CAR-T plus pembrolizumab shows ‘superior’ safety, promising responses in advanced lymphoma
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No patients who received pembrolizumab with a CD19/CD22-directed chimeric antigen receptor T-cell therapy experienced high-grade cytokine release syndrome, according to phase 1 study findings presented during ESMO Virtual Congress 2020.
Results of the ALEXANDER trial also showed clinically meaningful and durable responses to AUTO3 (Autolus Therapeutics) among the study population, which included patients with relapsed or refractory diffuse large B-cell lymphoma.
Cytokine release syndrome (CRS) is a common treatment-related toxicity of CAR T-cell therapy that requires inpatient monitoring and, often, pharmacologic intervention.
“The safety profile of AUTO3 appears superior to those seen in currently approved CAR-T constructs,” Eleni Tholouli, MD, PhD, consultant hematologist in the department of hematology at Manchester Royal Infirmary in the U.K., said during a presentation.
AUTO3 is a bidirected, genetically altered CAR designed to recognize and bind with both CD19 (OX40 costimulatory domain) and CD22 (41BB costimulatory domain) antigens on cancer cells.
The dose-escalation portion of the single-arm, multicenter phase 1/phase 2 study examined three dose levels of AUTO3 — 50 × 106, 150 × 106 and 450 × 106 CAR T cells — alone or in combination with one of two pembrolizumab (Keytruda, Merck) regimens. Regimen A consisted of 200 mg pembrolizumab every 3 weeks starting on day 14 after AUTO3 infusion. Regimen B consisted of 200 mg pembrolizumab on day 1 after infusion.
Tholouli said researchers employed the dual CAR T-cell/immune checkpoint inhibitor strategy to overcome two limitations often seen with either treatment alone: CD19 antigen loss on the surface of cancer cells and PD-L1 upregulation.
Study participants underwent lymphodepletion with fludarabine and cyclophosphamide before infusion with AUTO3. Bridging therapy before CAR T-cell infusion also was permitted.
No prophylactic measures were taken to prevent treatment-related toxicities, including neurotoxicity and CRS.
Frequency of severe adverse events — defined as grade 3 to grade 5 — served as the primary endpoint. Secondary efficacy endpoints included overall and complete response rates.
Interim results of the trial, presented during this year’s ASCO20 Virtual Scientific Program, showed an ORR at all dose levels of 65%, with a complete response rate of 48%. The safety analysis showed most toxicities greater than grade 3 were hematologic and most cases of CRS were grade 1.
The updated analysis included data of 35 patients (median age, 59 years; range, 28-83; 65.7% men) with DLBCL (n = 25), follicular lymphoma (n = 7) or marginal zone lymphoma (n = 1). These patients had received a median three (range, 1-10) prior therapies.
The safety analysis showed no cases of severe CRS at any dose level. However, nearly a quarter (22.9%) of patients experienced grade 1 CRS and five patients received tocilizumab (Actemra, Genentech) to resolve their symptoms. Median time to CRS was 6 days (range, 1-36), with median CRS duration of 3 days (range, 1-19).
Two patients (5.7%) experienced high-grade neurotoxicity.
None of the three patients who experienced any form of neurotoxicity achieved a complete response to therapy. However, these patients did have a “robust expansion” of CAR T cells in the body, according to the investigators.
“AUTO3 is safe and well-tolerated, with its best-in-class safety profile,” Tholouli said during the presentation. “Based on our experience, this profile appears clearly superior to that of currently approved CD19 CAR-T products.”
The efficacy analysis, which included 30 patients, showed an ORR of 68% and complete response rate of 54%. Patients (n = 14) who received a CAR T-cell dose of 150 x × 106 or greater plus pembrolizumab on day 1 had an ORR of 71% and a complete response rate of 64%.
All seven patients who received the recommended phase 2 dose (150 × 106 to 450 × 106 CAR T cells plus pembrolizumab on day 1) and achieved complete remission remained in remission at median follow-up of 6 months (range, 1-24).
Before the ALEXANDER trial moves to phase 2, Tholouli said, “AUTO3’s excellent safety profile has prompted an outpatient expansion cohort that is currently enrolling patients in the U.K. and the U.S.”
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Tholouli E, et al. Abstract 890MO. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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