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Expert Point of View: Daniel Y. Heng, MD, MPH, and Toni K. Choueiri, MD


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Study discussant Daniel Y. Heng, MD, MPH, a medical oncologist at Tom Baker Cancer Centre, University of Calgary, Canada, called the negative trial results important.

IMvigor010 randomly assigned patients with high-risk muscle-invasive urothelial carcinoma to adjuvant atezolizumab or observation after radical cystectomy or nephrectomy. “The study was negative for the primary endpoint of disease-free survival, even in the subgroup analysis of patients with PD-L1–positive disease. All subgroups were negative for a benefit from atezolizumab,” Dr. Heng noted. “Overall, there is currently no role for adjuvant atezolizu­mab for muscle-invasive urothelial carcinoma.”

According to Dr. Heng, the question centers on why PD-L1 therapy is beneficial in the metastatic setting and not in the adjuvant setting in muscle-invasive urothelial carcinoma. “Perhaps there needs to be tumor in situ in order for the immune system to have something to potentiate,” said Dr. Heng. “In situations where the tumor is already removed, perhaps the lack of neoantigens make the checkpoint inhibitor less effective.”

Daniel Y. Heng, MD, MPH

Daniel Y. Heng, MD, MPH

Toni K. Choueiri, MD

Toni K. Choueiri, MD

In IMvigor010, 48% of patients had neoadjuvant therapy, and there was no difference favoring atezolizumab, Dr. Heng continued. “There may be a slight benefit in those with T4 disease, but only a small number of patients were in this subgroup. This might be a space to watch in future clinical trials. Perhaps patients at higher risk will benefit.”

Further Commentary

“Unfortunately, IMvigor010 was a completely negative trial. No disease-free survival benefit was found for adjuvant atezolizumab,” said Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston. “Adjuvant single-agent atezolizumab is not advised in unselected muscle-invasive urothelial carcinoma, despite there being more than 50% of high-risk patients in this trial…. The trend is interesting, favoring some benefit for pN0 subsets. However, I would not recommend atezolizumab for this subgroup either.”

When asked how to identify patients at the highest risk of recurrence beyond imaging with computed tomography, Dr. Choueiri commented: “One possible approach is circulating methylated DNA immunoprecipitation with high throughput sequencing for residual disease in tumor or tissue. This technique appears to be able to identify patients with negative imaging and microscopic disease.”

“We also need to find the best biomarker for atezolizumab and other PD-L1 monotherapies,” Dr. Choueiri indicated. “Until we have that, we need to support adjuvant trials in high-risk patients, such as the AMBASSADOR trial.” 

DISCLOSURE: Dr. Heng has served as a consultant or advisor to Astellas Pharma, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, and Roche and has received institutional research funding from Bristol-Myers Squibb, Exelixis, Ipsen, Novartis, and Pfizer. Dr. Choueiri owns stock or other ownership interests in Pionyr and Tempest; has received honoraria from Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, the National Comprehensive Cancer Network, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; has served as a consultant or advisor to Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, European Society for Medical Oncology, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer, The Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, the National Comprehensive Cancer Network, The New England Journal of Medicine, Novartis, PlatformQ Health, Peloton Therapeutics, Pfizer, Prometheus Laboratories, Roche/Genentech, Sanofi/Aventis, and UpToDate; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera Biosciences, CDMRP/ DOD, Celldex, Cerulean Pharma, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, GATEWAY for Cancer Research, GlaxoSmithKline, Ipsen, Merck, the National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds a patent entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy” and a patent entitled “PBRM1 Biomarkers Predictive of Anti-immune Checkpoint Response”; has been reimbursed for travel, accommodations, or other expenses “in relation to consultancy/ad boards”; and has held other relationships with ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel.

 


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