Lung cancer patients treated for the first time with a combination of two immune checkpoint inhibitors lived longer without disease progression than those who received standard chemotherapy, according to preliminary results from the CheckMate-227 study announced this week by Bristol-Myers Squibb.

The Phase III findings came from a subset of study participants with previously untreated advanced non-small-cell lung cancer who had a high tumor mutation burden, meaning their cancer cells had accumulated many genetic changes. Patients using Opdivo (nivolumab) plus Yervoy (ipilimumab) had significantly longer progression-free survival than those using standard chemotherapy.

Non-small-cell lung cancer (NSCLC), which accounts for more than 80 percent of all lung cancers, is often detected late and has a high mortality rate. Lung cancer is the leading cause of cancer-related death for both men and women in the United States, according to the National Cancer Institute.

Opdivo is a monoclonal antibody that blocks the PD-1 receptor, an immune checkpoint on T cells that plays a role in regulating immune function. Some tumors can hijack PD-1 to turn off immune responses against them. Drugs like Opdivo block the interaction between PD-1 on T cells and its PD-L1 binding partner on cancer cells, releasing the brakes and restoring T-cell activity. Yervoy blocks a different immune checkpoint, CTLA-4, which turns off immune responses by suppressing T-cell multiplication.

The previous CheckMate-026 study produced disappointing outcomes for first-line therapy for NSCLC using Opdivo alone, showing that it did not extend survival significantly more than chemotherapy.

This was surprising because a drug in the same class—Merck’s Keytruda (pembrolizumab)—demonstrated improved survival for first-line patients with metastatic NSCLC in the KEYNOTE-024 trial, and it was approved by the Food and Drug Administration (FDA) for this indication.

But the patient populations chosen for the studies may have made a difference. Merck’s trial included people whose tumors had a high level of PD-L1 expression (at least 50 percent) and Keytruda was approved for this limited population. Bristol-Myers Squibb’s study enrolled people with much lower tumor PD-L1 levels (at least 1 percent). Opdivo is not yet approved for first-line NSCLC treatment but only for those who have already tried chemotherapy.

People with higher tumor PD-L1 levels should respond better to PD-1 checkpoint blockers. Or so the thinking went. Since then, researchers have found that PD-L1 levels do not seem to be the key to treatment response. Some people with high PD-L1 levels do not respond to PD-1 inhibitors, while some people with very low levels do respond well.

We now know that tumor mutation burden (TMB), or the number of genetic changes in a tumor, is also an important factor. Cancer that has accumulated more genetic mutations not present in normal cells is more easily recognized by the immune system, so T cells unleashed by this type of treatment are better able to find and kill cancer cells.

CheckMate-227 enrolled more than 2,500 previously untreated people with advanced NSCLC. About 45 percent of those evaluated with the Foundation one test had tumors with a high mutation burden, defined as at least 10 mutations per megabase, or 1 million base pairs of DNA.

Part 1a of the study compared Opdivo (3 milligrams per kilogram every two weeks) plus Yervoy (1 mg/kg every six weeks), Opdivo alone or platinum-based chemotherapy for patients with tumors that carry PD-L1. Part 1b compared Opdivo plus Yervoy, Opdivo plus chemotherapy or chemotherapy alone in patients with tumors that don’t express PD-L1.

The study had two primary endpoints: 1) progression-free survival in patients with a high tumor mutation burden regardless of PD-L1 levels; and 2) overall survival in patients whose tumors carry PD-L1.

Bristol-Myers Squibb announced in a press release that progression-free survival was longer for high-TMB patients treated with Opdivo plus Yervoy, regardless of PD-L1 expression. The difference was statistically significant, meaning it was probably not attributable to chance. The company did not report detailed findings, which it said would be presented at an upcoming conference. CheckMate-227 is ongoing and overall survival in the PD-L1 positive group will be reported in the future.

The major concern with checkpoint inhibitors is immune-related adverse events. In addition to restoring immune responses against cancer cells, they can also take the brakes off the immune system more broadly, leading to excessive inflammation of healthy tissue. The company said the side effects in this study were consistent with those previously reported for this combination.

Along with the better outcomes seen with the Opdivo plus Yervoy combination, this study validates tumor mutation burden as a biomarker for predicting treatment response—at least for this type of cancer and patient population.

“TMB has emerged as an important biomarker for the activity of immunotherapy. For the first time, this Phase III study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” study investigator Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center said in the press release. “CheckMate-227 showed that TMB is an important, independent predictive biomarker that can identify a population of first-line NSCLC patients who may benefit from the nivolumab plus ipilimumab combination.”

Click here to read Bristol-Myers Squibb’s press release about the study.