Encouraging Response Observed with Opdivo (nivolumab) Plus Investigational IDO1 Inhibitor, BMS-986205, in Heavily Pre-Treated Patients with Advanced Cancers in Phase 1/2a Study CA017-003

First disclosure of anti-tumor activity from the bladder and cervical cancer cohorts showed objective response rates of 32% and 14%, respectively, and was 46% and 25% in patients who express PD-L1 ≥1%

Increased proliferating cytotoxic T cell count and decreased kynurenine production were also observed, providing evidence of immunomodulation within the tumor

Safety profile is consistent with that previously reported for the BMS-986205 plus Opdivo combination

PRINCETON, NJ, USA I November 10, 2017 I Bristol-Myers Squibb Company (NYSE:BMY) today announced updated results for Opdivo (nivolumab) plus BMS-986205, a selective, once-daily oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor from the ongoing Phase 1/2a dose escalation and expansion study, CA017-003. In the dose escalation phase, the maximum tolerated dose (primary endpoint) of BMS-986205 in combination with Opdivo was 200 mg. Based on safety and pharmacodynamic data, the recommended dose for further study was determined to be 100 mg. In the dose expansion phase, findings for anti-tumor activity (primary endpoint) were reported in two cohorts – heavily pre-treated bladder (n=25) and cervical cancer patients (n=22). In the bladder cancer cohort, the objective response rate (ORR) and disease control rate (DCR) were 32% and 44%, respectively. In the cervical cancer cohort, the ORR was 14% and DCR was 64%. The study also measured ORR by PD-L1 expression levels; in patients who express PD-L1 ≥1%, ORR was 46% and 25% in the bladder (n=13) and cervical cancer cohorts (n=12), respectively. In patients who express PD-L1 <1%, ORR was 22% in the bladder cancer cohort (n=9); no response was observed in cervical cancer patients (n=7). Response was observed regardless of prior lines of therapy.

These data will be presented Saturday, November 11 at the Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting in National Harbor, Maryland, in an oral presentation during Late-Breaking Abstract Session II in the Maryland Ballroom from 12:00 – 12:15 p.m. ET (Abstract #O41).

Jason Luke, M.D., study investigator and assistant professor of medicine at the University of Chicago, commented, “The preliminary response observed with BMS-986205 plus nivolumab in this study adds to our understanding of this combination, and together with the increases in tumor CD8 positive T cells and decreases in kynurenine, suggests a potent effect, which warrants further investigation across advanced cancers.”

IDO1 is an enzyme that breaks down tryptophan, an essential amino acid which fuels cytotoxic T cells, to help regulate the immune system and avoid an over-response to threats. Some tumors express excessive amounts of IDO1 and deplete tryptophan, resulting in kynurenine production, which starves T cells of their fuel and prevents the immune system from responding appropriately to the cancer. Preclinical studies evaluating BMS-986205 suggest that targeting the IDO1 pathway in combination with other possible complementary immune pathways has the potential to more effectively activate the anti-tumor response. Early clinical data also show anti–PD-1 therapy may upregulate IDO1 expression in patients.

Mark Rutstein, development lead, IDO, Bristol-Myers Squibb, commented, “We are urgently pursuing transformative research to better understand tumor evasion mechanisms to help inform potential new treatment options for patients with advanced cancers. BMS-986205 has shown encouraging characteristics, including potent and selective inhibition of IDO1, as well as pharmacokinetic data that support once-daily dosing. We look forward to additional data from this study.”

About CA017-003

CA017-003 is an ongoing Phase 1/2a dose escalation and expansion study evaluating BMS-986205 in patients with advanced cancers in combination with other agents, including Opdivo and Yervoy (ipilimumab), at different doses and schedules. The primary objectives of the dose escalation study are to establish the safety, tolerability, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), maximum administered dose (MAD) or alternate dose; BMS-986205 doses from 25 to 400 mg once-daily (QD) were evaluated in combination with Opdivo given 240 mg every two weeks. The secondary objectives in the dose escalation phase include pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity. The primary objective of the dose expansion phase is to investigate preliminary anti-tumor activity, as well as safety and tolerability with BMS-986205 in combination with Opdivo. In this portion of the study, patients received BMS-986205 100 or 200 mg orally QD in combination with Opdivo 240 mg intravenously every two weeks, or 480 mg intravenously every four weeks.

The study evaluated potency of BMS-986205 by measuring serum kynurenine, an immune-modulating metabolite produced by the IDO1 enzyme that potentially allows cancer cells to escape the immune response. In addition to the anti-tumor activity data presented at SITC, additional results included evidence of increased kynurenine inhibition in the blood, with 56% inhibition achieved at the 100 mg dose selected for further evaluation. Kynurenine was also evaluated in pre- and on-treatment tumor samples, with reductions of up to 100% noted. Proliferating CD8 positive T cells were also increased in the paired tumor samples from a range of tumor types, providing evidence of immunomodulation within the tumor microenvironment by an IDO1 inhibitor in combination with a PD-1 inhibitor.

Across doses from 25 to 400 mg of BMS-986205 in combination with Opdivo (n=286), treatment-related Grade 3/4 toxicities occurred in 11% of patients. Those occurring in two or more participants included increased AST (1.7%), increased ALT (1.4%), anemia (1.4%), autoimmune hepatitis (1.4%), fatigue (0.7%), pneumonitis (0.7%), hepatitis (0.7%), hyponatremia (0.7%), hypophosphatemia (0.7%) and increased lipase (0.7%). In the study, 1.4% of patients were discontinued due to study-drug toxicity.

Bristol-Myers Squibb is evaluating BMS-986205 in combination with Opdivo across several advanced cancers, and recently initiated a Phase 3 study evaluating this combination in patients with previously untreated metastatic or unresectable melanoma.

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 leading 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 more than 15 clinical-stage programs 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. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

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.

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.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO ®

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO® (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma; Checkmate 040 – hepatocellular carcinoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd. (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

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.com or follow us on LinkedIn, Twitter, YouTube and Facebook.

SOURCE: Bristol-Myers Squibb

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