Bristol Myers Squibb is no stranger to mixing checkpoint inhibitors—see the many indications approved and in development for the combination of Opdivo and Yervoy.
Now, the drugmaker is one step closer to offering a new checkpoint inhibitor cocktail for the treatment of advanced melanoma, with the first phase 3 data for a LAG-3 antibody in tandem with the PD-1 blocker Opdivo.
The combination did twice as well as Opdivo at staving off cancer progression: patients who received the combo went a median of 10.1 months before their cancer got worse, compared to 4.6 months for the patients who received Opdivo alone.
The phase 3 results, to be presented virtually at the annual meeting of the American Society for Clinical Oncology, come from more than 700 patients with metastatic melanoma who had not tried any other therapies and whose cancer could not be treated with surgery. About half of the patients received the fixed-dose combination of Opdivo and the LAG-3 antibody relatlimab, while the other half got Opdivo.
At the one-year mark, nearly half (48%) of the patients who received the combo still had not seen their cancer worsen, compared to 36% of those who received Opdivo alone. The trial hasn’t been going long enough to report how long the combination is helping patients live, but the company will present those numbers when they’re ready, said Samit Hirawat, M.D., chief medical officer at BMS.
Patients taking the combination experienced severe or life-threatening side effects at about twice the rate of patients who got Opdivo alone (18.9% versus 9.7%). Side effects led 14.6% of the combo group and 6.7% of the Opdivo group to quit the study and there were three treatment-related deaths in the combo group and two in the Opdivo group, which come out to less than 1% of patients in each group.
“While there is discontinuation on the doublet versus monotherapy, the overall benefit is still maintained in the overall population,” Hirawat said. “We believe that... the overall side effect profile is manageable and certainly not unexpected with regards to adverse events seen in I-O and combinations thereof.”
“The data speak very loudly for themselves that single-agent PD-1 is probably a suboptimal therapy now that we have shown for the second time that I-O plus I-O is better than I-O alone,” he said.
That said, it’s important to note that BMS compared the Opdivo-relatlimab combination to Opdivo alone, and not to Opdivo and Yervoy.
“It’s impossible to say one is better than the other because we did not do that study,” Hirawat said.
So, where does BMS see the new combination in the spectrum of melanoma treatment?
“Currently, patients with melanoma in the firstline setting are divided into thirds: one-third gets I-O plus I-O... One-third gets single-agent I-O and one-third is without an I-O-based regimen,” Hirawat said. “So, one could say 66% of patients are undertreated to an extent because they’re not getting the best treatment available.”
Though PD-1 drugs like Opdivo, Merck’s Keytruda and Roche’s Tecentriq have transformed the treatment of melanoma and other cancers, they don’t work for everyone—that’s why so many clinical trials are testing combinations to see which drugs might boost their efficacy. The hope is that adding relatlimab to Opdivo could give doctors another option to get the PD-1 blocker to work in more people.
The LAG-3 protein is an immune checkpoint receptor found on the surface of T cells. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer.
“We look forward to discussing these registrational data with health authorities to potentially bring this treatment to patients,” said Jonathan Cheng, M.D., senior vice president and head of oncology development at BMS, in a statement.
If all goes well with its studies in other cancer types, such as non-small cell lung cancer and liver cancer, BMS aims to launch additional phase 3 studies of relatlimab and Opdivo in those indications toward the end of this year and early next year, Hirawat said.