[Updated 2/5/18, 2:36 p.m. See below.] A combination of two Bristol-Myers Squibb immunotherapies has achieved the main goal of a late-stage study in lung cancer, according to preliminary results the company released on Monday. But even though Bristol says the trial supports a new way of identifying patients who could best respond to its treatment, outside observers remain cautious and want to see more details.
Bristol (NYSE: BMS) is testing its two drugs, nivolumab (Opdivo) along with ipilimumab (Yervoy), which both boost the immune response to tumors, in patients newly diagnosed with non-small cell lung cancer. The company said that compared against chemotherapy, the two drugs together helped patients live longer without the cancer getting worse, also referred to as progression-free survival.
The combination of Bristol drugs is already approved as a treatment for melanoma. Nivolumab and ipilimumab are checkpoint inhibitors, part of a class of drugs that work by blocking a protein that tumors use to evade detection by the immune system. These drugs don’t work for everyone, so companies are trying different combinations in hopes of treating more cancer patients.
The Phase 3 study, called CheckMate-227, enrolled more than 2,500 patients. Bristol says the positive clinical trial results were observed in patients whose tumors have “high tumor mutation burden,” a measure of the level of genetic mutations carried by tumor cells. The company says this measure is an indicator of a subset of patients that could respond to the combination of its two drugs. Approximately 45 percent of the patients in the study had high tumor mutation burdens, Bristol said. Those patients were identified using a test developed by Cambridge, MA-based Foundation Medicine (NASDAQ: FMI)
Nivolumab blocks a protein called PD-L1, and the trial was initially designed to test the drug combination on patients whose tumors expressed that protein, as well as those patients whose tumors didn’t. Fouad Namouni, head of oncology development at Bristol, told Xconomy’s Ben Fidler that while this protein is a useful biomarker—an indicator of disease—reaching more patients will require the use of additional indicators. Namouni said he thinks tumor mutation burden will become an important biomarker for immunotherapy. In future cancer clinical trials, Bristol will be looking for this biomarker in tumors and in the blood, he added.
“One could imagine that multiple biomarkers could lead us to different types of combinations in patients, and that will probably improve the benefit for these subgroups of patients,” Namouni said.
Umer Raffat, an analyst at Evercore ISI, wrote in a research note that evidence has emerged suggesting that the key to showing an immunotherapy’s benefit is to target treatments to specific subsets of patients. But he added that while Bristol is showing that its drug combination works in a subset of patients, it’s a different approach than what the company initially set out to do in the trial and it’s not entirely clear why the company changed its plans.
Raffat said Evercore has confirmed with Bristol that the company went to the FDA for the O.K to use slightly different clinical trial goals. The study is still gauging overall survival in patients whose tumors express PD-L1. But Bristol has added the co-primary goal of progression-free survival in patients with high tumor mutation burden. Raffat also said that Bristol’s results so far don’t show how well the combination of nivolumab and ipilimumab are doing versus nivolumab alone.
“Ultimately, this is the most important question—mostly because we need to see incremental impact of Yervoy beyond Opdivo,” Raffat wrote.
[The following two paragraphs added with Jack West’s comments] Jack West, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle, said in an e-mail message to Xconomy that Bristol’s preliminary results add momentum to the growing evidence supporting tumor mutation burden as a relevant biomarker. But like Raffat, West, who is not involved in Bristol’s study, noted that this biomarker was not what the company initially set out to test. He added that Bristol set a lower threshold for what constitutes a high measure of tumor mutation burden than Foundation does for its test. The absence of consensus on a measure of the biomarker could undermine its usefulness in treating patients, West said.
“We should ensure that the lower threshold truly defines the group most likely to benefit from nivolumab/ipilimumab and isn’t being promulgated as a reverse-engineered result to maximize eligibility while still defining a population in which the positive result for [progression-free survival] is maintained,” he said.
Bristol isn’t the only company trying drug combinations to treat more lung cancer patients. In January, Merck (NYSE: MRK) reported positive results from a confirmational study in which patients newly diagnosed with non-small cell lung cancer were treated with its immunotherapy drug pembrolizumab (Keytruda) in combination with two chemotherapies. The FDA granted an accelerated approval of the combination last year on condition that the company conduct additional studies.
[Paragraph added with West comments] West is waiting to see more data, from both Bristol and Merck. Despite the FDA’s approval of the combination of the Merck’s pembrolizumab with chemotherapy, West said he and some other oncologists are unconvinced that Merck’s data support changing how they treat patients. Providing the therapies in sequence rather than in combination may yield the same improvements in overall survival, he said. West added that as oncologists become comfortable using the FDA-approved combination of Merck’s drug and chemotherapy, that treatment will become the true comparator to the combination of Bristol drugs.
Bristol said that the safety of its drug combination was consistent with earlier findings. Based on the interim analysis for overall survival, the other main goal of the clinical trial, the Data Monitoring Committee has recommended that the study continue.
Ben Fidler contributed to this report.
Lung cancer metastasis image by the National Cancer Institute.