr. Vose was awarded the SASS-ARENA Foundation’s John Ultmann Award for Major Contributions to Lymphoma Research.

Dr. Vose noted that only one subtype of PTCL, ALK+ ALCL, responds well to frontline treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Patients with the ALK+ ALCL signature treated with CHOP have a 5-year overall survival (OS) rate of 70%-90%, but this group only makes up about 6% of PTCL cases in North America, she added.

One of the most promising breakthroughs in treatment has been the addition of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) to chemotherapy with CHP (cyclophosphamide, doxorubicin, prednisone), Dr. Vose said. Results from the ECHELON-2 trial indicate that CD30+ PTCL patients have improved performance with R-CHP, compared with CHOP; 5-year progression free survival (PFS) rates were 51.4% with R+CHP versus 43.0% with CHOP, and 5-year overall survival rates were 70.1% versus 61.0%, respectively.

“ALCL is one of the most prevalent PTCL subtypes and accounts for about 24% of all PTCL; the current standard-of-care for induction treatment in these patients is BV-CHP,” said Jia Ruan, MD, PhD, of Weill Cornell Medicine in New York. Dr. Ruan explained the limitation of adding BV-CHP, saying “We don’t have as effective biological targeted therapies in other subtypes of T-cell lymphoma, such as PTCL NOS [not-other specified] or angioimmunoblastic T-cell lymphoma.”

There is evidence that autologous stem cell transplant (ACST) can increase PFS and OS in newly diagnosed patients with angioimmunoblastic T-cell lymphoma (AITL), but not in patients with other types of newly diagnosed PTCL. The estimated 2-year OS and PFS for patients with AITL who received ASCT + chemotherapy were 93.3% and 68.8 respectively versus 52.9% and 41.2 in the non-ASCT group. This news is promising, yet Dr. Vose presented statistics indicating that AITL PTCL has been estimated to account for less than 19% of PTCL cases.

Despite the improvements in PFS and OS in a few subtypes for frontline PTCL, 60% of patients with non-ALCL PTCL will relapse, and relapsed/ refractory (R/R) PTCL patients have a median PFS of 9.6 months. Several studies have shown some promise for improving outcomes in R/R PTCL patients, such as the phase-II PRIMO study of duvelisib (a dual PI3K-delta,gamma inhibitor), in which there was an overall response rate of 50% and a complete response rate of 32%. Despite these modest gains, the prognosis for most PTCL patients remains poor. Dr. Vose concluded her presentation by reiterating the need for new agents and for further research. She emphasized that studies will need to be collaborative and international to enroll sufficient patients.

Dr Ruan drew a similar conclusion, noting “We need to increase clinical, translational and basic research on a collaborative scale, so that we can advance bench-to-bedside discovery and bring new treatment to patients quickly.”

Dr. Vose disclosed research funding from Epizyme, GenMab, Kite, Novartis, and Lilly. Dr. Ruan disclosed clinical research trial support from BMS and Daiichi Sankyo.
 

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

Hormone receptor–positive breast cancer is the most common subtype, with established risk factors including exposure to exogenous hormones, reproductive history, and lifestyle components (alcohol intake, obesity). There are also less-recognized environmental influences that may disrupt endocrine pathways and, as a result, affect tumor development. Fine particulate matter (PM_2.5), produced by combustion processes (vehicles, industrial facilities), burning wood, and fires, among other sources, is composed of various airborne pollutants (metals, organic compounds, ammonium, nitrate, ozone, sulfate, etc.). Prior studies evaluating the association of PM_2.5 and breast cancer development have shown mixed results.^3,4 A prospective US cohort study including 196,905 women without a prior history of breast cancer estimated historical annual average PM_2.5 concentrations between 1980 and 1984 (10 years prior to enrollment) (White et al). A total of 15,870 breast cancer cases were identified, and a 10 μg/m³ increase in PM_2.5 was associated with an 8% increase in overall breast cancer incidence (HR 1.08; 95% CI 1.02-1.13). The association was observed for estrogen-receptor (ER)-positive (HR 1.10; 95% CI 1.04-1.17) but not ER-negative tumors. Future studies focusing on historic exposures, investigating geographic differences and the resultant effect on cancer development, are of interest.

HER2CLIMB was a pivotal phase 3 randomized, double-blinded trial that demonstrated significant improvement in survival outcomes with the combination of tucatinib/trastuzumab/capecitabine vs tucatinib/trastuzumab/placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.⁵ Real-world data help inform our daily practice because patients enrolled in clinical trials do not always accurately represent the general population. A retrospective cohort study including 3449 patients with HER2-positive metastatic breast cancer evaluated outcomes with tucatinib in a real-world setting, demonstrating results similar to those seen in HER2CLIMB. Among all patients who received tucatinib (n = 216), median real-world time to treatment discontinuation was 6.5 months (95% CI 5.4-8.8), median real-world time to next treatment (which can serve as a proxy for progression-free survival) was 8.7 months (95% CI 6.8-10.7), and real-world overall survival was 26.6 months (95% CI 20.2–not reached). Median real-world time to treatment discontinuation was 8.1 months (95% CI 5.7-9.5) for patients who received the approved tucatinib triplet combination after one or more HER2-directed regimens in the metastatic setting and 9.4 months (95% CI 6.3-14.1) for those receiving it in the second- or third-line setting (Kaufman et al). These results support the efficacy of tucatinib in a real-world population, suggesting that earlier use (second or third line) may result in better outcomes. Future studies will continue to address the positioning of tucatinib in the treatment algorithm for HER2-positive metastatic breast cancer, including the evaluation of novel combinations.

