Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.

Abstract

BACKGROUND:

Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).

METHODS:

We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.

RESULTS:

Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .).

CONCLUSIONS:

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

• Authors: Matthew D Hellmann, Tudor-Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory A Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S Ramalingam, Julie Brahmer, Martin Reck, Kenneth J O'Byrne, William J Geese, George Green, Han Chang, Joseph Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, Yali Fu, Faith Nathan, Luis Paz-Ares
• Journal: The New England journal of medicine (N Engl J Med) Vol. 378 Issue 22 Pg. 2093-2104 (May 31 2018) ISSN: 1533-4406 [Electronic] United States
• PMID: 29658845 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Ipilimumab
• Nivolumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antineoplastic Agents, Immunological (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Disease-Free Survival
• Female
• Humans
• Ipilimumab (administration & dosage, adverse effects)
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, genetics)
• Male
• Middle Aged
• Mutation
• Neoplasm Staging
• Nivolumab