PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment
Authors: Armand Philippe , Shipp Margaret A. , Ribrag Vincent , Michot Jean-Marie , Zinzani Pier Luigi , Gutierrez Martin , Snyder Ellen , Ricart Alejandro D. , Balakumaran Arun , Moskowitz Craig H. 
Published: October 2019

Abstract
Introduction: The PD-1 pathway provides an important mechanism of immune evasion and an actionable therapeutic target for many tumors. Classical Hodgkin lymphoma (cHL) frequently contains genetic amplification at the 9p24.1 locus, resulting in the overexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumor cell surface. cHL may therefore have a unique sensitivity to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands and can restore antitumor immune activity in several solid tumors. Based on its possible genetically driven dependence on PD-1, cHL was included as an independent expansion cohort in the KEYNOTE-013 study (NCT01953692), a phase 1b multicenter multicohort trial of pembrolizumab in patients with hematologic malignancies. Updated results of the cHL cohort are presented.
Methods: This cohort enrolled patients with relapsed or refractory cHL. Patients had to have relapsed after, be ineligible for, or refused autologous stem cell transplantation (ASCT). In addition, patients were required to have relapsed after or be refractory to brentuximab vedotin (BV) treatment. Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by computed tomography and positron emission tomography scans after 12 weeks of treatment and every 8 weeks thereafter, using International Harmonization Project 2007 criteria. The primary objectives were safety and complete remission (CR) rate; secondary objectives were progression-free survival, overall survival, overall response rate (ORR), duration of response (DOR), and biomarker assessments. Biomarkers included PD-L1/PD-L2 expression in formalin-fixed, paraffin-embedded tissue; flow cytometry evaluating absolute and relative numbers of circulating NK cells and T-cell subsets (naive and memory T cells, activated T cells, and regulatory T cells); and gene expression using the NanoString platform.
Results: At the time of data cutoff on May 26, 2015, 31 patients were evaluable for analysis. Median (range) age was 32 (20-67) years. 68% of patients had received ≥4 prior lines of therapy, 71% had failed prior ASCT, and by design 100% had failed prior BV. The most common treatment-related AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%). Five patients had grade 3 related AEs; no grade 4 AEs or treatment-related deaths occurred. ORR among the 31 patients was 65% (90% CI, 48-79). Five patients (16%) achieved CR, 15 (48%) partial remission, and 7 (23%) stable disease as their best response. With a median follow-up of 9.7 (1.3-17.5) months, the median DOR had not been reached (0+ to 13.4+ months). As of the data cutoff, 14 patients (45%) remained on treatment; 2 (6%) patients discontinued for toxicity, 12 (39%) for progression, and 3 (10%) for other reasons. Of the 20 responses, 14 are ongoing.
Eleven patients had evaluable pretreatment tumor tissue (archival or obtained for study). Among them, 10 (91%) were PD-L1+ by immunohistochemistry (IHC). Among 6 available tumor samples obtained at week 13, 4 (57%) were PD-L1+. Additionally, 10/10 patients assessed for PD-L2 expression by IHC showed high levels of PD-L2 staining. Based on flow cytometry analyses, a significant increase was observed at the 13-week time point in the absolute number of circulating total lymphocytes, T cells (CD4 and CD8 subsets), as well as NK cells. NanoString RNA profiling of pre- and posttreatment blood samples showed that several prespecified gene expression signatures were significantly upregulated with treatment, including the 10-gene IFN-γ-induced signature, the 18-gene expanded immune signature, and the 13-gene TCR signature.
Conclusion: PD-1 blockade with pembrolizumab was associated with a favorable safety profile and a high response rate in a very heavily pretreated cohort of patients with cHL. Responses appear durable with ongoing follow-up. Biomarker analyses confirm the frequent presence of PD-L1 and PD-L2 in tumors and further suggest that pembrolizumab results in an expansion of circulating T- and NK-cell populations, as well as in activation of IFN-γ and other pathways involved in regulation and differentiation of immune cells. Those biomarkers may be tested in larger ongoing studies for their relationship with treatment outcomes.

Disclosures
Armand: Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Shipp:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zinzani:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Snyder:Merck: Employment, Equity Ownership. Ricart:Merck: Employment; Pfizer Inc.: Equity Ownership. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Moskowitz:Seattle Genetics: Honoraria, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.