Additional References

1. Giuliano AE et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 
2. Bartels SAL, Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565
3. Gabet S, Lemarchand C, Guénel P, Slama R. Breast cancer risk in association with atmospheric pollution exposure: A meta-analysis of effect estimates followed by a health impact assessment. Environ Health Perspect. 2021;129:57012. doi: 10.1289/EHP8419
4. Hvidtfeldt UA et al. Breast cancer incidence in relation to long-term low-level exposure to air pollution in the ELAPSE pooled cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:105-113. doi: 10.1158/1055-9965.EPI-22-0720  
5. Murthy RK et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609

MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

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

MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

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

MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

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

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

A type of B-cell lymphoma called early-stage I primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) has highly favorable survival rates, according to new research presented at the European Society of Medical Oncology (ESMO) Congress 2023. While relapse is common, those rates are significantly lower with radiation therapy.

“Our study represents the largest institutional cohort analysis on the course of patients with stage I POAML,” said first author Linrui Gao, MD, of the department of radiation oncology at the National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College, in Beijing.

Dr. Gao presented these findings at ESMO 2023, held in Madrid.

“We confirm the indolent nature of this stage I disease, with mortality that is similar to the general population and a low rate of lymphoma-attributed mortality,” she said, adding that “radiation therapy was associated with the lowest relapse or disease progression, compared with [other treatments].”

POAML, which can involve lesions in areas including the eyelid, conjunctiva, orbit, and lacrimal gland, makes up about 7% of mucosa-associated lymphoid tissue (MALT) lymphomas. However, the incidence is reported to be steadily increasing. With the majority of patients, 70%-85%, diagnosed as stage I, consensus on treatment approaches is lacking.

Guidelines typically recommend radiation therapy as the standard of care, and approximately 70% of POAML patients do receive the therapy, compared with only about 36% of those with early-stage MALT lymphoma, with the indolent nature of the disease likely weighing on decisions to forgo the treatment, Dr. Gao reported.

“Adoption of initial radiotherapy in early-stage POAML is relatively low worldwide, with possible reasons being [concerns] of a low survival benefit and long-term toxicities,” she said.

To evaluate the long-term outcomes based on baseline clinical features and treatments, Dr. Gao and colleagues conducted a retrospective study of 262 patients with stage I POAML (ipsilateral or bilateral disease), enrolled between January 2000 and December 2020 at two hospitals in China.

Of the patients, who had a median age of 55 and a male-female ratio of 1:3, 82 were initially treated with radiation therapy, 81 with observation, 70 with surgery, and 29 with systemic treatment.

Those receiving radiation therapy had higher rates of an Eastern Cooperative Oncology Group performance status of 1 or higher (P = .02), higher elevations of LDH (P = .03), and higher rates of chronic disease (P < .001), while other baseline characteristics between the groups, including age, T stage, symptom duration, and other factors, were similar.

With a median follow-up of 66 months, the 5-year and 10-year overall survival rates were 96.8% and 90%, respectively, which is similar to the survival rate in the general population in China.

Likewise, the 5- and 10-year rates of lymphoma-specific mortality were both extremely low, at 0.4%, and the corresponding rates of competing nonlymphoma mortality at 5 and 10 years were 2.3% and 4.2%, also consistent with the general population.

The 5- and 10-year mortality rates remained similar to the general population in stratifying patients according to the initial treatment type (P = .767 between treatments).

In terms of recurrence, the overall failure rates were relatively high, with 19.5% of patients experiencing relapse at 5 years and 24.05% at 10 years.

“The failure rates show that the risk of relapse in POAML does not decrease over time,” Dr. Gao said.

Notably, those treated with radiation therapy had a significantly decreased 5-year cumulative risk of failure (8.5%), compared with those who only received observation (29.6%), surgery (22.9%), or systemic treatment (17.2%; overall, P = .002).

The most common failure site was the ipsilateral orbit, and again, rates of those relapses were significantly lower with radiation therapy (2.4%), compared with observation (23.5%), surgery (21.4%), and systemic treatment (17.3%).

However, rates of relapses in other sites, including the contralateral orbit, extraocular site, and multiple sites, were similar among all treatment groups. One patient receiving systemic treatment had large cell transformation, associated with poorer outcomes.

