A Phase 2 Study of Pembrolizumab (MK-3475) after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma

Introduction Peripheral T cell lymphomas (PTCL) are a heterogenous group of diseases that carry a poor prognosis except for ALK+ anaplastic large cell lymphoma (ALCL). Autologous stem cell transplantation (ASCT) in first remission is considered standard of care at most institutions to improve progression free survival (PFS). Despite this, more than 50% of patients will relapse after ASCT. PD-1 blockade has been studied as a treatment modality for PTCL. A phase 1b study evaluated nivolumab in PTCL and showed an ORR of 40% (Lesokhin et al., 2016). Another phase 2 study using single agent pembrolizumab in relapsed and refractory PTCL showed an ORR of 33% (Barta et al.,2019). In this current study, we explored the efficacy of PD-1 blockade as consolidation therapy after ASCT for patients with PTCL in first remission.

Methods We conducted a phase II, multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT for several lymphoma subtypes. Arm C enrolled patients with PTCL in 1st remission. The expected 18-month PFS rate after ASCT in chemosensitive T-NHL is ~40-50%. We hypothesized that consolidation treatment with pembrolizumab would improve the 18-month PFS rate to 70%. For the sample size of 21, we would consider the treatment promising if at least 13 patients remained alive and progression-free at 18 months post-ASCT. Pembrolizumab 200 mg IV was administered every 3 weeks up to 8 cycles starting, when possible, within 21 days of post-ASCT discharge. Secondary end points included overall survival (OS), response rate to pembrolizumab in those with measurable disease after ASCT and safety. Treatment response was assessed with PET and CT scans at weeks 10 and 22, and at 12 and 18 months post-ASCT. If radiographic progression was documented at week 10, continued treatment was allowed if the patient was tolerating treatment.

Results Twenty-one patients were enrolled between January 2017 and July 2020. The median age was 58 (range 33-73). The most common histology was PTCL NOS (52%). Other histologies included: angioimmunoblastic T-cell lymphoma (19%), extranodal NK/T-cell lymphoma, nasal type (14%), ALK- ALCL (10%) and monomorphic epitheliotropic intestinal T-cell lymphoma (5%). The median number of prior therapies was 1. Prior to ASCT, 90% of the patients were in complete metabolic response (CMR). At post-ASCT baseline, 95% of patients were in CMR. 14 of the 21 patients completed the planned 8 cycles of treatment. Reasons for discontinuing treatment were toxicity (4), progressive disease (PD) (1), withdrawal of consent (1) and COVID-19 (1).

Among all subjects, 13 of 21 (62%) were progression-free at 18-months post-ASCT meeting the primary endpoint. Of the remaining 8 patients, 3 had PD and 5 were lost to follow-up with 3/5 patients in CMR (up to months 4, 12 and 12). The one patient with AITL who had stable disease upon study entry achieved a CR after treatment with pembrolizumab. With a median follow-up of 34.8 months, the median PFS was 30.1 months (95% CI: 21.3 - NR) and median OS was 38.7 months.

All patients who received at least one dose of study treatment were included in the toxicity assessment (n = 21). Seventeen patients experienced at least one toxicity while on study including grade 1 (n = 5/21; 24), grade 2 (n = 8/21; 38) and grade 3 (n = 3/21; 14). The most common toxicities of any grade were nausea (n = 5/21; 24%), alkaline phosphatase increase (n = 4/21; 19%), diarrhea (n = 4/21; 19%), abdominal pain (n = 3/21; 14%), hypothyroidism (n = 3/21; 14%), alanine aminotransferase (ALT) increase (n = 2/21; 10%), anemia (n = 2/21; 10%), arthralgia (n = 2/21; 10%), and aspartate aminotransferase (AST) increase (n = 2/21; 10%). The most common grade 3 toxicities were abdominal pain (n = 1/21), colitis (n = 1/21), diarrhea (n = 1/21), ALT increase (n = 2/21), AST increase (n = 1/21) and headache (n = 1/21). One patient experienced grade 4 respiratory failure which was unrelated to study treatment. No other grade 4 toxicities or grade 5 toxicities occurred.

Conclusion Consolidation therapy after ASCT with pembrolizumab is feasible and led to a favorable PFS, meeting the study's primary endpoint. This is the first study to show a possible role for PD-1 blockade as consolidation therapy in PTCL. Since sensitivity to this therapy is likely variable across PTCL histologic or molecular subtypes, further studies might define a subpopulation most likely to benefit from this approach and justify a larger confirmatory study.

Chen:Actimium: Consultancy; Celularity: Consultancy; Equillium: Consultancy; Gamida Cell: Consultancy; Incyte: Consultancy; Jasper: Consultancy; Novartis: Consultancy. LaCasce:Research to Practice: Consultancy; Seattle Genetics: Consultancy. Herrera:Tubulis: Consultancy; Takeda: Consultancy; Adicet Bio: Consultancy; Regeneron: Consultancy; Pfizer: Consultancy; Gilead: Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; KiTE Pharma: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; Caribou: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobson:Humanigen: Consultancy, Honoraria, Other: Travel Support; Nkarta: Consultancy, Honoraria; Celgene: Other: Travel Support; Clinical Care Options: Speakers Bureau; Precision BioSciences: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Epizyme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; ImmPACT Bio: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Instil Bio: Consultancy, Honoraria; Ispen: Consultancy, Honoraria; Lonza: Consultancy, Honoraria, Other: Travel Support; Pfizer: Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Support; BMS/Celgene: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Merryman:Genentech/Roche: Research Funding; Pfizer: Research Funding; Merck & Co., Kenilworth, NJ: Research Funding; Epizyme: Consultancy; Intellia: Consultancy; Abbvie: Consultancy; Bristol Myers Squib: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genmab: Consultancy, Research Funding. Nieto:Affimed: Other: Scientific advisory Board, Research Funding; Secura Bio: Research Funding; Astra Zeneca: Research Funding. Sauter:Genzyme/Sanofi: Other: PI; Kite Pharma Inc.: Consultancy; CSL Behring: Consultancy; Ono Pharmaceuticals: Consultancy; Karyopharm Therapeutics Inc.: Consultancy; Gamida Cell: Consultancy; BMS: Other: PI; Precision Biosciences: Other: PI. Shah:Amgen: Research Funding; Beyond Spring: Research Funding; Janssen: Research Funding. Zain:Seattle Genetics: Research Funding, Speakers Bureau; CRSPR: Research Funding; 3M: Current holder of stock options in a privately-held company; Myeloid: Consultancy, Research Funding; AstraZeneca: Research Funding; Daichi Sankyo: Consultancy, Research Funding; Secura Bio: Consultancy, Research Funding; Affirmed: Research Funding; Kiyowa Kirin: Speakers Bureau. Armand:IGM: Research Funding; Adaptive: Research Funding; Kite: Research Funding; Xencor: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Regeneron: Consultancy; Enterome: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; ADC Therapeutics: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy, Honoraria, Research Funding.