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966 Blinatumomab in Combination with Immune Checkpoint Inhibitors (ICIs) of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Results of a Phase I Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Novel Therapies for ALL
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, clinical trials, Biological therapies, Research, ALL, Bispecific Antibody Therapy, Clinical Research, Checkpoint Inhibitor, Diseases, Immunotherapy, Therapies, Lymphoid Malignancies
Monday, December 11, 2023: 5:45 PM

Jonathan Allen Webster, MD1, Marlise R. Luskin, MD2, Joseph Rimando, MD3, Amanda Blackford4*, Amer M. Zeidan, MBBS, MHS5, Elad Sharon, MD, MPH6*, Howard Streicher, MD7*, Daniel J. DeAngelo8, Leo Luznik, MD9 and Ivana Gojo, MD10

1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, Johns Hopkins University School of Medicine, ATLANTA, GA
4Johns Hopkins University, Baltimore, MD
5Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT
6NCI Cancer Therapy Evaluation program (CTEP), Bethesda, MD
7NCI NIH IDB, Rockville, MD
8Dana-Farber Cancer Institute, Boston, MA
9Sidney Kimmel Comprehensive Cancer Ctr., Baltimore, MD
10Johns Hopkins, Baltimore, MD

Background: Blinatumomab (blina) improves outcomes in R/R CD19+ ALL compared to chemotherapy. However, the overall response rate to blina was 44%, and median overall survival (OS) is just 7.7 mos (Kantarjian. NEJM. 2017). Preclinical studies show increased PD-L1 expression on leukemic blasts potentially contributes to relapse after blina. The addition of PD-1 +/- CTLA-4 blockade to blina leads to increased in vitro T cell proliferation and enhanced cytotoxicity (Feucht. Oncotarget 2016). Thus, blockade of co-inhibitory pathways may enhance blina efficacy in vivo. We describe results of a multi-center phase I study combining blina with immune checkpoint inhibitors (ICIs) targeting PD-1 (nivolumab) +/- CTLA-4 (ipilimumab).

Methods: In a dose-escalation study, we evaluated the safety, tolerability, and preliminary efficacy of blina with nivolumab (nivo) +/- ipilimumab (ipi) using a 3+3 design. Pts ³16 years-old with R/R CD19+ B-ALL or mixed phenotype acute leukemia (MPAL) were eligible. Pts ³60 years could be untreated. Table 1 presents the dose escalation schema. Expansion cohorts of 6 pts were planned at the maximum tolerated dose (MTD) for blina + nivo AND blina + nivo + ipi. Pts received up to 5 cycles of blina and 1 year of ICIs. Pts removed from the study during the blina lead-in (days 1-10) were replaced. Dose-limiting toxicities (DLTs) were defined as grade 3+ non-hematologic toxicities requiring the permanent discontinuation of treatment in the first 42 days. Primary endpoints were toxicities and MTD. Secondary endpoints included complete remission (CR), MRD-negativity at a sensitivity of 0.01%, duration of response and OS from treatment initiation.

Results: Twenty-seven pts were enrolled to 3 dose levels (14 DLA1, 3 DLB1, and 10 DLB-1) from September 2017-December 2022. Six pts were replaced (4 prior to ICI dosing and 2 requiring subsequent therapy in the DLT window). The median age of enrolled pts was 55 (range 24-84), 14 were male (52%), and median baseline BM blasts were 60% (range 0.2-98%). Baseline characteristics are presented in Table 2. A single DLT (G4 infusion reaction and G3 hypotension) occurred among 6 pts at DLA1. Based on this safety and efficacy data, blina + nivo was expanded to include 6 additional pts without additional DLTs. There were 2 DLTs at DLB1 (G5 pneumonitis and G2 GVHD), which led to de-escalation to DLB-1, where there was 1 DLT (G3 delirium). Grade 2+ immune-related adverse events attributable to ICIs included pneumonitis (G2+G5), rash (G2+G3), transaminitis (G2+G3), colitis (G3), and hypothyroidism (G2). Grade 3+ adverse events attributable to blina included neutropenia (5-G4+3-G3), dysphasia (2-G3), weakness (G3), seizure (G4), and transaminitis (1-G4+4-G3). Among 22 pts evaluable for response, the CR rate was 68% (100% MRD-negative). Among 13 pts with >50% BM blasts at baseline, 62% achieved CR. Pts with B-myeloid MPAL (0/2) and a history of extramedullary disease (1/4) were less likely to respond. Nine responders subsequently relapsed including 3 with isolated extramedullary disease and 2 with CD19-negative disease. As shown in Figure 1, relapse-free survival (RFS) at 1 year was 27% (95% CI 10-46), while OS at 1 year was 63% (95% CI 38-79). Twelve pts underwent allogeneic blood or marrow transplant (alloBMT) following study treatment. At 1 year for alloBMT pts, RFS was 51% (95% CI 19-76) and OS was 61% (95% CI 26-83). Ongoing analyses of changes in T cell subpopulations, co-signaling molecule expression, and single cell RNA seq results will be presented.

Conclusions: Combination therapy with blina and ICIs in R/R ALL is safe, feasible, and associated with a high MRD-negative response rate. Long-term survival was promising in comparison to prior results with blina monotherapy, especially following consolidation with alloBMT. A randomized trial of blina +/- nivolumab is needed to confirm the benefit of this combination.

Disclosures: Webster: Servier: Consultancy; Pfizer: Consultancy. Luskin: Jazz: Honoraria; Pfizer: Honoraria; Novartis: Research Funding; Novartis: Honoraria; AbbVie: Research Funding. Rimando: Merck: Current equity holder in publicly-traded company. Zeidan: Notable: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Geron: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Astex: Research Funding; Shattuck Labs: Research Funding; Foran: Consultancy, Research Funding; Ionis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Agios: Consultancy, Honoraria. DeAngelo: Gilead: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; AbbVie: Research Funding; Servier: Honoraria; Jazz: Honoraria; Kite: Honoraria; Autolus: Honoraria; Novartis: Research Funding; Novartis: Honoraria; Amgen: Honoraria; Blueprint: Honoraria; GlycoMimetics: Research Funding; Blueprint: Research Funding. Luznik: Talaris Therapeutics: Consultancy; Precision Biosciences: Consultancy; WindMiL therpeutics: Patents & Royalties; Genentech: Research Funding; Gilead Sciences: Consultancy; Rubius Therapeutics: Consultancy. Gojo: Gilead: Research Funding; Scimentum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Incyte: Research Funding; Clearview: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MJH Healthcare Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Immune checkpoint inhibitors are off-label for R/R B ALL and the subject of this trial

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