Strategies after recurrence were salvage therapy for 53 patients, including 27 receiving radiation therapy, and observation for 10 patients.

Dr. Gao noted that treatment failure was not associated with higher mortality rates. “However, given the limited number of cases, we think more cases and longer follow-up are needed,” she told MDedge.

Among the most common acute toxicities were ocular dermatitis or mucositis, described as mild, among 23 patients receiving radiation therapy. Nine patients experienced postoperative complications of mild eye irritation and periorbital edema, and five patients receiving systemic treatment experienced grade 2-3 leukopenia. There were no severe adverse events.

In terms of late ocular adverse effects, overall, 3 patients in the radiation therapy group developed cataracts and 143 patients developed dry-eye disease.

“Radiation therapy was associated with the lowest rate of relapse progression, compared with observation, surgery, and systemic treatment, with similar overall and recurrent survival,” Dr. Gao said.

“Based on our study results, radiotherapy should be considered as the optimal treatment for all patients with stage I disease because of its lowest failure risk and minor toxicity,” Dr. Gao told MDedge.

“However, the radiotherapy dose and techniques should be further optimized in good clinical trials,” she noted. “There are some clinical studies undergoing to explore the modern radiotherapy strategy, including by our group.”

Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand, in Dijon, France, noted that “interestingly, radiotherapy reduced the risk of local relapse but not systemic relapse.”


 

Benefits linked to radiation therapy dose?

Furthermore, the study adds to evidence suggesting the role of dose in radiation therapy’s benefits in POAML, Dr. Casanovas noted. He pointed to previous research showing that, with a median radiotherapy dose of 26 Gy, stage I POAML patients had a local relapse rate of 9.5%, whereas in the current study, which reported a median radiotherapy dose of 30.6 Gy, the local relapse rate was just 2%.

“Regarding the risk of local relapse, it’s important to see that, as previous published, the risk of a local relapse depends probably on the dose of radiotherapy,” he said.

The results indicate that “radiation therapy could impact patients’ outcome. In comparison to previous research, this suggests benefits from a higher dose.”

He added that “it would be interesting to test in this series if patients receiving more or less 30 Gy had different outcomes or the risks of failure at different sites.”

Overall, the study confirms that POAML “can be safely treated with radiation therapy, which allows for a better chance of local control, compared with other options, but does not preclude relapse over time,” Dr. Casasnovas concluded, adding, “I think that a standardization of radiotherapy dose is warranted to provide guidelines to clinicians treating this infrequent population of patients.”

The authors had no disclosures to report.

A type of B-cell lymphoma called early-stage I primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) has highly favorable survival rates, according to new research presented at the European Society of Medical Oncology (ESMO) Congress 2023. While relapse is common, those rates are significantly lower with radiation therapy.

“Our study represents the largest institutional cohort analysis on the course of patients with stage I POAML,” said first author Linrui Gao, MD, of the department of radiation oncology at the National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College, in Beijing.

Dr. Gao presented these findings at ESMO 2023, held in Madrid.

“We confirm the indolent nature of this stage I disease, with mortality that is similar to the general population and a low rate of lymphoma-attributed mortality,” she said, adding that “radiation therapy was associated with the lowest relapse or disease progression, compared with [other treatments].”

POAML, which can involve lesions in areas including the eyelid, conjunctiva, orbit, and lacrimal gland, makes up about 7% of mucosa-associated lymphoid tissue (MALT) lymphomas. However, the incidence is reported to be steadily increasing. With the majority of patients, 70%-85%, diagnosed as stage I, consensus on treatment approaches is lacking.

Guidelines typically recommend radiation therapy as the standard of care, and approximately 70% of POAML patients do receive the therapy, compared with only about 36% of those with early-stage MALT lymphoma, with the indolent nature of the disease likely weighing on decisions to forgo the treatment, Dr. Gao reported.

“Adoption of initial radiotherapy in early-stage POAML is relatively low worldwide, with possible reasons being [concerns] of a low survival benefit and long-term toxicities,” she said.

To evaluate the long-term outcomes based on baseline clinical features and treatments, Dr. Gao and colleagues conducted a retrospective study of 262 patients with stage I POAML (ipsilateral or bilateral disease), enrolled between January 2000 and December 2020 at two hospitals in China.

Of the patients, who had a median age of 55 and a male-female ratio of 1:3, 82 were initially treated with radiation therapy, 81 with observation, 70 with surgery, and 29 with systemic treatment.

Those receiving radiation therapy had higher rates of an Eastern Cooperative Oncology Group performance status of 1 or higher (P = .02), higher elevations of LDH (P = .03), and higher rates of chronic disease (P < .001), while other baseline characteristics between the groups, including age, T stage, symptom duration, and other factors, were similar.

With a median follow-up of 66 months, the 5-year and 10-year overall survival rates were 96.8% and 90%, respectively, which is similar to the survival rate in the general population in China.

