Prabhu Bhagavatheeswaran

First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer

BACKGROUND Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small‐cell lung cancer (NSCLC). In an open‐label phase 3 trial, we compared first‐line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD‐L1)–positive NSCLC. METHODS We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD‐L1 tumor‐expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum‐based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression‐free survival, as assessed by means of blinded independent central review, among patients with a PD‐L1 expression level of 5% or more. RESULTS Among the 423 patients with a PD‐L1 expression level of 5% or more, the median progression‐free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment‐related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment‐related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS Nivolumab was not associated with significantly longer progression‐free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD‐L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol‐Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)

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

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. 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 Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.)

Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026

Background: CheckMate 026 is a randomized trial of nivolumab monotherapy versus platinum doublet chemotherapy in patients with untreated stage IV or recurrent non-small cell lung cancer (NSCLC) and ≥1% programmed death-1 ligand 1 (PD-L1) tumor expression. Nivolumab was not associated with improved progression-free survival (PFS) versus chemotherapy in patients with ≥5% PD-L1 expression, however, nivolumab had a favorable safety profile compared with chemotherapy and overall survival (OS) was similar between treatment arms. In an exploratory analysis, we assessed whether patients with high tumor mutation burden (TMB) may derive enhanced benefit from nivolumab compared with platinum doublet chemotherapy. Methods: TMB scores for missense, somatic mutations were determined in patients with sufficient samples for whole exome sequencing of tumor and matched whole blood DNA. For the initial analyses, patients were equally divided into groups based on TMB tertile distribution. Patients in the low, medium, and high TMB tertiles had 0-99, 100-242, and ≥243 mutations, respectively. Results: Of 541 randomized patients, 312 (57.7%) had evaluable data to determine TMB. The percentage of patients with high TMB was lower in the nivolumab arm than in the chemotherapy arm (29.7% vs 39.0%). Baseline characteristics, PFS, and OS in patients evaluable for TMB were similar to all randomized patients. In patients with high TMB, PFS was improved (median PFS of 9.7 vs. 5.8 months; HR, 0.62; 95% CI, 0.38 to 1.00) and objective response rate was higher with nivolumab versus chemotherapy (46.8% vs 28.3%). OS in patients with high TMB was similar between the 2 treatment arms, which may be attributable in part to a 65% crossover rate to nivolumab in the chemotherapy arm for this subgroup. Conclusions: This is the first pivotal randomized phase 3 trial to incorporate an analysis evaluating TMB and clinical benefit with programmed death-1 inhibitor therapy. The findings of this exploratory retrospective analysis suggest that nivolumab improves ORR and PFS compared with platinum doublet chemotherapy in patients with high TMB. Citation Format: Solange Peters, Benjamin Creelan, Matthew D. Hellmann, Mark A. Socinski, Martin Reck, Prabhu Bhagavatheeswaran, Han Chang, William J. Geese, Luis Paz-Ares, David P. Carbone. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT082. doi:10.1158/1538-7445.AM2017-CT082

A retrospective analysis of cross‐reacting cetuximab IgE antibody and its association with severe infusion reactions

Severe infusion reactions (SIRs) at rates of 5% or less are known side effects of biological agents, including mAbs such as cetuximab. There are currently no prospectively validated risk factors to aid physicians in identifying patients who may be at risk of experiencing an SIR following administration of any of these drugs. A retrospective analysis of 545 banked serum or plasma samples from cancer patients participating in clinical trials of cetuximab was designed to evaluate whether the presence of pretreatment IgE antibodies against cetuximab, as determined by a commercially available assay system, is associated with SIRs during the initial cetuximab infusion. Patients with a positive test indicating the presence of pretreatment antibodies had a higher risk of experiencing an SIR; however, at the prespecified cutoff utilized in this analysis, the test has a relatively low‐positive predictive value (0.577 [0.369–0.766]) and a negative predictive value of 0.961 (0.912–0.987) in an unselected patient population. Data collected in this large retrospective validation study support prior observations of an association between the presence of pretreatment IgE antibodies cross‐reactive with cetuximab and SIRs. Further analysis of the tests ability to predict patients at risk of an SIR would be required before this assay could be used reliably in this patient population.

An open label randomized Phase III trial of nivolumab or nivolumab plus ipilimumab vs platinum doublet chemotherapy (PT-DC) in patients with chemotherapy-naïve stage IV or recurrent non-small cell lung cancer (NSCLC) (CheckMate 227)

Meeting abstracts Patients with advanced NSCLC are treated with first-line PT-DC, which is associated with a median OS of 8–10 months and 1-year and 2-year survival rates of 30–40% and 10–15%, respectively. Nivolumab (a fully human IgG4 anti-programmed death-1 immune checkpoint inhibitor