Pembrolizumab and Involved Site Radiation Therapy Alone As an Alternative to Transplant in Patients with Localized Failure Following Chemotherapy for Hodgkin Lymphoma: A Prospective Multicenter Phase II Study

Background: Chemotherapy followed by autologous stem cell transplant (ASCT) is standard of care for relapsed/refractory Hodgkin Lymphoma (HL). In a phase II study, we evaluated pembrolizumab with involved site radiation therapy (ISRT) as an alternative salvage approach for localized favorable relapse.

Methods: Patients with relapsed/refractory stage IA/IIA, non-bulky (<10cm) HL after one line of therapy received positron emission tomography-computed tomography (PETCT) simulation followed by pembrolizumab 200mg IV every 21 days for 4 cycles and PETCT simulation 2-3 weeks later. Patients then received ISRT per response as follows: 1) 20 Gy for complete metabolic response (CMR) defined by Deauville Score (DS) 1-3; 2) 30 Gy for partial metabolic response (PMR) or stable disease (SD) (DS 4-5) and negative biopsy; or 3) 36-40 Gy for PMR/SD and positive biopsy. Patients who progressed (PD) were taken off study. PETCT was done 4-6 weeks after ISRT to document response. The primary endpoint was CMR rate after pembrolizumab-RT. Secondary endpoints were response to single agent pembrolizumab, 2-year progression free survival (PFS), and toxicity.

Results: 18 of planned 22 patients enrolled so far, with median age 37 (range 22-66). 3 (17%) had stage I, 14 (78%) stage II, and 1 had an unspecified limited stage at initial diagnosis. Frontline therapy was chemotherapy alone in 15 (83%) and combined modality in 3 (17%). 16 (89%) received adriamycin/bleomycin/vinblastine/dacarbazine (ABVD), 12 (67%) with <6 cycles. 13 (72%) had relapsed and 5 (28%) had refractory disease.

Of the 15 evaluable patients (3 still on therapy), 5 (33%) had CMR after pembrolizumab, 3 (20%) had PMR/SD with negative biopsy, 4 (27%) had PMR with positive biopsy, and 3 (20%) had PD. 12 patients proceeded to ISRT, of whom 5 (42%) with CMR received 20 Gy, 3 (25%) with PMR/SD and negative biopsy received 30 Gy, and 4 (33%) with PMR/SD and positive biopsy received 36-40 Gy. 10 (83% of these pts, 67% overall) achieved CMR. After median follow up of 42 months (3-82), 2-year PFS was 67% (95% CI 47-95).

3 patients progressed on pembrolizumab and 3 relapsed after a median of 12 months (range 7-70) from completion of pembrolizumab-RT. Among the 6 patients with PD during or after pembrolizumab-RT, 3 are currently in remission while the status for the other 3 is unknown. Subsequent treatment for the 3 patients currently in remission included pembrolizumab plus gemcitabine/vinorelbine/liposomal doxorubicin followed by ASCT (n=1), brentuximab vedotin (BV) plus nivolumab followed by ASCT (n=1) and 2 doses of BV followed by additional RT (n=1).

Immune-related toxicities were 3 (17%) grade 1 rash, and 2 (12%) grade 2 hypo/hyperthyroidism. Grade >2 toxicities were 1 (6%) grade 3 headache and 1 (6%) grade 4 lipase elevation.

Conclusion: Pembrolizumab-RT yielded excellent CMR rates and minimal toxicity. These data suggest pembrolizumab-RT as a potential alternative to high dose chemotherapy and ASCT in localized, favorable relapsed/refractory HL. Enrollment to the study continues.

Alencar:Epizyme: Consultancy; Janssen: Consultancy; Beigene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy; SeaGen: Consultancy; Loxo/Lilly: Consultancy, Research Funding; TG therapeutics: Consultancy; Abbvie: Consultancy. Boardman:Bristol Myers Squibb: Consultancy; OncLive: Honoraria; Cancer Study Group, LLC: Consultancy. Dogan:AstraZeneca: Research Funding. Epstein-Peterson:Genmab: Consultancy; Amgen: Research Funding; OncLive: Honoraria; Kymera: Research Funding; Viracta: Research Funding. Falchi:ADC Therapeutics: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EvolveImmune: Consultancy; Roche: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; Taylor Francis: Other: Journal Editor; Kaplan: Other: CME Presentation: Projects in Knowledge. Horwitz:Auxilius Pharma, Abcuro Inc., Corvus, Daiichi Sankyo, DrenBio, Farallon Capital Management, L.L.C., Kyowa Hakko Kirin, March Bio, Neovii Pharmaceuticals AG, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio, Treeline Bio and Takeda Pharmaceuticals.: Consultancy; ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio.: Research Funding; Auxilius Pharma, Abcuro Inc., Corvus, CTI BioPharma Corp, Daiichi Sankyo, DrenBio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio and Takeda Pharmaceuticals.: Honoraria. Imber:GT Medical Technologies: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Johnson:BioNTech: Consultancy; Sobi: Other: Advisory Board; Electra Therapeutics: Other: Advisory Board. Kumar:Kite Pharmaceuticals, Janssen: Honoraria; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Astra Zeneca: Honoraria, Research Funding; Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding. Lue:Kymera Therapeutics: Research Funding; Merck Pharmaceuticals: Consultancy; GenMab: Consultancy; ADC Therapeutics: Consultancy; Lumanity: Consultancy. Noy:NSCI: Honoraria; OncLIve: Honoraria; PER: Honoraria; Cornerstone Pharma: Honoraria, Research Funding; clearview: Consultancy; ADC therapeutics: Consultancy; Beigene: Consultancy; Medallion Healthcare: Honoraria; janssen Global: Consultancy, Other: drug provided for research; epizyme: Consultancy; EUSA: Consultancy; guidepoint global: Consultancy; health advance: Consultancy; AstraZeneca: Consultancy. Palomba:Bristo Meyer Squibb: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Cellectar: Consultancy. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Steiner:Seagen: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Rafael Pharmaceuticals: Research Funding; NCI: Research Funding; GSK: Research Funding. Stuver:Pfizer: Research Funding. Svoboda:Seagen: Honoraria; Incyte: Research Funding; Adaptive: Honoraria, Research Funding; TG Therapeutics: Honoraria; GenMab: Honoraria; Merck: Honoraria; BMS: Honoraria; Atara: Honoraria; Abbvie: Honoraria. Torka:TG Therapeutics: Consultancy; Seagen: Consultancy; GenMab: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy; Lilly Oncology: Consultancy. Zelenetz:MEI Pharma: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Janssen: Consultancy; BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy; Gilead/Kite: Consultancy; BeiGene: Consultancy, Research Funding; Novartis: Consultancy; Adaptive Biotechnology: Consultancy. Salles:Ipsen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; BMS/Celgene: Consultancy; Genentech/Roche: Consultancy, Research Funding; Incyte: Consultancy; Kite/Gilead: Consultancy; Merck: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding. Yahalom:Convergent RNR: Consultancy. Moskowitz:SGEN: Research Funding; Merk: Research Funding; ADCT: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; Beigene: Research Funding; Takeda Therapeutics: Honoraria; Seattle Genetics: Honoraria, Research Funding; Miragen Therapeutics: Honoraria; Secura Bio: Research Funding; Brystal-Meyers Squibb: Research Funding; ADC therapeutics: Research Funding; Merck: Research Funding; Tessa Therapeutics: Honoraria.