Likewise, the 5- and 10-year rates of lymphoma-specific mortality were both extremely low, at 0.4%, and the corresponding rates of competing nonlymphoma mortality at 5 and 10 years were 2.3% and 4.2%, also consistent with the general population.

The 5- and 10-year mortality rates remained similar to the general population in stratifying patients according to the initial treatment type (P = .767 between treatments).

In terms of recurrence, the overall failure rates were relatively high, with 19.5% of patients experiencing relapse at 5 years and 24.05% at 10 years.

“The failure rates show that the risk of relapse in POAML does not decrease over time,” Dr. Gao said.

Notably, those treated with radiation therapy had a significantly decreased 5-year cumulative risk of failure (8.5%), compared with those who only received observation (29.6%), surgery (22.9%), or systemic treatment (17.2%; overall, P = .002).

The most common failure site was the ipsilateral orbit, and again, rates of those relapses were significantly lower with radiation therapy (2.4%), compared with observation (23.5%), surgery (21.4%), and systemic treatment (17.3%).

However, rates of relapses in other sites, including the contralateral orbit, extraocular site, and multiple sites, were similar among all treatment groups. One patient receiving systemic treatment had large cell transformation, associated with poorer outcomes.

Strategies after recurrence were salvage therapy for 53 patients, including 27 receiving radiation therapy, and observation for 10 patients.

Dr. Gao noted that treatment failure was not associated with higher mortality rates. “However, given the limited number of cases, we think more cases and longer follow-up are needed,” she told MDedge.

Among the most common acute toxicities were ocular dermatitis or mucositis, described as mild, among 23 patients receiving radiation therapy. Nine patients experienced postoperative complications of mild eye irritation and periorbital edema, and five patients receiving systemic treatment experienced grade 2-3 leukopenia. There were no severe adverse events.

In terms of late ocular adverse effects, overall, 3 patients in the radiation therapy group developed cataracts and 143 patients developed dry-eye disease.

“Radiation therapy was associated with the lowest rate of relapse progression, compared with observation, surgery, and systemic treatment, with similar overall and recurrent survival,” Dr. Gao said.

“Based on our study results, radiotherapy should be considered as the optimal treatment for all patients with stage I disease because of its lowest failure risk and minor toxicity,” Dr. Gao told MDedge.

“However, the radiotherapy dose and techniques should be further optimized in good clinical trials,” she noted. “There are some clinical studies undergoing to explore the modern radiotherapy strategy, including by our group.”

Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand, in Dijon, France, noted that “interestingly, radiotherapy reduced the risk of local relapse but not systemic relapse.”


 

Benefits linked to radiation therapy dose?

Furthermore, the study adds to evidence suggesting the role of dose in radiation therapy’s benefits in POAML, Dr. Casanovas noted. He pointed to previous research showing that, with a median radiotherapy dose of 26 Gy, stage I POAML patients had a local relapse rate of 9.5%, whereas in the current study, which reported a median radiotherapy dose of 30.6 Gy, the local relapse rate was just 2%.

“Regarding the risk of local relapse, it’s important to see that, as previous published, the risk of a local relapse depends probably on the dose of radiotherapy,” he said.

The results indicate that “radiation therapy could impact patients’ outcome. In comparison to previous research, this suggests benefits from a higher dose.”

He added that “it would be interesting to test in this series if patients receiving more or less 30 Gy had different outcomes or the risks of failure at different sites.”

Overall, the study confirms that POAML “can be safely treated with radiation therapy, which allows for a better chance of local control, compared with other options, but does not preclude relapse over time,” Dr. Casasnovas concluded, adding, “I think that a standardization of radiotherapy dose is warranted to provide guidelines to clinicians treating this infrequent population of patients.”

The authors had no disclosures to report.

A type of B-cell lymphoma called early-stage I primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) has highly favorable survival rates, according to new research presented at the European Society of Medical Oncology (ESMO) Congress 2023. While relapse is common, those rates are significantly lower with radiation therapy.

“Our study represents the largest institutional cohort analysis on the course of patients with stage I POAML,” said first author Linrui Gao, MD, of the department of radiation oncology at the National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College, in Beijing.

Dr. Gao presented these findings at ESMO 2023, held in Madrid.

“We confirm the indolent nature of this stage I disease, with mortality that is similar to the general population and a low rate of lymphoma-attributed mortality,” she said, adding that “radiation therapy was associated with the lowest relapse or disease progression, compared with [other treatments].”

POAML, which can involve lesions in areas including the eyelid, conjunctiva, orbit, and lacrimal gland, makes up about 7% of mucosa-associated lymphoid tissue (MALT) lymphomas. However, the incidence is reported to be steadily increasing. With the majority of patients, 70%-85%, diagnosed as stage I, consensus on treatment approaches is lacking.

Guidelines typically recommend radiation therapy as the standard of care, and approximately 70% of POAML patients do receive the therapy, compared with only about 36% of those with early-stage MALT lymphoma, with the indolent nature of the disease likely weighing on decisions to forgo the treatment, Dr. Gao reported.

