To put the CheckMate 914, IMmotion010, and PROSPER trials into context, The ASCO Post spoke with Bernard Escudier, MD, former Chair of the Genitourinary Group of the Institut Gustave Roussy, Villejuif, France. In general, Dr. Escudier believes that studies to date are not robust enough to justify adjuvant immunotherapy in renal cell carcinoma (RCC) as standard of care, and the next logical step is to study neoadjuvant immunotherapy at a time when the tumor is still in the patient’s body.

Bernard Escudier, MD

“Atezolizumab is not as good a drug as pembrolizumab, and this is no big surprise to me. There was a trend, but to me, it is not significant,” he said.

“PROSPER was a study of nivolumab as neoadjuvant and adjuvant therapy. This was a poor trial because it is an academic study, with all the biases you have in the United States for academic trials. A total of 96 patients were lost to follow-up, and there was a high rate of crossover. The study was negative for disease-free survival,” he continued.

“CheckMate 914 was problematic for me because nivolumab/ipilimumab is supposed to be one of the most active combinations. The study was negative for disease-free survival, so, of course, it will be negative for overall survival,” Dr. Escudier said.

“When you have three negative trials in the adjuvant setting, and a fourth that doesn’t show improved overall survival [pembrolizumab], why should we accept the fourth trial? Is pembrolizumab better than the other drugs? This is not likely, because nivolumab is a very good drug. Maybe there was some bias selection in the pembrolizumab trial, but if we don’t see an overall survival benefit, it won’t become the standard of care in the adjuvant setting. We can introduce checkpoint inhibition once the patient becomes metastatic, so why use pembrolizumab as adjuvant therapy?” Dr. Escudier commented.

“We learned that we should probably introduce immunotherapy in the neoadjuvant setting. This will be the next frontier,” he added.

Another Perspective

Brian I. Rini, MD, Professor of Medicine at Vanderbilt University Medical Center, Nashville, had a different interpretation of these studies. “The pembrolizumab trial [KEYNOTE-564] was a well-done, large, positive study for pembrolizumab. It was ‘clean’ for disease-free survival. You can’t throw those results away, but the treatment has risks, and patients may be being overtreated,” Dr. Rini commented.

Brian I. Rini, MD

“The three negative trials are somewhat of a setback. In the IMmotion010 trial, you could explain the results because atezolizumab—a PD-L1 drug—is less active in RCC than pembrolizumab—a PD-1 drug. For PROSPER, there were operational challenges. A lot of participants did not get the intended therapy. At the end of the day, this was not an adequate test of preoperative nivolumab. The CheckMate 914 trial is more difficult to explain. A total of 40% of patients did not get full drug delivery, and immunotherapy was given for 6 months, not 12 months. I don’t have any other adequate explanations for the results,” he stated. 

DISCLOSURE: Dr. Escudier reported financial relationships with Bristol Myers Squibb, EUSA Pharma, Ipsen, Novartis, Oncorena, Pfizer, Roche/Genentech, AVEO, BMS France, and MSD. Dr. Rini reported financial relationships with Pfizer, F. Hoffmann–LaRoche, Incyte, AstraZeneca, Taris, Seattle Genetics, BMS, Mirati, GNE/Roche, Pinoyr Immunotherapeutics, AVEO, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Shionogi, Eisai, Nikang Therapeutics, EUSA, Athenex, Allogene, and Debiopharm.