Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: The CheckMate 914 trial does not demonstrate a disease-free survival (DFS) benefit with the use of nivolumab plus ipilimumab in patients who have successfully undergone nephrectomy for localised renal cell carcinoma (RCC) but are at high risk of relapse, delegates have been told at the ESMO Congress 2022 in Paris, France.
Presenting author Robert Motzer, from Memorial Sloan Kettering Cancer Center in New York, USA, reported the part A results for the phase III trial, focusing on the 405 patients who were randomly assigned to receive a 24-week regimen of adjuvant nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks and the 411 patients instead given placebo.
The patients all had negative surgical margins after radical or partial nephrectomy, a good ECOG performance status, predominantly clear cell histology and pathological staging of pT2a, G3/4, N0 M0 to pT any, G any, N1 M0.
After a median 37.0 months of follow-up, median DFS by blinded independent central review was unreached in the combination arm and 50.7 months with placebo, giving a nonsignificant hazard ratio (HR) of 0.92; identical to that found in the investigator-assessed analysis.
The 24-month rate of DFS was 76.4% with nivolumab plus ipilimumab and 74.0% with placebo, the presenter said.
Robert Motzer noted that the median duration of treatment was 5.1 months in both arms and that just 57% of patients in the active treatment arm completed all 12 nivolumab and four ipilimumab doses, compared with 89% of those given placebo.
Although the safety of nivolumab plus ipilimumab “was consistent with the known profile for this combination in advanced RCC”, the presenter emphasized that a third of patients discontinued the combination due to toxicity compared with 1% of controls.
Grade 3 or more severe treatment-related adverse events (AEs) occurred in 28% and 2% of patients in the nivolumab plus ipilimumab and placebo arms, respectively, and a “considerable” 29% and 1% of patients, respectively, discontinued treatment because of these toxicities, he observed.
James Larkin, from The Royal Marsden Hospital in London, UK, discussed the presentation at the session, observing that both the Checkmate 914 study and the KEYNOTE-564 trial, which has previously showed a positive DFS outcome for adjuvant pembrolizumab in a similar patient population, used an “anti-PD1 therapy with clear activity and approvals in advanced disease.”
He postulated: “I think unlikely there is a significant difference between [nivolumab] and [pembrolizumab]”.
The discussant highlighted that 23% of CheckMate 914 participants given nivolumab plus ipilimumab required at least 40 mg/day of prednisolone or equivalent immunosuppression to manage AEs compared with just 2% of controls in the study and 8% of pembrolizumab-treated patients in KEYNOTE-564.
He questioned whether this level of “immunosuppression might affect efficacy in this setting” and emphasized that there was a need for “clinically usable molecular markers for treatment selection” so that ipilimumab might be targeted to RCC patients with the greatest need.
James Larkin concluded that Part B of CheckMate 914 assessing the impact of adjuvant nivolumab monotherapy in the same patient population is yet to be reported and he hoped that a comparison of the study’s two arms “will be important and hopefully illuminating.”
A third phase III study – IMmotion010 – assessing a 1-year regimen of adjuvant atezolizumab 1200 mg every 3 weeks in patients with high-risk RCC after nephrectomy, was presented at the meeting by Alex Bex, from The Royal Free London NHS Foundation Trust in the UK, and simultaneously published in The Lancet.
This study also failed to show a significant improvement in the primary endpoint of investigator-assessed DFS compared with placebo (median 57.2 vs 49.5 months, HR=0.93), in overall survival (OS; median unreached in both arms, HR=0.97) and other secondary endpoints.
However, exploratory analysis indicated that patients with PD-L1 tumour expression of 5% or higher may experience longer DFS with atezolizumab than placebo, at median durations of unreached versus 49.5 months and a HR of 0.57, prompting Alex Bex to suggest that further analysis of this subgroup is “warranted”.
Session discussant Tom Powles, from Barts Health and Royal Free NHS Trust in London, UK, commented that the “contradictory findings of these three adjuvant trials won’t be down to luck alone.”
He noted that the PROSPER trial, presented at the meeting by Mohamed Allaf, from Johns Hopkins University School of Medicine in Boston, Massachusetts, USA, found no significant recurrence-free survival benefit from the use of nivolumab before and after nephrectomy in high-risk RCC patients versus surgery alone.
Tom Powles said the “design and methodology issues” in PROSPER means that “it is not possible to judge the comparative activity of nivolumab based on this study.”
The discussant concluded: “Patients should be aware that pembrolizumab delays DFS with a chance of life changing toxicity” and “may improve OS in the future.”
And he cautioned that patients “should also be aware that other [immune checkpoint inhibitors] have not been able to replicate the pembrolizumab data, creating new uncertainty in renal cancer.”
References
LBA4 - Motzer RJ, Russo P, Grünwald V, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localized renal cell carcinoma at high risk of relapse after nephrectomy: results from the randomized, phase III CheckMate 914 trial. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089
LBA66 - Bex A, Uzzo R, Karam JA, et al. IMmotion010: Efficacy and safety from the phase III study of atezolizumab vs placebo as adjuvant therapy in patients with renal cell carcinoma at increased risk of recurrence after resection. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089
Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet; Advance online publication, 10 September 2022. doi.org/10.1016/ S0140-6736(22)01658-0
Capitanio U, Montorsi F. Identifying patients for adjuvant therapy after nephrectomy. Lancet; Advance online publication 10 September 2022. doi: 10.1016/S0140-6736(22)01747-0 10 Sept 2022
LBA67 - Allaf M, Kim SE, Harshman LC, et al. Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group