“Adoption of initial radiotherapy in early-stage POAML is relatively low worldwide, with possible reasons being [concerns] of a low survival benefit and long-term toxicities,” she said.

To evaluate the long-term outcomes based on baseline clinical features and treatments, Dr. Gao and colleagues conducted a retrospective study of 262 patients with stage I POAML (ipsilateral or bilateral disease), enrolled between January 2000 and December 2020 at two hospitals in China.

Of the patients, who had a median age of 55 and a male-female ratio of 1:3, 82 were initially treated with radiation therapy, 81 with observation, 70 with surgery, and 29 with systemic treatment.

Those receiving radiation therapy had higher rates of an Eastern Cooperative Oncology Group performance status of 1 or higher (P = .02), higher elevations of LDH (P = .03), and higher rates of chronic disease (P < .001), while other baseline characteristics between the groups, including age, T stage, symptom duration, and other factors, were similar.

With a median follow-up of 66 months, the 5-year and 10-year overall survival rates were 96.8% and 90%, respectively, which is similar to the survival rate in the general population in China.

Likewise, the 5- and 10-year rates of lymphoma-specific mortality were both extremely low, at 0.4%, and the corresponding rates of competing nonlymphoma mortality at 5 and 10 years were 2.3% and 4.2%, also consistent with the general population.

The 5- and 10-year mortality rates remained similar to the general population in stratifying patients according to the initial treatment type (P = .767 between treatments).

In terms of recurrence, the overall failure rates were relatively high, with 19.5% of patients experiencing relapse at 5 years and 24.05% at 10 years.

“The failure rates show that the risk of relapse in POAML does not decrease over time,” Dr. Gao said.

Notably, those treated with radiation therapy had a significantly decreased 5-year cumulative risk of failure (8.5%), compared with those who only received observation (29.6%), surgery (22.9%), or systemic treatment (17.2%; overall, P = .002).

The most common failure site was the ipsilateral orbit, and again, rates of those relapses were significantly lower with radiation therapy (2.4%), compared with observation (23.5%), surgery (21.4%), and systemic treatment (17.3%).

However, rates of relapses in other sites, including the contralateral orbit, extraocular site, and multiple sites, were similar among all treatment groups. One patient receiving systemic treatment had large cell transformation, associated with poorer outcomes.

Strategies after recurrence were salvage therapy for 53 patients, including 27 receiving radiation therapy, and observation for 10 patients.

Dr. Gao noted that treatment failure was not associated with higher mortality rates. “However, given the limited number of cases, we think more cases and longer follow-up are needed,” she told MDedge.

Among the most common acute toxicities were ocular dermatitis or mucositis, described as mild, among 23 patients receiving radiation therapy. Nine patients experienced postoperative complications of mild eye irritation and periorbital edema, and five patients receiving systemic treatment experienced grade 2-3 leukopenia. There were no severe adverse events.

In terms of late ocular adverse effects, overall, 3 patients in the radiation therapy group developed cataracts and 143 patients developed dry-eye disease.

“Radiation therapy was associated with the lowest rate of relapse progression, compared with observation, surgery, and systemic treatment, with similar overall and recurrent survival,” Dr. Gao said.

“Based on our study results, radiotherapy should be considered as the optimal treatment for all patients with stage I disease because of its lowest failure risk and minor toxicity,” Dr. Gao told MDedge.

“However, the radiotherapy dose and techniques should be further optimized in good clinical trials,” she noted. “There are some clinical studies undergoing to explore the modern radiotherapy strategy, including by our group.”

Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand, in Dijon, France, noted that “interestingly, radiotherapy reduced the risk of local relapse but not systemic relapse.”


 

Benefits linked to radiation therapy dose?

Furthermore, the study adds to evidence suggesting the role of dose in radiation therapy’s benefits in POAML, Dr. Casanovas noted. He pointed to previous research showing that, with a median radiotherapy dose of 26 Gy, stage I POAML patients had a local relapse rate of 9.5%, whereas in the current study, which reported a median radiotherapy dose of 30.6 Gy, the local relapse rate was just 2%.

“Regarding the risk of local relapse, it’s important to see that, as previous published, the risk of a local relapse depends probably on the dose of radiotherapy,” he said.

The results indicate that “radiation therapy could impact patients’ outcome. In comparison to previous research, this suggests benefits from a higher dose.”

He added that “it would be interesting to test in this series if patients receiving more or less 30 Gy had different outcomes or the risks of failure at different sites.”

Overall, the study confirms that POAML “can be safely treated with radiation therapy, which allows for a better chance of local control, compared with other options, but does not preclude relapse over time,” Dr. Casasnovas concluded, adding, “I think that a standardization of radiotherapy dose is warranted to provide guidelines to clinicians treating this infrequent population of patients.”

The authors had no disclosures to report.

