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Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).
The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.
They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
Why Was This Study Done?
Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.
EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?
Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.
The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.
“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.
Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
What Were the Differences Between the EV and Non-EV Groups?
Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.
The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).
For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.
EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.
“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
What Are the Implications of These Findings?
“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”
Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.
The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.
“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.
They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.
Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.
Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).
The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.
They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
Why Was This Study Done?
Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.
EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?
Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.
The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.
“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.
Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
What Were the Differences Between the EV and Non-EV Groups?
Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.
The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).
For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.
EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.
“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
What Are the Implications of These Findings?
“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”
Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.
The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.
“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.
They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.
Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.
Identifying biomarkers to predict how patients will respond to targeted therapies is crucial to improve treatments for patients with cancer, authors Niklas Klümper, MD, with the Department of Urology and Pediatric Urology at University Hospital Bonn, in Germany, and colleagues, wrote in the Journal of Clinical Oncology (doi: 10.1200/JCO.23.01983).
The researchers used a Nectin-4-specific fluorescence in situ hybridization (FISH) assay in an (m)UC cohort of 108 patients to test Nectin-4’s ability to predict responses, analyzing slides with a fluorescence microscope. The copy number variations (CNVs) were correlated with membranous Nectin-4 protein expression, responses to EV treatment, and outcomes.
They also evaluated the prognostic value of Nectin-4 CNVs with biopsies of 103 (m)UC patients not treated with EV. Additionally, they searched The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for Nectin-4 CNVs.
Why Was This Study Done?
Urothelial carcinoma accounts for 90% of bladder cancer cases globally. Though EV was approved to treat (m)UC in 2019, lasting benefit has been achieved only in a small subset of patients.
EV is given to all without selecting patients based on biomarkers that may predict how well they will respond to EV. In this study, researchers investigated whether response to EV was better when people had amplification — defined as increased numbers of copies — of Nectin-4.
How Common Is It for Patients With (m)UC to Have Nectin-4 Amplifications?
Nectin-4 amplifications happen frequently in (m)UC; they occurred in about 26% of the (m)UC patients the researchers studied, according to the new paper.
The amplifications are frequent in other cancer types as well, and this study suggests that this biomarker is a promising candidate for developing Nectin-4–targeted antibody-drug conjugates for other cancers.
“Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response,” the authors wrote.
Currently, (m)UC is the only cancer for which EV is approved as standard-of-care, the researchers explain, in their paper.
What Were the Differences Between the EV and Non-EV Groups?
Almost all (27 of the 28) patients in the cohort (96%) who had Nectin-4 amplifications had objective responses to EV compared with 24 of 74 (32%) in the group without amplifications (P less than .001). Among the 96% with a response, 82% had partial response and 14% had a complete response.
The amplifications for those treated with EV were linked with longer progression-free survival (90% 12-month PFS vs 41% for those with nonamplified tumors) and longer overall survival (OS).
For those patients treated with EV who had the amplifications, OS was not reached. This was because the researchers could not calculate the OS at 12 months for this group due to more than half of the patients still being alive at that time. That finding contrasts with a median OS of 8.8 months in those patients treated with EV who did not have the amplifications.
EV-treated patients who had Nectin-4 amplifications had a 92% lower risk of death compared with EV-treated patients without the amplifications, according to an analysis that adjusted for factors including age and sex.
“Importantly, in the non–EV-treated patients with (m)UC, Nectin-4 amplifications have no impact on OS [overall survival], suggesting that Nectin-4 amplifications are neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker,” the researchers wrote.
What Are the Implications of These Findings?
“[O]ur study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with (m)UC. The frequent occurrence of Nectin-4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs in a tumor-agnostic context.”
Choosing the best therapy sequence for (m)UC is crucial, the authors write. Considering Nectin-4 amplifications could inform EV drug development — even at earlier stages of the disease — by defining which patient subgroup has the highest chance for long-term benefit.
The authors acknowledge that the primary limitation of the study is that it is retrospective, using archived primary and metastatic tumor specimens with varying ranges between the time of tumor sampling and start of EV treatment.
“Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory,” the authors wrote.
They note that EV plus pembrolizumab [Keytruda] (EV/P) was recently approved as the new standard of care in first-line treatment for (m)UC, so the predictive value of Nectin-4 amplification in this new treatment setting warrants further research.
Dr. Klümper reports stock and other ownership interests in Bicycle Therapeutics, Pfizer, Daiichi Sankyo/UCB Japan, and Immatics; and honoraria for Astellas Pharma and MSD Oncology; and consulting or advisory roles with Astellas Pharma, MSD Oncology, and Eisai. He reports travel reimbursements from Ipsen, Photocure, and MSD Oncology. Other author disclosures are available with the full text of the paper.
FROM JOURNAL OF CLINICAL ONCOLOGY