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“tumor mutation burden,” or TMB, a measure of the level of genetic mutations in the tumor cells. Checkmate-227 is all about TMB. Bristol said earlier this year that a combination of its two checkpoint inhibitors, nivolumab and ipilimumab, kept cancer from spreading better than chemotherapy—at least in patients whose tumors have high TMB. The picture should fill in with much more detail in coming days.
Doctors want to know about the toxicity of the combination; ipilimumab on its own has a track record of more severe side effects. They also want to compare the combination to nivolumab alone and—even though comparisons across trials are always tricky—to pembrolizumab alone or pembrolizumab plus chemotherapy. Survival rates are important. Chae of Northwestern wants to know if the nivolumab/ipilimumab combination is “just buying a few more months and then everyone progresses.”
“Response rate and progression-free survival are important, but overall survival is always the most important endpoint,” he says.
Heymach of MD Anderson says good results could make the ipilimumab-nivolmuab combination a preferred option for one type of lung cancer: squamous cell carcinoma with low PD-L1 levels and high TMB.
Even if these questions turn up positive for Bristol, Chae has another concern. DNA sequencing is required to calculate TMB and can take a few weeks. Will oncologists and their patients newly diagnosed with advanced lung cancer be willing to wait until they can start treatment? “I think with time and advancements in technology this will be solved eventually,” Chae says, but “at the moment I can easily see that becoming an issue.”
When the FDA approved the pembro-chemo regimen in May 2017, it did so based on a small randomized study, Keynote-21G, that didn’t have the drug’s effect on overall survival as a main goal. The 616-patient Keynote-189 will have survival results: How much longer people receiving the combination live than people taking only chemo. The magnitude of that effect will be telling, says Heymach of MD Anderson. If it’s significant, it could “cement chemotherapy plus pembrolizumab” for NSCLC patients who have lower PD-L1 levels and don’t have squamous cell carcinoma.
Martins is watching for another key detail from Keynote-189. Patients receiving chemo alone were allowed to add pembrolizumab to their treatment if they progressed. If the crossover rate is high, that bolsters the idea that providing the combination early produces better results than waiting. “I think that will be a pretty big deal,” he says.
The wild card with all this, however, is the Keynote-042 study that Merck partially released earlier this week. Again, the hint is that pembrolizumab alone could be better for first-line patients than pembrolizumab combined with chemo. If those tantalizing results hold up in detail, Keynote-042 “changes everything,” Martins says.
Roche’s combination is the most aggressive and complicated of the new studies. In addition to the immunotherapy atezolizumab, it includes the Roche drug bevacizumab (Avastin) that has helped scores of patients with a variety of cancers since it was first approved in 2004. The mix also includes chemotherapies.
So many drugs at once gives the oncologists we interviewed some pause. Toxicity is one concern; Chae notes that Roche is using the chemotherapy paclitaxel instead of pemetrexed even though paclitaxel is associated with more frequent side effects like peripheral neuropathy, which isn’t associated with pemetrexed. There’s also “financial” toxicity: “That is a pretty pricey therapy,” Martins says. “At some point we will not be able to afford it.”
But the early details on IMpower150, released in December, gave oncologists a hint that chemo, immunotherapy, and bevacizumab could work well together. It also held out hope for patients with a mutation in the EGFR gene who haven’t fared well on targeted drugs like erlotinib (Tarceva).
“That’s probably how I would take advantage of IMpower150,” Chae says. “I think it has its role.”
No matter how the data play out in coming days, the pace of change is “overwhelming,” says Chae.
With tumor mutation burden now coming to light as an important diagnostic measurement, for instance, lung cancer is becoming ever more stratified. Chae is looking forward to each study’s analysis of patient subgroups, not just the overall numbers. “It will truly be a personalized approach with this many options coming aboard,” he says.
Who will be able to afford personalized cancer medicine? Heymach, Martin, and Chae all say they’ve had no problems getting patients access to immunotherapies so far.
But as many observers have noted when competition doesn’t seem to bring down the cost of similar drugs, Heymach says, the market “isn’t operating as other markets commonly do.”
With combinations that pile on the drug costs, will insurers finally push back? Add to that the cost of the diagnostic tests—genomic sequencing and the like—to predict patients’ responses. For a lung cancer patient, are payers “going to pay for mutation testing and TMB testing and PD-L1 testing?” Heymach says. “Will they specify one of these regimens, or will they leave it open for any of these regimens for patients meeting the criteria? That’s something that we don’t know yet.”