News Releases

Opdivo Plus Low-Dose Yervoy Combination Reduces the Risk of Progression or Death by 42% Versus Chemotherapy in First-Line Lung Cancer Patients with High Tumor Mutational Burden (TMB)

In the Phase 3 CheckMate -227 trial, the one-year progression-free survival rate was more than triple with the combination versus chemotherapy (43% vs. 13%) in first-line non-small cell lung cancer patients with high TMB ≥10 mut/Mb

 

Near doubling of overall response rate with the combination (45.3%) versus chemotherapy (26.9%); 68% of responders had ongoing responses at one year (25% with chemotherapy)

 

 

Grade 3-4 treatment-related adverse event rate with the Opdivo plus low-dose Yervoy combination was 31% versus 36% with chemotherapy

17/04/18

Bristol-Myers Squibb Company (NYSE: BMY) announced yesterday the 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."

This data was presented yesterday during the official press program at the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago (Abstract #CT077). 2

Findings were 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 3

(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.

About Tumor Mutational Burden (TMB)

Over time, cancer cells accumulate mutations that are not seen in normal cells of the body. Tumor mutational burden, or TMB, is a quantitative biomarker that reflects the total 4

number of mutations carried by tumor cells. Tumor cells with high TMB have higher levels of neoantigens, which is thought to help the immune system recognize tumors and incite an increase in cancer-fighting T cells and an anti-tumor response. TMB is one type of biomarker that may help predict the likelihood a patient responds to immunotherapies.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are advancing the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. Through our leading translational capabilities, we are pioneering immune biology research and identifying a number of potentially predictive biomarkers, including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of precision medicine for more patients with cancer.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers. 5

 

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.ca.

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