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PARIS -- While pembrolizumab (Keytruda) has been approved as an adjuvant treatment for patients with high-risk renal cell carcinoma (RCC), three phase III studies presented at the European Society for Medical Oncology (ESMO) annual congress here failed to support the immune checkpoint inhibitor in this setting.

In Part A of the , the median disease-free survival (DFS) was not reached with nivolumab (Opdivo) plus ipilimumab (Yervoy) compared with 50.7 months with placebo in patients with localized RCC at high risk of post-nephrectomy relapse at a median follow-up of 37 months (HR 0.92, 95% CI 0.71-1.19, P=0.5347), reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City.

In the , Mohamad E. Allaf, MD, of Johns Hopkins University in Baltimore, reported that with a median follow-up of 16 months, perioperative nivolumab failed to improve recurrence-free survival (RFS) compared with surgery alone in patients with high-risk RCC (HR 0.97, 95% CI 0.74-1.28, P=0.43).

In the trial, median DFS was 57.2 months with adjuvant atezolizumab (Tecentriq) compared with 49.5 months with placebo in RCC patients at increased risk for recurrence after nephrectomy at a median follow-up of 44.7 months (HR 0.93, 95% CI 0.75-1.15, P=0.50), according to Axel Bex, MD, of University College London and the Netherlands Cancer Institute in Amsterdam. Results from IMmotion010 were also published in .

Considering the results from IMmotion010 and "listening to the presentations ... on CheckMate-914, but also on PROSPER, which are contradictory to the results of pembrolizumab, I think it is clear that further studies are needed to clarify the role of immunotherapy in the adjuvant setting for RCC," Bex observed.

Addressing the IMotion010 and PROSPER studies, ESMO discussant Thomas Powles, MBBS, MD, of Barts Cancer Centre at St. Bartholomew's Hospital in London, said that while pembrolizumab has been shown to be strongly positive for DFS, with an overall survival (OS) signal that was supportive (although not mature), "patients should also be aware that other immune checkpoint inhibitors have been unable to replicate the pembrolizumab data ... creating new uncertainty in renal cancer."

CheckMate-914

Among 816 patients -- 405 randomized to nivolumab plus ipilimumab and 411 to placebo -- the estimated DFS rates at 24 months were 76.4% and 74.0%, respectively.

Any-grade treatment-related adverse events (TRAEs) were reported in 88.9% treated with nivolumab/ipilimumab versus 56.8% of patients in the placebo group, while grade ≥3 TRAEs were reported in 28.5% and 2.0%, respectively. TRAEs led to discontinuation in 29% and 1% of patients.

During a press briefing, Motzer was asked to put his findings into context considering the results of the KEYNOTE-564 trial, which led to FDA approval of pembrolizumab for adjuvant treatment of patients with high-risk RCC.

"They're different studies, and they have different designs, different duration of therapies," Motzer said. "I don't think this in any way takes away from standard-of-care pembrolizumab for patients in the adjuvant setting."

The results from CheckMate-914 will "help us learn in terms of moving forward -- the best direction to take," he added.

PROSPER

This trial, which randomized 819 patients to perioperative nivolumab (n=404) or surgery alone (n=415) from February 2017 to June 2021, was stopped early due to futility. Nivolumab 480 mg IV was administered every 4 weeks, with one dose prior to surgery followed by nine adjuvant doses. The control arm was followed by surveillance without a placebo.

OS data were not mature at the time of analysis, but OS was not statistically different between study arms (HR 1.48, 95% CI 0.89-2.48, P=0.93), Allaf reported.

Adverse events were similar to what has been seen in other nivolumab monotherapy trials, with 93% of patients in this arm experiencing an adverse event of any kind. More serious adverse events also occurred in the nivolumab arm (33% vs 13%).

Allaf noted that PROSPER's "unique" trial design resulted in 51 patients not receiving neoadjuvant nivolumab, and 45 not undergoing surgery (compared with 28 patients in the observation arm who did not receive surgery).

"This is a trial in the beginning of its analysis cycle, and there are many things we do not yet know," Allaf pointed out. "For example, why did some patients not receive nivolumab? Why did some patients not undergo surgery? What about overall survival? Lots of questions."

Powles noted that this trial "has a number of design and methodology issues," suggesting it "is not possible to judge the comparative activity of nivolumab based on this trial."

IMmotion010

In this study of 778 patients enrolled from January 2017 to February 2019 and randomized 1:1 to atezolizumab or placebo, the 3-year DFS rate was 59.4% in the atezolizumab group and 59.0% in the placebo group.

At data cutoff, OS data were immature. There were 107 deaths, 54 in the atezolizumab group and 53 in the placebo group. There was no evidence of a reduced risk of death from any cause with adjuvant atezolizumab compared with placebo (HR 0.97, 95% CI 0.67-1.42). The 3-year OS rates were 90.3% in the atezolizumab group and 89.8% in the placebo group.

The most common grade 3/4 adverse events were hypertension (2% with atezolizumab vs 4% with placebo), hyperglycemia (3% vs 2%), and diarrhea (1% vs 2%). Serious adverse events occurred in 18% of patients who received atezolizumab and 12% of patients who received placebo.

Powles noted that the trial showed a response rate of 25% and a complete response rate of 11% with atezolizumab in patients with treatment-naive metastatic RCC. "So, atezolizumab has activity in kidney cancer," he said. "I think it is fair to say that atezolizumab looks less active in this setting."