Which conditions are caused by infection? Though it may seem like an amateur concern in the era of advanced microscopy, some culprits evade conventional methods of detection. Large medical databases hold the power to unlock answers. 

A recent study from Sweden and Denmark meticulously traced the lives and medical histories of nearly one million men and women in those countries who had received blood transfusions over nearly five decades. Some of these patients later experienced brain bleeds. The inescapable question: Could a virus found in some donor blood have caused the hemorrhages?

Traditionally, brain bleeds have been thought to strike at random. But the new study, published in JAMA, points toward an infection that causes or, at the very least, is linked to the condition. The researchers used a large databank to make the discovery. 

“As health data becomes more available and easier to analyze, we’ll see all kinds of cases like this,” said Jingcheng Zhao, MD, of the clinical epidemiology division of Sweden’s Karolinska Institutet in Solna and lead author of the study.

Scientists say the field of medical research is on the cusp of a revolution as immense health databases guide discovery and improve clinical care. 

“If you can aggregate data, you have the statistical power to identify associations,” said David R. Crosslin, PhD, professor in the division of biomedical informatics and genomics at Tulane University in New Orleans. “It opens up the world for understanding diseases.”

With access to the large database, Dr. Zhao and his team found that some blood donors later experienced brain bleeds. And it turned out that the recipients of blood from those same donors carried the highest risk of experiencing a brain bleed later in life. Meanwhile, patients whose donors remained bleed-free had the lowest risk.
 

Not so fast in the United States

In Nordic countries, all hospitals, clinics, and pharmacies report data on diagnoses and health care visits to the government, tracking that began with paper and pen in the 1960s. But the United States health care system is too fragmented to replicate such efforts, with several brands of electronic medical records operating across different systems. Data sharing across institutions is minimal. 

Most comparable health data in the United States comes from reimbursement information collected by the Centers for Medicare & Medicaid Services on government-sponsored insurance programs.

“We would need all the health care systems in the country to operate within the same IT system or use the same data model,” said Euan Ashley, MD, PhD, professor of genomics at Stanford (Calif.) University. “It’s an exciting prospect. But I think [the United States] is one of the last countries where it’ll happen.”

States, meanwhile, collect health data on specific areas like sexually transmitted infection cases and rates. Other states have registries, like the Connecticut Tumor Registry, which was established in 1941 and is the oldest population-based cancer registry in the world.

But all of these efforts are ad hoc, and no equivalent exists for heart disease and other conditions.

Health data companies have recently entered the U.S. data industry mainly through partnerships with health systems and insurance companies, using deidentified information from patient charts.

The large databases have yielded important findings that randomized clinical trials simply cannot, according to Dr. Ashley.

For instance, a study found that a heavily-lauded immunotherapy treatment did not provide meaningful outcomes for patients aged 75 years or older, but it did for younger patients.

This sort of analysis might enable clinicians to administer treatments based on how effective they are for patients with particular demographics, according to Cary Gross, MD, professor at Yale University in New Haven, Conn.

“From a bedside standpoint, these large databases can identify who benefits from what,” Dr. Gross said. “Precision medicine is not just about genetic tailoring.” These large datasets also provide insight into genetic and environmental variables that contribute to disease. 

For instance, the UK Biobank has more than 500,000 participants paired with their medical records and scans of their body and brain. Researchers perform cognitive tests on participants and extract DNA from blood samples over their lifetime, allowing examination of interactions between risk factors. 

A similar but much smaller-scale effort underway in the United States, called the All of Us Research Program, has enrolled more than 650,000 people, less than one-third the size of the UK Biobank by relative populations. The goal of the program is to provide insights into prevention and treatment of chronic disease among a diverse set of at least one million participants. The database includes information on sexual orientation, which is a fairly new datapoint collected by researchers in an effort to study health outcomes and inequities among the LGBTQ+ community.

Dr. Crosslin and his colleagues are writing a grant proposal to use the All of Us database to identify genetic risks for preeclampsia. People with certain genetic profiles may be predisposed to the life-threatening condition, and researchers may discover that lifestyle changes could decrease risk, Dr. Crosslin said. 
 

Changes in the United States

The COVID-19 pandemic exposed the lack of centralized data in the United States because a majority of research on the virus has been conducted abroad in countries with national health care systems and these large databases. 

The U.S. gap spurred a group of researchers to create the National Institutes of Health–funded National COVID Cohort Collaborative (N3C), a project that gathers medical records from millions of patients across health systems and provides access to research teams investigating a wide spectrum of topics, such as optimal timing for ventilator use.

But until government or private health systems develop a way to share and regulate health data ethically and efficiently, significant limits will persist on what large-scale databases can do, Dr. Gross said. 

“At the federal level, we need to ensure this health information is made available for public health researchers so we don’t create these private fiefdoms of data,” Dr. Gross said. “Things have to be transparent. I think our country needs to take a step back and think about what we’re doing with our health data and how we can make sure it’s being managed ethically.”

