Phase II Study of Pembrolizumab and Fractionated External Beam Radiotherapy in Patients with Relapsed and Refractory Large B-Cell Lymphoma

Background: Relapsed/refractory (R/R) large B-cell lymphoma (LBCL) poses a therapeutic challenge, however immune based interventions are changing the landscape of salvage therapy. Manipulation of immune checkpoint pathways involving programmed cell death protein 1 (PD-1) and its ligands PD-L1/PD-L2 can trigger anti-tumor effects in LBCL. However, results with checkpoint inhibitor monotherapy for LBCL have been disappointing with reported overall response rates (ORR) of 10% for patients who experienced relapse after autologous stem cell transplantation (ASCT) and 3% for those ineligible for ASCT (Lesokhin AM et al J Clin Oncol. 2016). Radiation therapy (RT) is highly effective in R/R LBCL and may enhance response when coupled with immune based therapy. We sought to evaluate the efficacy of RT combined with pembrolizumab among patients with R/R non-Hodgkin Lymphoma (NHL) treated with RT to 1-2 sites of refractory disease with at least one index lesion excluded from the RT field for evaluation of abscopal effect.

Methods: We conducted a single center, open label, phase II trial of patients with R/R NHL with progressive lymphoma after 2 or more lines of therapy. Eligible patients had PET avid disease amenable to RT and at least one distinct lesion outside of the planned RT field that would serve as the index (abscopal) lesion(s) by which the response to therapy would be defined. Patients were administered a fixed dose of 200 mg of pembrolizumab intravenously every 21 days beginning on day 2 of RT planned for 24 months or until progression. External beam RT was planned to dose of 40-50 Gy in ≤3 Gy fractions. The primary endpoint was ORR (defined as complete and partial response) of the unirradiated lesion(s) at 3 months (after completion of RT and 3 cycles of pembrolizumab). Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). ORR and dose limiting toxicity (DLT) were monitored simultaneously using Bayesian stopping boundaries based on an ORR of at least 35% at 3 months and DLT rate at cycle one below 30%. A sample size of 20 was planned.

Results: Between February 2018 and November 2020, 17 patients were enrolled on the study and received at least 1 cycle of pembrolizumab and at least 1 fraction of RT. The median age was 66 years (range 24 - 83); 29% (n=5) of patients were female. Most patients had LBCL (88%, n=15, double hit, n=5), one patient had PMBCL (6%) and one patient had NK T-cell lymphoma (6%). The median number of prior therapies was 3 (range 2-13) with 53% (n=9) of patients having received ≥3 prior lines of treatment. Eighteen percent (n=3) of patients received prior ASCT and 53% (n=9) received CAR-T cell therapy prior to enrollment.

The median number of unirradiated lesions excluded from the RT field was 2 (range 1-24). The median diameter of the largest unirradiated lesion was 2.4 cm (range 1.1 - 8.0 cm). The median RT dose delivered was 45 Gy (range 22.5 -50).

The median follow up for the 17 patients was 34.75 months. Sixteen patients had a response assessment, one patient suffered from a stroke and response was not assessed. The ORR was 28% (CR 23% [n=3] and PR 15% [n=2]). Local control within the radiated field was achieved in 11 of the 16 patients (69%). For all 17 patients, the median PFS and OS were 2.7 months and 6.3 months respectively. The 2 year PFS and OS rates were 11.8% and 23.5% respectively (Figure 1). There were 13 deaths, 12 due to lymphoma and 1 due to stroke. For the five responding patients, the median duration of response was 13.3 months (range 5.0 - 50.5 months). Two patients remain in CR 37.6 (PMBCL) and 50.5 (double hit LBCL) months after protocol therapy. The trial was terminated early due to poor accrual.

Treatment was generally well tolerated. One of the long term survivors with a history of chronic steroid use experienced grade 4 avascular necrosis in the RT field.

Conclusion: In this single center, phase II trial of pembrolizumab and concurrent RT among patients with highly refractory LBCL, local control within the radiation field was encouraging however abscopal responses were minimal. Further exploration of the mechanism behind the exceptional responses in two patients treated with RT and pembrolizumab in this high-risk population is warranted.

Pinnix:Merck Inc: Research Funding. Ahmed:Seagen: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Chimagen: Consultancy, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy. Steiner:BMS: Research Funding; Seagen: Research Funding; GSK: Research Funding; Rafael Pharmaceuticals: Research Funding. Nair:Incyte Corporation: Honoraria. Strati:Kite Gilead: Consultancy; TG Therapeutics: Consultancy; Hutchinson MediPharma: Consultancy; Astrazeneca Acerta: Research Funding; Roche Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Sobi: Research Funding; ALX Oncology: Research Funding. Westin:Calithera: Consultancy, Research Funding; Iksuda: Consultancy; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy; Genentech/Roche: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; MonteRosa: Consultancy; Novartis: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Iyer:Legend: Research Funding; Affimed: Research Funding; Seagen: Consultancy, Research Funding; Rhizen: Research Funding; Takeda: Research Funding; Myeloid: Research Funding; Target Oncology: Consultancy, Honoraria; Salarius Pharmaceuticals, Inc.: Consultancy; Innate: Research Funding; Yingli: Consultancy, Research Funding; Spectrum: Research Funding; Merck: Research Funding; CRISPR Therapeutics: Research Funding; CureBio: Honoraria. Lee:Pharmcyclics: Research Funding; Octernal Therapeutics: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Briston-Myers Squibb: Research Funding; Janssen: Honoraria; Guidepoint Global: Honoraria; Deloitte: Honoraria; Olson Research: Honoraria; Korean Society of Cardiology: Honoraria; Curio Science: Honoraria; Cancer Experts: Honoraria; Aptitude Health: Honoraria; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees. Samaniego:TG Therapeutics: Honoraria. Chihara:AstraZeneca: Honoraria; Eisai: Honoraria. Jain:Aptitude Health: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Beigene: Research Funding; Kite Pharma: Consultancy, Research Funding; Pharmacy Times: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Company: Consultancy, Honoraria. Flowers:Denovo Biopharma: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; SeaGen: Consultancy; Spectrum: Consultancy; 4D: Research Funding; NPower: Current holder of stock options in a privately-held company; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen Pharmaceutical: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; BeiGene: Consultancy; Abbvie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Neelapu:Bristol Myers Squibb: Consultancy, Honoraria, Other: Personal fees, Research Funding; Legend Biotech: Consultancy, Honoraria, Other: Personal fees; Cell Medica/Kuur: Consultancy, Honoraria, Other: Personal fees; Precision Biosciences: Consultancy, Honoraria, Other: Personal fees, Research Funding; Allogene Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Pfizer: Consultancy, Honoraria, Other: Personal fees; Aptitude Health: Consultancy, Research Funding; Medscape: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Unum Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Honoraria, Other: Personal fees, Research Funding; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Bio Ascend: Consultancy, Honoraria; Calibr: Consultancy, Honoraria, Other: Personal fees; Adicet Bio: Consultancy, Honoraria, Other: Personal fees, Research Funding; Incyte: Consultancy, Honoraria, Other: Personal fees; Kite: Consultancy, Honoraria, Other: Personal fees, Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties: related to cell therapy. Nastoupil:ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; Genentech/Roche, MEI, Takeda: Other: DSMC; BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding.