Merck's Keytruda extends life for kidney cancer patients after surgery, while Bristol's Opdivo fails again

Merck’s unique approval for Keytruda as a postsurgical treatment for resectable kidney cancer has gained new backing in the form of data showing the PD-1 inhibitor can extend patients’ lives. 

Keytruda slashed the risk of death by 38% compared with placebo when used after kidney removal in patients with clear cell renal carcinoma, the most common form of kidney cancer, according to newly released trial results. After four years of treatment, investigators estimated that 91.2% of patients in the Keytruda arm were still alive, versus 86% for the control group.

The results, which reached statistical significance, come from an update of the Keynote-564 trial. Previously, disease-free survival results from the same trial supported Keytruda’s 2021 approval as an adjuvant therapy for certain kidney cancer patients at risk of recurrence after surgery.

Keytruda’s survival win comes just as Bristol Myers Squibb’s rival PD-1 inhibitor, Opdivo, failed for a second time in the same adjuvant kidney cancer setting, further consolidating Keytruda’s position as the only successful immunotherapy in the blockbuster market.

Results from Keynote-564 and a second part of the CheckMate-914 trial are being shared at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Industry watchers weren’t holding their breath for the new Opdivo readout. Back in 2022, the first part of the CheckMate-914 study showed that Bristol’s dual immunotherapy regimen of Opdivo and Yervoy couldn’t outdo placebo in patients with localized renal cell carcinoma at increased risk of relapse after surgery. The PD-1/CTLA-4 combo only reduced the risk of disease recurrence or death by 8%.

This time around, Opdivo alone reduced the risk of recurrence or death versus placebo by 13%, which didn’t reach statistical significance. At 18 months, 78.4% of Opdivo takers were estimated to be alive without disease worsening, compared with 75.4% of their counterparts in the placebo arm.

As for Keytruda, the latest update linked the Merck drug to a 28% reduction in the risk of cancer recurrence or death versus placebo after a median follow-up of 57.2 months.

“By having this robust five-year follow-up, we’re able to demonstrate the benefit across time,” Marjorie Green, M.D., head of oncology global clinical development at Merck Research Laboratories, said in an interview. The results are “clinically compelling,” she added.

A few years ago, the Opdivo-Yervoy flop, plus a separate failure by Roche’s Tecentriq, didn’t exactly help Keytruda’s case in postsurgery early-stage kidney cancer. Because existing PD-1 inhibitors are largely viewed as more similar than different, the contrasting outcomes from the trials raised the question of whether Keytruda got lucky in its study. An overall survival win, the gold standard efficacy endpoint in oncology studies, could dispel some of those doubts.

Keytruda’s life-extension benefit was shared across subgroups. Among patients with M0 stage cancer at an intermediate-high risk of recurrence, Keytruda slashed the risk of death by 41%. The numbers were 22% and 49% for patients with M0 high-risk and M1 cancer, respectively. M0 is an earlier stage in which no distant cancer spread has been found, and those patients made up the majority of the study.

Among patients whose tumors had PD-L1 expression, the death-risk reduction was 38%. For PD-L1-negative patients, the rate was 35%. The subgroup data are not powered for statistical significance.

In addition to the adjuvant label, Keytruda is also approved alongside either Eisai’s Lenvima or Pfizer’s Inlyta to treat patients with newly diagnosed advanced kidney cancer. In Keynote-564, 41% of patients in the Keytruda arm and 70% of those in the placebo group received subsequent anti-PD-1/L1 therapy.

Trying to improve on the Keytruda-Lenvima regimen, Merck is running a three-arm trial testing whether adding newly FDA-approved HIF-2a inhibitor Welireg or the Akeso-partnered CTLA-4 antibody, quavonlimab, can produce better results.

The company is exploring a similar strategy in the adjuvant setting with another phase 3 evaluting Welireg on top of Keytruda to treat clear cell renal cell carcinoma post nephrectomy.