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4051 Interim Results of a Phase 1/2 Study of Pembrolizumab Combined with Blinatumomab in Patients with Relapsed/Refractory (r/r) ALLClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Bispecific Antibody Therapy, Clinical Research, Combination therapy, Checkpoint Inhibitor, Therapies, Immunotherapy
Monday, December 12, 2022, 6:00 PM-8:00 PM

Karamjeet S. Sandhu, MD1, Alan Macias2*, Marissa Del Real, PhD2*, Asuscena L. Beltran1*, Young Sun Kim, MD3*, Jianying Zhang, PhD4*, Joycelynne Palmer, PhD5*, Marjorie Robbins, PhD6*, Reyna Loomis, BSN1*, Mojtaba Akhtari, MD7*, Ahmed Aribi, MD1*, Shukaib Arslan, MD1*, Amandeep Salhotra, MD1, Matthew Mei, MD1, Hoda Pourhassan, MD1*, Paul B. Koller, MD1, Idoroenyi Amanam, MD1, Vaibhav Agrawal, MD1, Peter T. Curtin, MD1, Ricardo Spielberger, MD1*, Vinod A. Pullarkat, MD1*, Ibrahim Aldoss, MD1, F. Mark Stewart, MD1*, Eileen P. Smith, MD1, Stephen J Forman, MD1, Anthony S. Stein, MD1*, Guido Marcucci, MD1 and Elizabeth L. Budde, MD, PhD8

1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
2T-Cell Therapeutics Research Laboratory, BRI, City of Hope National Medical Center, Duarte, CA
3Department of Pathology, City of Hope National Medical Center, Duarte, CA
4Department of Computational and Quantitative Medicine-BRI, City of Hope National Medical Center, Duarte, CA
5Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA
6Department of Clinical and Translational Project Development, City of Hope National Medical Center, Duarte, CA
7Loma Linda University Cancer Center, Loma Linda, CA
8Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA

Background: Blinatumomab, a bispecific anti-CD19/CD3 antibody has resulted in significantly improved outcomes in patients (pts) with r/r B-ALL compared to conventional chemotherapy. However, over half of treated pts fail to respond (CR/CRh/PR 44%), and majority of responders eventually relapse without consolidation therapy. There is an unmet need to design novel strategies to improve efficacy. Upregulation of PD-L1 on leukemic blasts and PD-1 on T cells has been shown to associate with resistance to blinatumomab in preclinical and clinical studies. Therefore, blockade of the PD-1 pathway represents a reasonable strategy to augment blinatumomab efficacy. Here we set out to test the combination of pembrolizumab and blinatumomab in a single arm, phase 1/2 trial (NCT03512405).

Methods: Pts [≥18 years old (yo); ECOG <1] with CD19+ R/R B-ALL, received standard blinatumomab 9 mcg/day on days 1-7, 28 mcg/day on days 8-28 in cycle 1, and on days 1-28 in subsequent cycles. Pembrolizumab 200mg was given on day 15 (schedule A) or day 22(schedule B) in cycle 1, and on days 1 and 22 in subsequent cycles. Cycle length was 42 days except 35 days for cycle 1 in schedule A. The study completed the schedule A phase 1 portion with primary objectives of safety, tolerability and proceeded with recommended phase 2 dose (RP2D) using the “3+3” design.

Results: As of June 15, 2022, 7 pts were enrolled to phase 1 with one unevaluable, and 8 patients to phase 2. All received schedule A dosing. Fourteen evaluable pts received a median of 2 (1-6) cycles of treatment. At baseline, the median age was 53 yr (24-76) with median 2 (1-3) prior lines of regimens, and median 62% (10-95) BM blasts. All except one patient accrued were poor risk. In cycle 1, 64% experienced cytokine release syndrome (CRS) with 1 gr 3 CRS and no gr 4. All CRS except 1 started prior to the day 15 dose of pembrolizumab. Neurologic toxicities were all reversible with only 1 pt with ≥ gr3 AE. All-non-hematologic gr3 toxicities were reversible. No dose limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment related deaths were seen. The complete remission (CR/CRi) rate is 79% (11/14). Ten of 14 evaluable pts (71%) achieved flow cytometry MRD negative CR/CRi after a median of 1(1-2) cycle. 6/8 patients with ≥50% blast achieved CR/CRi. One patient had >83% blasts after cycle 1 and achieved CR after cycle 2, supporting the positive impact of pembrolizumab. Seven pts in CR received allogeneic transplant (alloHCT) with post-transplant cyclophosphamide (PTCy) as graft versus host disease (GVHD) prophylaxis. Only 1 patient had ≥gr3 acute GVHD which resolved with treatment. With a median follow-up of 9.6 (1.8- 34) months, 6 CRs are ongoing (5 post-transplant) and 10 of 14 evaluable pts are still alive at the data cut-off. PD-1 detection decreased among both responders and non-responders after pembrolizumab administration. Responders after cycle 1 had higher CD8+ T cells which increased further following pembrolizumab administration. Correlative studies are ongoing.

Conclusions: The combination of pembrolizumab and blinatumomab in phase 1/2 of this study in pts with r/r B-ALL was deemed safe with a manageable side effect profile. Encouraging anti-leukemic activity has been seen in the majority of treated patients (CR+CRi rate of 79%) and most CR are MRD negative, supporting the rational combination of these 2 agents. The phase 2 portion of the trial is continuing to recruit patients.

Disclosures: Akhtari: Karyopharm: Speakers Bureau; Incyte: Speakers Bureau; Takeda: Speakers Bureau; Secura Bio: Speakers Bureau; MorPhosys: Speakers Bureau; PharmaEssentia: Speakers Bureau; CTI: Speakers Bureau; Jazz Pharma: Speakers Bureau. Salhotra: Kadmon: Other: Advisory board meeting ; BMS: Research Funding; Orca Bio: Research Funding. Mei: Novartis: Honoraria; CTI: Honoraria; Incyte/Morphosys: Research Funding, Speakers Bureau; EUSA: Honoraria; BMS: Research Funding; Beigene: Research Funding. Koller: Treadwell Therapeutics: Other: Safety Review Committee; Takeda: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Aldoss: Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MacroGenics: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Smith: Johnson and Johnson: Current equity holder in publicly-traded company. Stein: Amgen: Honoraria. Marcucci: Lynx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Speaker and advisory scientific board meetings. Budde: Amgen: Research Funding; AstraZeneca: Research Funding; Ziopharm: Other: DMSC member for a phase 1 clinical; Mustang Therapeutics: Research Funding; Merck: Research Funding; Amgen: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH