Bristol-Myers' Opdivo-Yervoy team scores coveted win in first-line lung cancer

Bristol-Myers Squibb finally got its win in first-line lung cancer—and it’s a success that not only helps confirm one immunotherapy combo approach that has been in doubt, but puts forward a diagnostic biomarker that could apply to other cancer types.

In a phase 3 trial dubbed Checkmate-227, the company’s PD-1 checkpoint inhibitor Opdivo, teamed with its CTLA4 drug Yervoy, beat chemo at holding off disease progression in previously untreated lung cancer patients with a high tumor mutation burden.

It’s an early vindication of the PD-1-plus-CTLA4 tandem approach, which fell into question when AstraZeneca’s Imfinzi-plus-tremelimumab combo fell short in its closely watched Mystic trial, right on the heels of a big win for Merck & Co.’s Keytruda in combination with chemotherapy.

It’s also confirmation of the tumor mutation burden (TMB) biomarker, which popped up as a potential predictor for response to immunotherapy drugs. Previous analyses had suggested that mutation-high tumors generated more neoantigens, which are vulnerable to immuno-oncology agents, making the treatment more efficacious. Bristol changed the 227 trial, with input from the FDA, to capture prospective data on TMB-high cancers.

“CheckMate -227 showed that TMB is an important, independent predictive biomarker that can identify a population of first-line NSCLC patients who may benefit from the nivolumab plus ipilimumab combination,” said trial investigator Matthew D. Hellmann, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center.

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And it’s big news for Bristol-Myers, which couldn’t afford another first-line failure in lung cancer after missing its shot at an Opdivo monotherapy nod. With that misstep, BMS ceded its overall lead in the lung-cancer race to Merck, whose Keytruda now boasts two front-line nods.

“This is a clear win for BMS, in our view, particularly, given the company's confidence in a positive outcome in the PDL1+ OS co-primary endpoint,” Leerink analyst Seamus Fernandez wrote.

The details of today’s data are as-yet unannounced, and the study is continuing, to gauge performance on a co-primary endpoint: overall survival. That’s the gold standard in oncology, because winning on overall survival means a therapy extends patients' lives. The progression-free survival (PFS) win has executives more confident of success in overall survival, analysts said.

One quirk, however, as pointed out by analysts: Overall survival calculations are divided into subgroups defined by PD-L1 expression—the standard biomarker for Opdivo’s class of drugs—rather than PD-L1 and TMB as the interim analysis did.

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“We believe the stock should trade up on the positive progression-free survival news, but expect a lot of questions on the conference call as to why Bristol-Myers chose a different biomarker to drive the overall survival analysis and how much today's positive news should impact expectations on the ultimate overall survival results,” Credit Suisse analyst Vamil Divan wrote in a Monday morning note.

Since the Mystic trial shortfall on progression-free survival, AstraZeneca has maintained its own combo could still deliver on overall survival when the trial’s final results read out. And meanwhile, Opdivo and Yervoy together chalked up a win in kidney cancer for overall survival—in first-line, intermediate- and higher-risk patients, compared with Pfizer’s Sutent—after falling short on PFS in an earlier trial analysis.

And then there’s the question of side effects, Bernstein’s Tim Anderson said, citing the results for an Opdivo-Yervoy combo in a previous study. “And of course, [we] need safety information—recall that with Checkmate-067, safety issues seemed to negate the progression-free survival benefit when measuring overall survival,” he wrote Monday, “i.e., while there was a PFS benefit, on OS there was not much of one with the combination.”

Meanwhile, Bristol-Myers reported fourth-quarter numbers on both drugs, and they delivered mixed results. Opdivo grew 4% to $1.36 billion, topping consensus analyst estimates by a tad. Yervoy, though, shrank to $269 million, below consensus estimates of $313 million.