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Bristol-Myers Squibb Announces Studies Evaluating liso-cel in Multiple Additional Patient Populations, Site of Care and Disease Areas Presented at American Society of Hematology (ASH) Annual Meeting

Heavily pre-treated patients with chronic lymphocytic leukemia receiving liso-cel achieved durable complete responses, including undetectable minimal residual disease

Preliminary data from the PILOT study showed promising efficacy and safety as second-line therapy in patients with aggressive relapsed or refractory large B-cell non-Hodgkin lymphoma who were transplant ineligible

Separate analysis of patients treated in the outpatient setting across three studies also presented

Bristol-Myers Squibb Company (NYSE: BMY) today announced data from multiple studies evaluating lisocabtagene maraleucel (liso-cel), an investigational CD19-directed CAR T-cell therapy with a defined composition of purified CD8+ and CD4+ CAR T cells, were presented during the 2019 ASH Annual Meeting in Orlando, Fla. These studies included an evaluation of liso-cel in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (TRANSCEND CLL 004); a study in second-line patients with relapsed or refractory large B-cell non-Hodgkin’s lymphoma (NHL) patients who were ineligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT) (PILOT); and a separate analysis of patients with relapsed/refractory large B-cell non-Hodgkin lymphoma who received liso-cel in the outpatient setting across three studies.

"As we continue to evaluate liso-cel in important new disease settings and areas of unmet medical need, we are encouraged to see the early results from these studies," said Stanley Frankel, M.D., Senior Vice President, Cellular Therapy Development for Bristol-Myers Squibb. "The results in relapsed or refractory CLL and SLL demonstrated a high rate of durable complete responses achieved in heavily pre-treated patients, including patients who have failed ibrutinib and venetoclax. We are encouraged by the potential of liso-cel to treat second-line relapsed or refractory large B-cell NHL patients who are not able to undergo a stem cell transplant. Finally, the analysis evaluating liso-cel administered in the outpatient setting demonstrates that not all patients require hospitalization and that the safety and efficacy profile across a variety of types of clinical sites is consistent."

TRANSCEND CLL 004

In the phase 1/2 TRANSCEND CLL 004 study, at the data cutoff, 23 patients with CLL/SLL who had received at least three (standard-risk disease) or two (high-risk disease) prior treatments were evaluable for safety, with 22 patients evaluable for efficacy. Patients had a median of 5 prior lines of therapy (range 2-11). All patients (23/23) had received prior ibrutinib and most (21/23) were refractory to or had relapsed on the BTK inhibitor. There were nine patients (39%) that had failed both a BTK inhibitor (progressed on treatment) and venetoclax (did not achieve a response after at least 3 months). Most patients (83%) had high-risk features including deletion 17p (35%, 8/23) and TP53 mutation (61%, 14/23). Patients received liso-cel target doses of either 50 × 106 (n=9) or 100 × 106 (n=14) CAR+ T cells following lymphodepletion.

Treatment-emergent adverse events (TEAE) of any grade occurred in 100% (23/23) of patients with 96% (22/23) of patients experiencing a grade 3 or higher TEAE. The most common grade 3 or higher TEAEs occurring in at least 25% of patients were anemia (78%, 18/23), thrombocytopenia (70%, 16/23), neutropenia (56.5%, 13/23), leukopenia (43.5%, 10/23), febrile neutropenia (26%, 6/23), lymphopenia (26%, 6/23) and cytokine release syndrome (9%, 2/23).

Seventy-four percent (17/23) of patients had cytokine release syndrome (CRS) of any grade with 9% of patients (2/23) experiencing grade 3 CRS. Thirty-nine percent (9/23) of patients had neurological events (NE) of any grade, while 22% (5/23) of patients had grade 3 or higher NE. Median time to onset of CRS was 4 days (range 1-10 days) and of NE was 4 days (range 2-21). Incidence and severity of CRS and NEs were similar for patients who failed a BTK inhibitor and venetoclax. Seventy-four percent (17/23) of patients received tocilizumab and/or corticosteroids. There were no grade 5 events.

