Mutation Burden and PD-L1 Expression Influence Response to Nivolumab in NSCLC

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A new study in the New England Journal of Medicine has found that a combination of tumor mutation burden and expression of the programmed death ligand-1 (PD-L1) can predict patient response to nivolumab in non—small-cell lung cancer (NSCLC).

According to a new study, the immunotherapy drug nivolumab showed efficacy similar to chemotherapy in the entire sample of patients with non—small-cell lung cancer (NSCLC), but demonstrated improved response rates and survival times in subgroups of patients with certain clinical characteristics.

The traditional first-line treatment for advanced NSCLC is platinum-based chemotherapy, which generally results in just 4 to 6 months of median progression-free survival (PFS). Nivolumab, sold as Opdivo, is a programmed death 1 (PD-1) immune-checkpoint—inhibitor antibody. Prior research has shown promising effects on progression-free survival, with a median of 10.6 months. The clinical benefits of nivolumab appear to be enhanced for patients with higher (at least 5%) levels of programmed death ligand-1 (PD-L1) expression.

The research published in the New England Journal of Medicine details results of a randomized phase 3 trial comparing the efficacy and safety of nivolumab and chemotherapy as a first-line treatment for 541 patients with stage IV or recurrent NCSLC. The primary efficacy analysis population (78% of all randomized patients) consisted of those with a PD-L1 expression level of at least 5%, while those with lower levels made up the secondary efficacy analysis population.


PFS was similar between the 2 treatment groups in both the primary efficacy analysis population and all randomized patients: median PFS was 4.2 months in nivolumab group and 5.9 months in the chemotherapy group in the primary efficacy analysis population (not statistically significant); it was 4.2 months in the nivolumab group and 5.8 months in the chemotherapy group in the overall randomized population (not statistically significant). There was also no significant difference in median overall survival time between the 2 treatment groups in the primary efficacy analysis population (14.4 months for nivolumab vs 13.2 months for chemotherapy).

Among patients with a PD-L1 expression level of 5% or more, those receiving nivolumab had lower response rates, but a higher percentage achieved a best response of progressive disease, compared with those receiving chemotherapy. The groups had a similar median time to response, but the nivolumab group had a median response duration of 12.1 months, more than double the median duration of 5.7 months in the control group.

Despite not finding improved PFS times overall with nivolumab, the researchers gained valuable information about which disease characteristics may make a patient more likely to respond to nivolumab.

“The good news is that we discovered that a subset of patients who had both high tumor mutation burden and high PDL-1—positive status did experience a significant benefit from immunotherapy,” said lead investigator David Carbone, MD, PhD, in a press release from The Ohio State University Comprehensive Cancer Center, where he is director of the James Thoracic Center.

Specifically, 75% of patients with both a high tumor-mutation burden and a PD-L1 expression level of at least 50% responded to nivolumab, compared with 32% among patients with only high mutation burden, 34% with only high PD-L1 levels, and 16% with neither factor. Of the patients with a high tumor-mutation burden, median PFS was 9.7 months with nivolumab and 5.8 months with chemotherapy.

Patients in the nivolumab group were less likely to experience treatment-related adverse events of any grade, as well as of grade 3 or 4, than those treated with chemotherapy.

Researchers noted that the results supported the hypothesis that immunotherapy may be more efficacious for those with high tumor-mutation burden, but cautioned that further study is needed.

“This study is an important step toward understanding the impact of tumor mutation burden and PDL-1 in immunotherapy response,” said Carbone in the press statement. “This data shows we should evaluate these two factors independently to most accurately define who will benefit from immunotherapy.”