Bristol Myers Squibb's and Roche's immunotherapies have both failed to move the needle when used after surgery in early-stage kidney cancer. But the two companies’ setbacks aren’t necessarily a full relief for Merck’s rival drug Keytruda.
BMS’ Opdivo and Yervoy couldn’t significantly reduce relapses compared with placebo when used after surgical removal of the kidney in high-risk, localized renal cell carcinoma. The immunotherapy combo only reduced the risk of disease recurrence or death by 8% in the CheckMate-914 trial, according to results reported at the European Society for Medical Oncology (ESMO) congress 2022.
Similarly, Roche’s Tecentriq only pared down the risk of relapse or death by 7% in its IMmotion010 study in postsurgery kidney cancer.
The two failures leave Merck’s Keytruda as the only PD-1/L1 inhibitor currently approved in the adjuvant setting of early kidney cancer, a market that SVB Securities analyst Daina Graybosch, Ph.D., suggests could be mean $1.5 billion in U.S. sales for Keytruda in 2023 and up to $6.4 billion globally by 2027, according to a Monday note to clients. But to Keytruda, the rivals’ flops may not be entirely positive.
“I don’t fundamentally think that [Keytruda] is that different from [Opdivo]. So where you do have one success, I think we could have another one,” Graybosch said in an interview about the adjuvant trials ahead of the ESMO presentation.
The CheckMate-914 trial remains ongoing with an Opdivo monotherapy arm. Graybosch suggests that arm may still have a chance to be positive.
But another cooperative group-initated trial, dubbed PROSPER RCC (ECOG-ACRIN EA8143), that tested Opdivo alone both before and after surgery in high-risk kidney cancer has also turned out negative. The trial was stopped early by an independent data monitoring committee as the trial wasn’t likely to be successful. Again, the risk of disease relapse was similar between Opdivo and simple surveillance, according to data shared at ESMO congress 2022.
Within kidney cancer, patients could respond to immunotherapy differently based on certain risk factors such as circulating tumor DNA, Graybosch noted. That could mean that different patient characteristics might have caused the different outcomes among the trials.
But at this point, “there really isn’t a subgroup in the study that suggests—at least at first blush—an obvious group that would benefit” from Tecentriq in the IMmotion010 trial, Charlie Fuchs, M.D., global head of oncology and hematology drug development at Roche’s Genentech, told Fierce Pharma in an interview.
In patients with PD-L1-positive tumors, Tecentriq did prolong the median time to disease recurrence or death by nearly an additional 10 months to 57.2 months. But Fuchs argued that risk reduction, at a non-statistically significant 17%, is more appropriate to capture the bigger picture.
The multiple negative trials could cast doubts around Keytruda, or bring questions as to which specific subsets of patients in Keytruda’s successful Keynote-564 trial are really pulling the weight.
“Sometimes in oncology, where you have multiple studies—some positive, some negative—that could be by chance,” Genentech’s Fuchs said. “But it also could reflect the fact that one study enrolled a certain greater proportion of patients with a particular biology that the others didn’t.
“We have multiple studies that are negative [but] using a common mechanism of action,” Fuchs added. “I think the jury’s still out on the role of cancer immunotherapy in the adjuvant setting in renal cell carcinoma.”
But in her Monday note, Graybosch noted that at the ESMO meeting, two experts, including the presenter for the Opdivo-Yervoy trial, lent their support for Keytruda’s success in a large clinical trial.
“The Keynote study with Keytruda […] set the bar and showed in a large 1,000 patient trial, meticulously performed, that a year of [Keytruda] delays relapse or disease-free survival in [kidney cancer]; I’m a believer in that and I think the bar has been set,” CheckMate-914 investigator Robert Motzer, M.D., of Memorial Sloan Kettering Cancer Center said during a Q&A, as quoted by Graybosch. “The question really is: why did the other studies not show that same benefit?”
“Can differences in trial design and study populations explain these dissimilarities? Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” Dominik Berthold, M.D., from Switzerland’s Centre Hospitalier Universitaire Vaudois commented on the adjuvant kidney cancer trials in a statement facilitated by ESMO.
Meanwhile, AstraZeneca is expected to read out its own adjuvant kidney cancer data soon, Graybosch noted. The phase 3 Rampart trial tests Imfinzi alone and in combination with AZ’s CTLA-4 inhibitor trememlimumab. And Graybosch said it could further inform if Keytruda will be the only immunotherapy player in adjuvant kidney cancer.
Editor's Note: The story has been updated with additional comments from Daina Graybosch from a Monday note to clients.