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

Which conditions are caused by infection? Though it may seem like an amateur concern in the era of advanced microscopy, some culprits evade conventional methods of detection. Large medical databases hold the power to unlock answers. 

A recent study from Sweden and Denmark meticulously traced the lives and medical histories of nearly one million men and women in those countries who had received blood transfusions over nearly five decades. Some of these patients later experienced brain bleeds. The inescapable question: Could a virus found in some donor blood have caused the hemorrhages?

Traditionally, brain bleeds have been thought to strike at random. But the new study, published in JAMA, points toward an infection that causes or, at the very least, is linked to the condition. The researchers used a large databank to make the discovery. 

“As health data becomes more available and easier to analyze, we’ll see all kinds of cases like this,” said Jingcheng Zhao, MD, of the clinical epidemiology division of Sweden’s Karolinska Institutet in Solna and lead author of the study.

Scientists say the field of medical research is on the cusp of a revolution as immense health databases guide discovery and improve clinical care. 

“If you can aggregate data, you have the statistical power to identify associations,” said David R. Crosslin, PhD, professor in the division of biomedical informatics and genomics at Tulane University in New Orleans. “It opens up the world for understanding diseases.”

With access to the large database, Dr. Zhao and his team found that some blood donors later experienced brain bleeds. And it turned out that the recipients of blood from those same donors carried the highest risk of experiencing a brain bleed later in life. Meanwhile, patients whose donors remained bleed-free had the lowest risk.
 

Not so fast in the United States

In Nordic countries, all hospitals, clinics, and pharmacies report data on diagnoses and health care visits to the government, tracking that began with paper and pen in the 1960s. But the United States health care system is too fragmented to replicate such efforts, with several brands of electronic medical records operating across different systems. Data sharing across institutions is minimal. 

Most comparable health data in the United States comes from reimbursement information collected by the Centers for Medicare & Medicaid Services on government-sponsored insurance programs.

“We would need all the health care systems in the country to operate within the same IT system or use the same data model,” said Euan Ashley, MD, PhD, professor of genomics at Stanford (Calif.) University. “It’s an exciting prospect. But I think [the United States] is one of the last countries where it’ll happen.”

States, meanwhile, collect health data on specific areas like sexually transmitted infection cases and rates. Other states have registries, like the Connecticut Tumor Registry, which was established in 1941 and is the oldest population-based cancer registry in the world.

But all of these efforts are ad hoc, and no equivalent exists for heart disease and other conditions.

Health data companies have recently entered the U.S. data industry mainly through partnerships with health systems and insurance companies, using deidentified information from patient charts.

The large databases have yielded important findings that randomized clinical trials simply cannot, according to Dr. Ashley.

For instance, a study found that a heavily-lauded immunotherapy treatment did not provide meaningful outcomes for patients aged 75 years or older, but it did for younger patients.

This sort of analysis might enable clinicians to administer treatments based on how effective they are for patients with particular demographics, according to Cary Gross, MD, professor at Yale University in New Haven, Conn.

“From a bedside standpoint, these large databases can identify who benefits from what,” Dr. Gross said. “Precision medicine is not just about genetic tailoring.” These large datasets also provide insight into genetic and environmental variables that contribute to disease. 

For instance, the UK Biobank has more than 500,000 participants paired with their medical records and scans of their body and brain. Researchers perform cognitive tests on participants and extract DNA from blood samples over their lifetime, allowing examination of interactions between risk factors. 

A similar but much smaller-scale effort underway in the United States, called the All of Us Research Program, has enrolled more than 650,000 people, less than one-third the size of the UK Biobank by relative populations. The goal of the program is to provide insights into prevention and treatment of chronic disease among a diverse set of at least one million participants. The database includes information on sexual orientation, which is a fairly new datapoint collected by researchers in an effort to study health outcomes and inequities among the LGBTQ+ community.

Dr. Crosslin and his colleagues are writing a grant proposal to use the All of Us database to identify genetic risks for preeclampsia. People with certain genetic profiles may be predisposed to the life-threatening condition, and researchers may discover that lifestyle changes could decrease risk, Dr. Crosslin said. 
 

Changes in the United States

The COVID-19 pandemic exposed the lack of centralized data in the United States because a majority of research on the virus has been conducted abroad in countries with national health care systems and these large databases. 

The U.S. gap spurred a group of researchers to create the National Institutes of Health–funded National COVID Cohort Collaborative (N3C), a project that gathers medical records from millions of patients across health systems and provides access to research teams investigating a wide spectrum of topics, such as optimal timing for ventilator use.

But until government or private health systems develop a way to share and regulate health data ethically and efficiently, significant limits will persist on what large-scale databases can do, Dr. Gross said. 

“At the federal level, we need to ensure this health information is made available for public health researchers so we don’t create these private fiefdoms of data,” Dr. Gross said. “Things have to be transparent. I think our country needs to take a step back and think about what we’re doing with our health data and how we can make sure it’s being managed ethically.”