At a median follow-up of 11 months, the overall response rate (ORR) for patients receiving liso-cel was 81.5% (18/22, 95% CI: 59.7 – 94.8) with 45.5% (10/22) of patients achieving a complete response (CR). In patients that had failed a BTK inhibitor and venetoclax, the ORR was 89% (8/9, 95% CI: 51.8 – 99.7) with 67% (6/9) achieving a CR. By day 30 following treatment, 68% (15/22) of patients had achieved an early objective response with 10 of 12 responders at 6 months remaining progression-free after at least 9 months, and eight patients in response at 12 months or longer. Among 20 patients evaluable for minimal residual disease (MRD), the majority achieved undetectable MRD in the blood (75%) and bone marrow (65%) by next-generation sequencing. All patients who achieved undetectable MRD have maintained this status at last follow-up.

PILOT

In the phase 2 PILOT study, patients had relapsed/refractory large B-cell NHL, had received only 1 prior line of immunochemotherapy and had been deemed ineligible for HSCT due to patient factors including age, comorbidities or performance status. Patients received liso-cel at a target dose of 100 × 106 CAR+ T cells following lymphodepletion and could be treated in the outpatient setting at the investigator’s discretion.

At the time of data cutoff, 19 patients had been leukapheresed, with 13 patients receiving lymphodepletion followed by liso-cel.

Of the 13 patients, eight (61.5%) had at least one grade 3 or higher TEAE and these were primarily cytopenias. Four patients (31%) had prolonged grade 3 or higher cytopenias at day 29. No patients had grade 3 or higher CRS and no patients experienced NE of any grade. Grade 1-2 CRS occurred in 3 (23%) patients. There were no grade 5 TEAEs. Finally, of the 6 patients treated in the outpatient setting, none were admitted to the hospital in the first 29 days following liso-cel infusion.

All 12 (100%) patients eligible for response evaluation achieved a response with 6 (50%) patients achieving a CR. Seven of 12 (58%) patients maintained response levels at 3 months following liso-cel infusion.

Outpatient Administration

A report of the safety and efficacy of liso-cel in patients with relapsed/refractory large B-cell NHL treated in the outpatient treatment setting was also presented. The analysis encompassed three studies including OUTREACH (n=13), the only trial evaluating CAR T-cell therapy in an outpatient setting at non-university centers, including treatment sites not accredited by the Foundation for the Accreditation of Cellular Therapy. The analysis also included TRANSCEND NHL 001 (n=25) and PILOT (n=6).

Outpatient treatment required patient education regarding CAR T-cell therapy, a caregiver and proximity to the treatment location. Additionally, each site was required to have specific readiness plans for patient care and monitoring for AEs, such as CRS and NE, in the outpatient setting.

In the analysis, at data cutoff, 44 patients treated in the outpatient setting from across the studies were evaluated and received liso-cel on day 1. Seventeen (39%) patients had CRS of any grade, while 13 (30%) patients had NE (n=13) of any grade. There was 1 case of grade 3 or higher CRS and 2 cases of grade 3 or higher NE and these were reversible. A total of 9 patients received supportive tocilizumab and/or corticosteroids. Fifty-five percent (24/44) of patients required hospitalization at some point and these were all from TRANSCEND or OUTREACH. Of these patients, 9 (20%) were admitted on study day 4 or earlier. Two (5%) patients required intensive care unit-level care lasting a median of 4 days. No patients from PILOT were admitted to hospital in the first 29 days. Following treatment, the median time to hospitalization was 5 days (range 2-22) and the median length of stay was 6.5 days (range 1-23). TEAEs of any grade reported in at least 20% of patients included fatigue, neutropenia, decreased appetite, CRS, anemia, constipation, nausea, headache, cough, dizziness, hypotension, thrombocytopenia, vomiting, back pain, diarrhea hypomagnesemia and tremor.

Across the studies, the ORR was 80% (35/44) with 55% (24/44) of patients achieving a complete response.

Liso-cel is not approved for any indication in any country.

Bristol-Myers Squibb: Advancing Cancer Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase quality, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational chimeric antigen receptor (CAR) T-cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

About Lisocabtagene Maraleucel (liso-cel)

Liso-cel is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. Liso-cel CAR T cells aim to target CD19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. The defined composition of CD4+ and CD8+ CAR T cells in liso-cel may limit product variability; however, the clinical significance of defined composition is unknown.

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, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results will be consistent with the results to date, that liso-cel may not achieve its primary study endpoints or receive regulatory approval for the indications described in this release in the currently anticipated timeline or at all and, if approved, whether such product candidate for such indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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