GU cancer

Hopes dashed over the future of immunotherapy in RCC 

Results from three phase III trials presented at ESMO 2022 congress have raised fresh and unexpected doubts over the use of adjuvant immunotherapy in renal cell carcinoma (RCC).

PROSPER-RCC, IMmotion010, CheckMate 914 all missed their primary endpoints, showing no improvement in disease free survival (DFS) or recurrence free survival (RFS).

In the PROSPER-RCC [link here] trial one dose of nivolumab was given prior to surgery and nine doses given after nephrectomy. Recurrence-free survival (RFS) was similar in both arms (HR 0.97; 95% CI 0.74–1.28; p=0.43) and the trial was stopped early by the data and safety monitoring committee due to futility. 

“Perioperative nivolumab did not improve recurrence-free survival in patients with renal cell carcinoma and at high risk for recurrence,” said lead investigator Dr. Mohamad Allaf, a member of the ECOG-ACRIN cancer research group and urologist in chief at the Johns Hopkins Hospital in Baltimore, Maryland. 

“Ongoing radiomic, pathomic, and other biomarker analyses within this trial may inform the design of future neoadjuvant trials in this disease,” he said. 

CheckMate 914 [link here] compared nivolumab plus ipilimumab to placebo in patients with RCC and a high risk of relapse. Median DFS by blinded central review was not reached with nivolumab plus ipilimumab versus 50.7 months with placebo (HR 0.92; 95% CI 0.71–1.19; p=0.5347). DFS probability at 24 months was 76.4% and 74.0%, respectively. 

Similarly, no benefits in DFS or OS were seen in the IMmotion010 [link here] trial which compared atezolizumab to placebo. Results showed that after a median follow-up of 44.7 months, median investigator-assessed DFS was 57.2 months (95% confidence interval [CI] 44.6–not estimable [NE]) for atezolizumab and 49.5 months (95% CI 47.4–NE) for placebo (hazard ratio [HR] 0.93; 95% CI 0.75–1.15; p=0.495). 

The safety findings with the immunotherapies evaluated in the three studies were within expected ranges. 

Commenting on the findings, Dr Dominik Berthold of the Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland, said expectations for positive results from the three trials were high, given the previous positive DFS data in this disease setting with pembrolizumab in the KEYNOTE-564 trial.

“The negative results are unexpected…“At the moment, reasons for failure of the IMmotion010, CheckMate 914 and PROSPER trials are unclear, but could reflect differences in the patient populations, such as the proportions of patients with very advanced or resected metastatic disease, the different mechanism of action of the respective immunotherapy agents tested or differences in follow-up times,” he said in a statement to the ESMO Daily Reporter. 

“We are still missing some important information, such as the impact of follow-up on overall survival, which was a secondary endpoint in all trials. This is something to figure out over time. Another important question relates to the use of immunotherapy as neoadjuvant treatment, potentially combined with other agents. There are more data to come and much more still to learn about how to prevent recurrence in these patients,” he added. 

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