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

Which conditions are caused by infection? Though it may seem like an amateur concern in the era of advanced microscopy, some culprits evade conventional methods of detection. Large medical databases hold the power to unlock answers. 

A recent study from Sweden and Denmark meticulously traced the lives and medical histories of nearly one million men and women in those countries who had received blood transfusions over nearly five decades. Some of these patients later experienced brain bleeds. The inescapable question: Could a virus found in some donor blood have caused the hemorrhages?

Traditionally, brain bleeds have been thought to strike at random. But the new study, published in JAMA, points toward an infection that causes or, at the very least, is linked to the condition. The researchers used a large databank to make the discovery. 

“As health data becomes more available and easier to analyze, we’ll see all kinds of cases like this,” said Jingcheng Zhao, MD, of the clinical epidemiology division of Sweden’s Karolinska Institutet in Solna and lead author of the study.

Scientists say the field of medical research is on the cusp of a revolution as immense health databases guide discovery and improve clinical care. 

“If you can aggregate data, you have the statistical power to identify associations,” said David R. Crosslin, PhD, professor in the division of biomedical informatics and genomics at Tulane University in New Orleans. “It opens up the world for understanding diseases.”

With access to the large database, Dr. Zhao and his team found that some blood donors later experienced brain bleeds. And it turned out that the recipients of blood from those same donors carried the highest risk of experiencing a brain bleed later in life. Meanwhile, patients whose donors remained bleed-free had the lowest risk.
 

Not so fast in the United States

In Nordic countries, all hospitals, clinics, and pharmacies report data on diagnoses and health care visits to the government, tracking that began with paper and pen in the 1960s. But the United States health care system is too fragmented to replicate such efforts, with several brands of electronic medical records operating across different systems. Data sharing across institutions is minimal. 

Most comparable health data in the United States comes from reimbursement information collected by the Centers for Medicare & Medicaid Services on government-sponsored insurance programs.

“We would need all the health care systems in the country to operate within the same IT system or use the same data model,” said Euan Ashley, MD, PhD, professor of genomics at Stanford (Calif.) University. “It’s an exciting prospect. But I think [the United States] is one of the last countries where it’ll happen.”

States, meanwhile, collect health data on specific areas like sexually transmitted infection cases and rates. Other states have registries, like the Connecticut Tumor Registry, which was established in 1941 and is the oldest population-based cancer registry in the world.

But all of these efforts are ad hoc, and no equivalent exists for heart disease and other conditions.

Health data companies have recently entered the U.S. data industry mainly through partnerships with health systems and insurance companies, using deidentified information from patient charts.

The large databases have yielded important findings that randomized clinical trials simply cannot, according to Dr. Ashley.

For instance, a study found that a heavily-lauded immunotherapy treatment did not provide meaningful outcomes for patients aged 75 years or older, but it did for younger patients.

This sort of analysis might enable clinicians to administer treatments based on how effective they are for patients with particular demographics, according to Cary Gross, MD, professor at Yale University in New Haven, Conn.

“From a bedside standpoint, these large databases can identify who benefits from what,” Dr. Gross said. “Precision medicine is not just about genetic tailoring.” These large datasets also provide insight into genetic and environmental variables that contribute to disease. 

For instance, the UK Biobank has more than 500,000 participants paired with their medical records and scans of their body and brain. Researchers perform cognitive tests on participants and extract DNA from blood samples over their lifetime, allowing examination of interactions between risk factors. 

A similar but much smaller-scale effort underway in the United States, called the All of Us Research Program, has enrolled more than 650,000 people, less than one-third the size of the UK Biobank by relative populations. The goal of the program is to provide insights into prevention and treatment of chronic disease among a diverse set of at least one million participants. The database includes information on sexual orientation, which is a fairly new datapoint collected by researchers in an effort to study health outcomes and inequities among the LGBTQ+ community.

Dr. Crosslin and his colleagues are writing a grant proposal to use the All of Us database to identify genetic risks for preeclampsia. People with certain genetic profiles may be predisposed to the life-threatening condition, and researchers may discover that lifestyle changes could decrease risk, Dr. Crosslin said. 
 

Changes in the United States

The COVID-19 pandemic exposed the lack of centralized data in the United States because a majority of research on the virus has been conducted abroad in countries with national health care systems and these large databases. 

The U.S. gap spurred a group of researchers to create the National Institutes of Health–funded National COVID Cohort Collaborative (N3C), a project that gathers medical records from millions of patients across health systems and provides access to research teams investigating a wide spectrum of topics, such as optimal timing for ventilator use.

But until government or private health systems develop a way to share and regulate health data ethically and efficiently, significant limits will persist on what large-scale databases can do, Dr. Gross said. 

“At the federal level, we need to ensure this health information is made available for public health researchers so we don’t create these private fiefdoms of data,” Dr. Gross said. “Things have to be transparent. I think our country needs to take a step back and think about what we’re doing with our health data and how we can make sure it’s being managed ethically.”

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

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.