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Opdivo Plus Low-Dose Yervoy Combination Reduces the Risk of Progression or Death…

Bristol-Myers Squibb  announced initial results from the pivotal Phase 3 study, CheckMate -227, evaluating the Opdivo (nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab, 1 mg/kg) combination in first-line advanced non-small cell lung cancer (NSCLC) patients with high tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb). In the study, the combination demonstrated a superior benefit for the co-primary endpoint of progression-free survival (PFS) versus chemotherapy (HR 0.58; 97.5% CI: 0.41 to 0.81; p=0.0002). The PFS benefit was observed regardless of PD-L1 expression levels and in both squamous and non-squamous tumor histology. Additionally, based on an early descriptive analysis, encouraging overall survival was observed with the combination versus chemotherapy in patients with high TMB ≥10 mut/Mb (HR 0.79; 95% CI: 0.56 to 1.10).

“CheckMate -227 is the first Phase 3 study to demonstrate the important clinical benefit of combining two immunotherapy agents to treat first-line NSCLC patients with high TMB,” said Matthew D. Hellmann, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “Results demonstrated that first-line nivolumab plus ipilimumab can provide frequent, deep and durable responses compared with chemotherapy in patients with NSCLC who have TMB ≥10 mut/Mb. The trial also supports the rationale for molecular testing to determine potential biomarkers in patients with lung cancer.”

These data were featured during the official press program at the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago (Abstract #CT077). Findings will be presented at 11:35-11:55 AM CDT during the Clinical Trials Plenary Session, Immunotherapy Combinations: The New Frontier in Lung Cancer, and simultaneously published in The New England Journal of Medicine.

“Lung cancer is a highly complex disease, defined by multiple subtypes, making it increasingly important to define a more precise treatment approach for this disease,” said Sabine Maier, development lead, thoracic cancers, Bristol-Myers Squibb. “We are excited to have advanced the science by establishing in this study that TMB was an important biomarker that predicted which first-line lung patients experienced a clinically meaningful progression-free survival benefit with a chemotherapy-sparing option, Opdivo plus low-dose Yervoy combination. These results are an example of our goal to understand each patient type through our leading translational research capabilities.”

Grade 3-4 treatment-related adverse events (AEs) with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%) and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Additional Data from CheckMate -227 Presented at AACR 2018

Additional data from CheckMate -227 presented at AACR 2018 include subgroup analyses by tumor PD-L1 expression in patients with TMB ≥10 mut/Mb. In these analyses, PFS was significantly improved with the combination versus chemotherapy in patients with PD-L1 ≥1% (HR 0.62; 95% CI: 0.44 to 0.88) and PD-L1 <1% (HR 0.48; 95% CI: 0.27 to 0.85). Increased benefit with Opdivo plus low-dose Yervoy versus chemotherapy was also observed in patients with squamous histology (HR 0.63; 95% CI: 0.39 to 1.04) and non-squamous histology (HR 0.55; 95% CI: 0.38 to 0.80).

In the study, PFS also was evaluated with Opdivo versus chemotherapy among patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression as a secondary endpoint. An improvement in PFS with Opdivo monotherapy was not observed (HR 0.95; 97.5% CI: 0.61 to 1.48; p=0.7776).

About CheckMate -227

CheckMate -227 is an open-label Phase 3 trial evaluating Opdivo-based regimens versus platinum-doublet chemotherapy in patients with first-line advanced non-small cell lung cancer (NSCLC) across non-squamous and squamous tumor histologies. This program is comprised of three parts:

Part 1a: Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1
Part 1b: Opdivo plus low-dose Yervoy or Opdivo plus chemotherapy versus chemotherapy in patients whose tumors do not express PD-L1
Part 2: Opdivo plus chemotherapy versus chemotherapy in a broad population, regardless of PD-L1 or TMB status
There are two co-primary endpoints in Part 1 for the Opdivo plus Yervoy combination (versus chemotherapy): overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and progression-free survival (PFS) in patients with high tumor mutational burden (TMB) ≥10 mut/Mb across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). The primary endpoint in Part 2 is OS.

Secondary endpoints in TMB-selected patient populations were analyzed hierarchically: PFS with Opdivo monotherapy versus chemotherapy in patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression, and OS with Opdivo plus Yervoy versus chemotherapy in patients with TMB ≥10 mut/Mb. Based on this statistical hierarchy, OS in patients with TMB ≥10 mut/Mb with Opdivo plus Yervoy versus chemotherapy was a descriptive analysis.

In Part 1 of this study, patients were randomized 1:1:1 to Opdivo 3 mg/kg every two weeks plus low-dose Yervoy 1 mg/kg every six weeks; histology-based platinum-doublet chemotherapy every three weeks for up to four cycles; and Opdivo 240 mg every two weeks (Part 1a) or Opdivo 360 mg plus histology-based platinum-doublet chemotherapy every three weeks for up to four cycles, followed by Opdivo monotherapy (Part 1b).

Of all randomized patients in Part 1 (N=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB ≥10 mut/Mb, including 139 patients randomized to Opdivo plus Yervoy and 160 patients randomized to chemotherapy. In the trial, TMB was assessed using the validated assay, FoundationOne CDx.