High Tumor Mutation Burden in SCLC May Predict Improved Immunotherapy Response

October 18, 2017

Small-cell lung cancer patients with high tumor mutation burden treated with immunotherapy had greater objective response rate, progression-free survival, and overall survival compared with patients with medium or low tumor burden.

Patients with small-cell lung cancer (SCLC) and high tumor mutation burden had about double the objective response rate and 1-year overall survival when treated with the combination of nivolumab and ipilimumab compared with nivolumab alone, according to the results of the CheckMate 032 study. However, regardless of treatment arm, those patients with high tumor mutation burden had greater objective response rate, progression-free survival, and overall survival compared with patients with medium or low mutation burden.

Results were presented by Naiyer Rizvi, MD, of Columbia University Medical Center in New York, at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer, held October 15–18 in Yokohama, Japan.

Initial findings from CheckMate 032, a phase I/II clinical trial evaluating nivolumab with or without ipilimumab in solid tumors, showed that this treatment is promising. However, there have been no clear biomarkers to predict patient response.

CheckMate 032 was a pooled analysis of nivolumab plus ipilimumab in non-randomized and randomized cohorts. Whole exome sequencing was performed in tumor and matched blood samples. Tumor mutation burden was defined as low, medium, or high based on the total number of nonsynonymous somatic mutations.

About one-half of patients (n = 211) had evaluable tumor mutation burden. Among these patients treated with nivolumab alone, the objective response rate was higher in patients with high TMB compared with median and low TMB (21.3% vs 6.8% and 4.8%). The same was true for 1-year progression-free survival (21.2% vs 3.1% and not calculable) and 1-year overall survival (35.2% vs 26% and 22.1%).

Similar benefits were seen in patients treated with the combination of nivolumab plus ipilimumab for objective response rate (46.2% vs 16% and 22.2%), 1-year progression-free survival (30% vs 8% and 6.2%) and 1-year overall survival (62.4% vs 19.6% and 23.4%).  Additionally, the researchers found that in each cohort of TMB, nivolumab plus ipilimumab outperformed nivolumab treatment alone.

Their findings highlight that high TMB is associated with improved responses to nivolumab with or without ipilimumab in patients with SCLC and suggest that TMB may be a relevant biomarker across all patients with lung cancers.

“The results from our study provide the clearest evidence to date demonstrating the power of TMB as a biomarker,” said Rizvi. “This may even begin to impact prescribing practice in SCLC by clarifying the benefit that can be achieved for some patients, encouraging molecular testing for estimating mutation burden in SCLC and using greater precision to identify subgroups of patients with SCLC who may exceptionally benefit from nivolumab with ipilimumab.”