trial data but a patient’s condition and, in coming months and years, other biological indicators beyond PD-L1 status that are under exploration—as we’ll see in a moment. “The exciting thing is that we have more possibilities than ever before,” she says.
Checkmate-227
Merck’s success with pembrolizumab and pembro-chemo have amped up the pressure on rival Bristol-Myers Squibb (NYSE: [[ticker:BMY]]), whose immunotherapy nivolumab (Opdivo) has fallen behind its rival in lung cancer. Bristol is trying to show that the combination of nivolumab and its other approved immunotherapy, ipilimumab (Yervoy), has a role to play. (Let’s call this nivo-ipi from now on.) It’s focusing on people whose tumors have unusually high levels of genetic mutations. The measure, known as tumor mutational burden, or TMB, is emerging as a new way, beyond PD-L1, to predict who might respond to immunotherapy. The study’s lead investigator, Memorial Sloan Kettering Cancer Center medical oncologist David Hellman, says Checkmate-227 “validates the value of TMB.” (Bristol and its partner Ono Pharmaceutical paid for the study.)
“We’re carving out a distinct population of patients with lung cancer that can benefit from immunotherapy by itself and avoid the need for chemo in the first-line setting,” he says.
The study dosed patients with TMB of 10 mutations per megabase or greater. This is Bristol’s definition of high TMB; there is not yet a “community consensus about what TMB is precisely,” as The Jackson Laboratory president and CEO Edison Liu, a cancer genomics expert, notes.
Another caveat: a subset of the more than 1,700 patients enrolled in Checkmate-227 were measured as high TMB; 139 received nivo-ipi and 160 received chemotherapy alone. Those numbers make for a small sample size compared to many other Phase 3 immuno-oncology trials. But Hellmann says it nonetheless found a “representative population and a statistically relevant degree of benefit.”
The results were published this morning in the NEJM: 42.6 percent of nivo-ipi patients with high TMB registered progression-free survival at the one-year mark, versus 13 percent of chemo patients. Median progression-free survival was 7.2 months for nivo-ipi patients with high TMB, versus 5.5 months for chemo patients. Nivo-ipi led to a 42 percent reduction in risk of disease progression or death for high TMB patients. The combo’s benefit over chemotherapy was “broadly consistent within subgroups,” the NEJM paper says, including patients with very low levels of PD-L1. According to the paper, 38 nivo-ipi patients had less than 1 percent of PD-L1 on their tumors. and 101 had more than 1 percent. (Nivo-ipi didn’t fare nearly as well all-comers: 1-year progression-free survival was 30.9 percent for the combo compared to 17 percent for chemo patients, and median progression-free survival was 4.9 months. The results equaled a 17 percent risk reduction in disease progression or death for nivo-ipi versus chemo.)
There was improvement over time as well: 68 percent of the high-TMB patients who responded to nivo-ipi had their tumors held in check for at least a year, compared to just 25 percent of the chemo responders, suggesting that those who had a response to the combo would see a durable benefit.
Safety is an important consideration for this study. Bristol’s ipilumumab, which attacks a different tumor protein called CTLA-4, historically has harsher side effects than other immunotherapy products. The results are in Bristol’s favor. Serious side effects hit the nivo-ipi patients at a slightly lower rate than the chemo patients, 31 percent versus 36 percent. To that end: Dangerous lung inflammation (pneumonitis), which has been associated with ipilimumab at a higher dose for melanoma patients, occurred in just 3 percent of patients on the combination, says Hellmann.
“I could see that it would be a reasonable option for patients that do not want chemotherapy,” says Laura Chow, the associate director of the Phase 1 Clinical Trials Program at Seattle Cancer Care Alliance. “But you still need exceptionally fit patients.” She adds that the response rate to nivo-ipi, while impressive, is comparable to what pembrolizumab alone has shown. “Do you want that extra toxicity?” she says.
So who might be eligible for high-TMB immunotherapy? About 44 percent enrolled in Checkmate-227 had high TMB by Bristol’s definition. Hellmann expects that is “probably in the ballpark” of the worldwide NSCLC population.
Health economist Gary Lyman, who specializes in the cost of cancer care, says he’s skeptical and wants to see more data before putting a solid number on the high-TMB population. “Such population claims can rarely be made from one study,” says Lyman, co-director of the Hutchinson Institute for Cancer Outcomes Research in Seattle.
Whatever the population, it is no sure thing that nivo-ipi will become the preferred option. Here are some concerns: lung cancer experts want to see how much the combination extends patients’ lives. Bristol doesn’t have the final numbers yet, but early results published today show 67 percent of the TMB-high patients on nivo-ipi were alive after one year of treatment, compared to 59 percent of those on chemotherapy. Though early, Hellmann says that slight separation “is certainly encouraging.”
Doctors also expressed concern about the two to three weeks it might take to test for TMB, which requires DNA sequencing, rather than getting patients started faster on another regimen—say, pembrolizumab, or pembro-chemo. Hellmann acknowledges “the turnaround time matters” but argues that tests are become more frequent and routine, meaning delays could start to shrink.
What of the price of lumping two expensive immunotherapies together, rather than one and a cheaper chemotherapy? Confining nivo-ipi to high-TMB patients could mitigate the impact of its cost, says Hellmann. But when people respond to immunotherapy, those responses tend to last, and they keep getting treated. Chow has patients who have been on immunotherapy more than 6 years.
“Nobody wants to go off of it,” she says. “I’m not sure that’s sustainable.”
That concern extends to all checkpoint inhibitors—another name for nivolumab, pembrolizumab, and their rivals—all with a price tag of roughly $150,000 a year. Lyman doesn’t see competition between Merck, Bristol, and others bringing costs down anytime soon. Instead, he says, to reduce unnecessary costs, biomarkers like TMB “will be key” to identify the patients who should be taking a drug, and who shouldn’t.
IMPower150
To some extent, Roche has already answered the two main questions for this 1,200-patient study: whether its four-drug cocktail can lengthen the time a patient remains alive (overall survival); and how long her cancer is kept from spreading (progression-free survival). Its immunotherapy atezolizumab, when added to Roche’s bevacizumab (Avastin) and a one-two punch of chemotherapy, held tumors in check—8.3 months, compared to 6.8 months for Avastin plus chemo. Those results were detailed at a medical meeting in December.
Roche has also previously revealed that
