Three negative phase III trials presented at the European Society for Medical Oncology (ESMO) Congress 2022 may dampen enthusiasm for immunotherapy as adjuvant therapy for renal cell carcinoma (RCC). None of the three trials—CheckMate 914, IMmotion010, and PROSPER—met its primary endpoint.1-3 The trials differ from each other somewhat in design: CheckMate 914 evaluated adjuvant nivolumab and nivolumab/ipilimumab; IMmotion010 evaluated adjuvant atezolizumab; and PROSPER evaluated neoadjuvant plus adjuvant nivolumab.
Adjuvant trials in RCC have been mainly disappointing using VEGF tyrosine kinase inhibitors. KEYNOTE-564 showed improved disease-free survival for adjuvant pembrolizumab and was the first immunotherapy trial to be positive in this setting.4 Pembrolizumab is now approved as adjuvant therapy for RCC based on KEYNOTE-564.
CheckMate 914
“The safety of nivolumab/ipilimumab was consistent with the known profile for the combination in metastatic RCC. But the rate of treatment discontinuations due to adverse events was considerable with nivolumab/ipilimumab in the adjuvant setting. Part B of the trial investigating nivolumab monotherapy is ongoing,” said lead author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York.
Robert J. Motzer, MD
Standard treatment of localized nonmetastatic RCC stage I–III is radical or partial nephrectomy. After undergoing surgery, patients with stage II–III disease still have a high risk of relapse. The approved options for adjuvant therapy to reduce the risk of relapse are sunitinib and pembrolizumab, the only approved immunotherapy in this setting.
CheckMate 914 had two parts. Part A evaluated nivolumab/ipilimumab vs placebo following complete resection. The primary objective of part B evaluated nivolumab alone vs placebo, and these results will be presented in the future. Dr. Motzer focused on Part A, which included 816 patients with high-risk nonmetastatic RCC following radical or partial nephrectomy and negative surgical margins. Patients were randomly assigned 1:1 to nivolumab/ipilimumab vs placebo, with an expected treatment duration of 24 weeks or 6 months but could be treated for up to 36 weeks if there were treatment delays.
Baseline characteristics were balanced in the two arms. More than 90% had a radical nephrectomy. Most patients (75%–80%) had stage pT3 disease. PD-L1 levels were analyzed, but results are yet not available, Dr. Motzer said.
The endpoint of disease-free survival was not met. Median disease-free survival was not reached for nivolumab/ipilimumab and was 58 months for placebo. The 24-month disease-free survival rate was 78% with nivolumab/ipilimumab and 74% with placebo. Overall survival was not analyzed.
There was no difference in disease-free survival between treatment arms across most subgroups, but a trend toward improvement was observed for nivolumab/ipilimumab in the 20% of patients with a disease stage other than pT3. Also, nivolumab/ipilimumab appeared more effective in the 5% of patients with sarcomatoid features, but this was in small numbers of patients.
Even with a short 6-month course of treatment with nivolumab/ipilimumab, higher rates of adverse events, treatment-related adverse events, and treatment discontinuations due to toxicity were reported in the nivolumab/ipilimumab arm vs placebo. Adverse events of any grade were reported in 88.9% of the nivolumab/ipilimumab arm vs 56.8% of the placebo arm. The rate of discontinuation due to toxicity was 29% in the nivolumab/ipilimumab arm—higher than expected—vs 1% on placebo. The most common treatment-related adverse events were pruritus, diarrhea, fatigue, and rash.
“I was very disappointed this didn’t read out positive. I thought it was going to, based on the high level of benefit we see for patients treated with this combination for advanced, metastatic RCC, but probably the tolerability of the combination in the adjuvant setting may have been a factor here,” Dr. Motzer said.
IMmotion010
Adjuvant therapy with atezolizumab failed to improve disease-free survival compared with placebo in patients with RCC at high risk of recurrence, according to the results of the phase III IMmotion010 trial.2 At a median follow-up of 44.7 months, the median investigator-assessed disease-free survival was 57.2 months with atezolizumab compared with 49.5 months with placebo. At 2 years, the rate of disease-free survival was 67% for atezolizumab vs 65% for placebo.
