A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

Author:

Ansell Stephen1,Gutierrez Martin E2,Shipp Margaret A.3,Gladstone Douglas4,Moskowitz Alison5,Borello Ivan6,Popa-Mckiver Mihaela7,Farsaci Benedetto7,Zhu Lili7,Lesokhin Alexander M.8,Armand Philippe910

Affiliation:

1. Mayo Clinic, Rochester, MN

2. Hackensack University Medical Center, Hackensack, NJ

3. Dana-Farber Cancer Institute, Boston, MA

4. Johns Hopkins University, Baltimore, MD

5. Memorial Sloan Kettering Cancer Center, New York, NY

6. Johns Hopkins Medical Center, Baltimore, MD

7. Bristol-Myers Squibb, Princeton, NJ

8. Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

9. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Abstract

Abstract Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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