MADRID, Spain—Bristol-Myers Squibb smashed doubt about Opdivo and Yervoy’s utility in first-line kidney cancer on Sunday with data showing patients lived longer when treated up front with the combo, rather than with Pfizer’s standard-of-care med, Sutent.
The fleshed-out data followed closely on a surprise stop for the Checkmate-214 trial after an interim analysis, when a monitoring committee decided the Opdivo-Yervoy combo was too effective to restrict only to the control arm in the study.
Why a surprise? Because in August, the company unveiled mixed results from the same trial. Opdivo and Yervoy hit their primary goal on response rates, but didn’t significantly outperform Sutent at holding off cancer progression, though the study data did show a trend in that direction. The fact that it delivered on overall survival not only counts as a win for Bristol-Myers, but offers hope for other IO drug regimens that have fallen short at delaying disease progression in early trial results.
“We were able to demonstrate a robust improvement in response rate and those responses last longer,” Vicki Goodman, Bristol-Myers’ head of new asset development, said in an interview ahead of the Sunday presentation at the European Society for Medical Oncology Congress in Madrid.
“We saw a trend toward improved progression-free survival," Goodman noted, "with an 18% reduction in rates of progression that didn’t meet statistical significance, but now we are seeing overall survival playing out.”
In intermediate- and poor-risk patients, the Opdivo-Yervoy pairing delivered a 37% reduction in the risk of death compared with Sutent, Goodman said during a press presentation Friday, with a p-value of 0.00003, which indicates that the result isn’t a chance finding. In all the trial patients, the reduction in death risk amounted to 32%. In both groups, the median overall survival hadn't yet been reached for the combo arm.
In essence, Opdivo and Yervoy may not have hit their goal of delaying cancer growth, but did show they could help patients live longer, which is the gold-standard endpoint in cancer. That means Bristol-Myers could file for a full FDA approval for first-line treatment of renal cell carcinoma—another example of IO drugmakers’ push into earlier use of their therapies.
Leerink analyst Seamus Fernandez called the results “a strong positive,” saying, “[T]he overall survival benefit likely confirms the durability of the signal seen on progression-free survival, leading to a very high likelihood of approval.”
The Checkmate-214 trial enrolled previously untreated patients screened up front for clinical measurements, such as hemoglobin levels, that suggest they would be less likely to respond to Sutent. The patients were followed for a minimum of 17.5 months, and a median of 25 months.
The cocktail beat Sutent at the co-primary endpoint of overall survival in intermediate- and poor-risk patients and the secondary endpoint of overall survival in all of the study’s randomized patients. Importantly, those results came with a new dosing regimen—3 mg/kg of Opdivo plus 1 mg/kg for Yervoy—that Bristol-Myers had hoped would be effective and more tolerable than the typical doses tested in melanoma. There, Yervoy has been dosed at 3 mg/kg, with Opdivo at the 1 mg/kg level.
“As we’ve seen, Opdivo is more tolerable than Yervoy,” Goodman noted, so it stands to reason that “a combination where Opdivo’s dose is higher is more tolerable, and fewer patients will stop therapy as a result of toxicity.”
In the Checkmate-214 trial, 22% of patients in the combo arm quit therapy because of side effects, compared with 12% of Sutent patients. The most common severe side effects were high blood pressure and fatigue.
The Checkmate-214 data are more broadly significant, too. Opdivo is a PD-1 checkpoint inhibitor, and Yervoy a CTLA4-targeting drug. That combo lagged Merck & Co.’s Keytruda-chemo combo in lung cancer, judging from previous data, and AstraZeneca’s PD-L1 plus CTLA4 cocktail—Imfinzi plus tremelimumab—fell short in the closely watched Mystic study, also in lung cancer. Experts attempting to keep score in immuno-oncology figured that the PD-1/L1 plus chemo approach had tipped the scales. This data suggests that conclusion might have been too hasty.
Plus, the new Bristol-Myers data could raise hopes for AstraZeneca’s Imfinzi combo, which failed at the progression-free survival (PFS) point in the recently unveiled Mystic study data. Checkmate-214 helps illustrate that a shortfall on PFS doesn’t necessarily mean that an immunotherapy—or immuno-oncology combination—won’t succeed at extending patients’ lives, arguably a more important achievement.
“We are really seeing how the improved overall response rate and durability of response translate into an OS benefit,” Goodman noted.
Bernstein analyst Tim Anderson said results in future studies could well show the same pattern. “This is precisely why the majority of IO trials now incorporate OS as part of the primary endpoint, with the idea that PFS may not be the best measurement because of the unique way in which IO therapies work,” Anderson said in a note last week. “In other words, PFS is not destiny.”
For Bristol-Myers itself, the first-line success once again puts the company ahead of its rivals in kidney cancer. Opdivo is already the only PD-1/L1 drug approved in renal cell carcinoma, with a second-line nod in 2015, Credit Suisse analyst Vamil Divan noted last week.
A potential launch in kidney cancer for the combo next year “would keep Bristol-Myers well ahead of competitors from Roche, Pfizer and Merck,” with their launches in that field estimated for 2019 for the first two and 2021 for Merck, Divan said.