Axel Bex, MD, PhD
“There was no evidence that atezolizumab reduced the risk of recurrence vs placebo, and there was no evidence of reduction in the risk of death with atezolizumab,” said presenting author Axel Bex, MD, PhD, of the Royal Free London NHS Foundation Trust and UCL Division of Surgery and Interventional Science, Netherlands/UK. The study was published in TheLancet to coincide with Dr. Bex’s presentation.5
IMmotion010 was a randomized, double-blind, phase III trial conducted at 215 clinical sites in 28 countries. Starting in 2017, the 778 enrolled patients had clear cell RCC or a sarcomatoid component and were at increased risk of recurrence after nephrectomy with or without metastasectomy. At baseline, median patient age was 60. Overall, 79% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. A total of 64% of patients had stage T2 or T3a disease. A total of 40% of patients had PD-L1–negative tumors.
Patients were randomly assigned in a 1:1 ratio to adjuvant therapy with atezolizumab at 1,200 mg (n = 390) once every 3 weeks for 16 cycles or 1 year or matching placebo (n = 388). The primary endpoint was investigator-assessed disease-free survival in the intention-to-treat population.
Atezolizumab was reported to be well tolerated, and safety results were consistent with the known safety profile of atezolizumab. The most frequently reported grade 3 or 4 adverse events were hypertension, hyperglycemia, and diarrhea. Serious adverse events were reported in 18% (n = 69) of the atezolizumab arm and 12% (n = 46) of the placebo arm. No treatment-related deaths were reported.
Given the discordant results of studies of adjuvant immunotherapy with checkpoint inhibitors, further studies are needed to clarify the role of adjuvant immunotherapy in RCC, Dr. Bex noted.
PROSPER Trial
The phase III, randomized, open-label, controlled PROSPER trial differed in design from the other two trials discussed here. PROSPER compared perioperative nivolumab vs surgery alone in patients with RCC undergoing nephrectomy.
“This nivolumab study is very, very different,” said the formal discussant of PROSPER, Thomas Powles, MD, PhD, Director of Barts Cancer Centre at St. Bartholomew’s Hospital, London. “To get into it, you had to have a radiology definition, not a pathology definition. That means there were a lot more low-risk patients. It’s an open-label trial, so patients knew what they were getting, and that could influence disease-free survival. The investigator-assessed disease-free survival included those patients who didn’t have surgery.”
Thomas Powles, MD, PhD
PROSPER randomly assigned 819 patients to perioperative nivolumab (n = 404) or surgery alone (n = 415). The trial was stopped early due to futility, and median follow-up was 16 months. The median recurrence-free survival was not reached, and overall survival data, though not mature, did not point toward a difference. According to Dr. Powles, the 16-month follow-up is short for an adjuvant trial.
Despite these negative trials, correlative research may identify patients who can benefit from these approaches. “I think we’re in the early days [of adjuvant immunotherapy in RCC], but at least there’s some hope now for patients,” said Dr. Motzer.
DISCLOSURE: CheckMate 914 was sponsored by Bristol Myers Squibb and Ono Pharmaceuticals; IMmotion010, by F. Hoffmann–La Roche; PROSPER, by the National Cancer Institute and the Canadian Cancer Society. Dr. Motzer reported relationships with AstraZeneca, AVEO, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, Pfizer, and Bristol Myers Squibb. Dr. Bex reported relationships with F. Hoffmann–La Roche, Bristol Myers Squibb, and Pfizer. Dr. Powles reported relationships with AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and MSD.
REFERENCES
1. Motzer R, Gruenwald V, Tomita Y, et al: ESMO Congress 2022. Abstract LBA4.
2. Bex A, Uzzo R, Karam JA, et al: ESMO Congress 2022. Abstract LBA66.
3. Allaf M, Kim SE, Harshman LC, et al: ESMO Congress 2022. Abstract LBA67.
4. Choueiri T, Tomczak P, Park SH, et al: N Engl J Med 385:683-694, 2021.
5. Pal S, Uzzo R, Karam JA, et al: Lancet 400:1103-1116, 2022.
