CHICAGO — Bristol-Myers Squibb $BMY ran smack dab into a high level of professional static when it changed up its study design for Checkmate-227, a pivotal test for Opdivo plus Yervoy in treating new cases of non-small cell lung cancer. But they’ve arrived at AACR with data they say spell out a compelling case for their PD-1/CTLA-4 combo.
“The data we report here are exciting,” says Fouad Namouni, the oncology development chief at Bristol-Myers, “with an important level of activity.”
Their drug reduced the risk of progression or death by 42% with a hazard ratio of 0.58.
At the one-year mark, Namouni told me in a preview of today’s release, the progression-free survival rate in the combo arm was 43%, compared to only 13% in the control arm. And that’s regardless of PD-L1 expression status and histology, with no changes for squamous or nonsquamous cases.
Researchers involved in the study ripped up the original trial design, meshing data together and claiming a success against a novel goal for patients with a “high tumor mutation burden.” And they went their own way on defining the TMB so that it included close to half of all patients in the population, rather than the more minimal subgroup tracked by the test maker Foundation Medicine, which uses a bar that is set twice as high to classify patients.
Clearly, Namouni says, this marks a big advance for patients — to say nothing about their intense rivalry with Merck. And he adds that it makes sense.
“A high tumor mutation burden is a surrogate for neo-antigens,” he adds, which makes the tumor more visible to the immune system, and in turn makes it more likely to be responsive to a PD-1/L1 checkpoint.
Their work here, says Namouni, involves deepening the field’s understanding of the biology of lung cancer.
They’ve also got evidence to back up their position that 10 mutations/megabase is the right inflection point, rather than moving the scale up even as high as 15. The Foundation test sets the mark at 20.
For some rivals, that kind of assertion looks like a boast that can’t be proven at this early stage of the game. But in a chat with AstraZeneca’s David Berman, their chief of I/O programs, he agreed that their own work backed up the standard used by Bristol-Myers — noting that in lung cancer specifically 10 mutations/megabase marked the right cutoff for the assay on high TMB. Every cancer type is different, he adds, and they’ve been carefully studying this themselves in their work on durvalumab in lung cancer.
There are other problems that are presented by using the test, though. One is that it currently takes about 2 weeks to get back results on the tumor mutation burden, and some critics say patients and doctors may not want to delay therapy to run the test. But Bristol-Myers’ Namouni says that that is within the usual consultation time it takes to decide on therapy — adding that what takes 2 weeks now could be quickly sliced back to a couple of days with the proper focus.
Bristol-Myers’ approach may continue to raise hackles among some observers — but this is a highly respected R&D organization that is determined to remain a leader in lung cancer, come what may or might at Merck or any of its other rivals.
Namouni says they’ve been in conversations with regulatory groups about the data, but he isn’t offering any timelines on filings.
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