The programmed death-1 (PD-1) pathway serves as an immune checkpoint to temporarily dampen immune responses upon chronic antigen stimulation. Normal antigen presenting cells and certain tumor cells express the PD-1 ligands, PD-L1 and PD-L2, which engage PD-1 receptors on activated T cells and induce T-cell exhaustion. PD-1 signaling is a potent mechanism of tumor immune escape and a compelling target for therapy. Antibody-mediated PD-1 blockade has already been successfully exploited as a therapeutic strategy in solid tumors and is currently being evaluated in hematologic malignancies. Classical Hodgkin lymphoma (cHL) may represent a uniquely vulnerable target for PD-1 blockade therapy. This disease is characterized by an extensive inflammatory immune cell infiltrate and a dominant genetic alteration in chromosome 9p24.1 that leads to PDL1 and PDL2 copy gain and associated overexpression of these PD-1 ligands. In cHL, Epstein-Barr virus infection represents an additional mechanism of upregulating PD-1 ligand expression. For these reasons, cHL was included as a cohort of the ongoing, multicenter, open-label, phase 1b clinical trial of the monoclonal antibody pembrolizumab (MK-3475; Merck, Whitehouse Station, NJ) in hematologic malignancies (KEYNOTE-013; ClinicalTrials.gov identifier, NCT01953692). Eligibility criteria for the cHL arm of KEYNOTE-013 include relapsed or refractory cHL, relapse from or failure to respond to brentuximab vedotin treatment, and adequate performance status and organ function. Patients with autoimmune disease or interstitial lung disease are excluded. Treatment consists of single-agent pembrolizumab 10 mg/kg administered intravenously every 2 weeks until confirmed tumor progression, excessive toxicity, or completion of 2 years of therapy. The main end points of this study are safety, tolerability, and complete remission (CR) rate. The first time point for radiologic restaging is at week 12 (ie, after 6 cycles of treatment). Herein, we report preliminary results from the 15 patients with cHL who were evaluable for response to pembrolizumab at the 12-week time point. The median patient age was 28 years (range, 21-67), and the median number of prior therapies was 4. By design, all patients previously failed brentuximab vedotin; 67% also failed prior autologous stem cell transplantation. Pembrolizumab was well tolerated. There were no serious adverse events (AEs), and only 1 patient experienced grade 3-5 AEs (grade 3 pain and grade 3 joint swelling, both considered to be unrelated to study drug). Overall, 10 patients experienced ≥1 AE. The most common drug-related AEs were grade 1-2 respiratory events (20%) and thyroid disorders (20%). One patient discontinued study treatment because of an AE (grade 2 pneumonitis), and 3 patients ended therapy after progressive disease (PD). Based on investigator assessment using the Cheson 2007 International Harmonization Project response criteria, 3 patients (20%) had a CR at 12 weeks. Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%. Four patients (27%) experienced PD, although all 4 experienced a decrease in their overall tumor burden (Figure 1). In conclusion, pembrolizumab therapy appears to be safe, tolerable, and associated with clinical benefit in patients with heavily pretreated cHL. Figure 1: Best percentage change from baseline in tumor size for all patients. Figure 1 Figure 1. Disclosures Moskowitz: Merck: Research Funding. Off Label Use: Pembrolizumab is a humanized, monoclonal IgG4-kappa isotype antibody against PD-1 that is currently in clinical development for multiple advanced solid tumors and hematologic malignancies.. Ribrag:Servier: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Epizyme: Research Funding; Pharmamar: Consultancy; Celgene: Consultancy. Martinelli:Novartis: Speakers Bureau; Ariad: Consultancy; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Giallella:Merck: Employment. Weimer Anderson:Merck: Employment. Derosier:Merck: Employment. Wang:Accenture: Employment. Yang:Merck: Employment. Rubin:Merck: Employment. Rose:Merck: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Armand:Merck: Consultancy.

Key Points• BV and AVD followed by ISRT is well tolerated, without significant pulmonary toxicity. • BV and AVD followed by ISRT is an effective therapy for unfavorable-risk early stage HL, including bulky disease.This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD.Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV 1 AVD, and 25 patients BV 1 AVD 1 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events ( ‡grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV 1 AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV 1 AVD 1 ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients ( ‡90%) achieved negative interim PET scans after 2 and 4 cycles of BV 1 AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was

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Background: Brentuximab vedotin has not been previously studied in combination with combined modality therapy for the frontline treatment of early stage Hodgkin lymphoma. We designed a pilot study to assess the safety and early efficacy of four cycles of brentuximab vedotin (BV) + AVD chemotherapy followed by 30 Gray involved-site radiotherapy (ISRT) for the treatment for early stage, unfavorable risk HL. Methods: Patients with newly diagnosed, stage I/II, classical HL with unfavorable risk profile (defined by the German Hodgkin Study Group (GHSG) with one of the following criteria: bulky mediastinal mass (≥1/3 maximum transverse thoracic diameter on PA-CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients with “B” symptoms, extranodal involvement, or >2 involved lymph node sites) were eligible. Patients with stage IIB disease with disease bulk or extranodal involvement were included (conventionally classified as advanced stage per GHSG). Patients were treated with four cycles of brentuximab vedotin 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gray involved-site radiotherapy. The primary endpoint of the study was to evaluate the safety of this regimen, with particular attention to the development of pulmonary toxicity. A PET/CT was performed after 2 and 4 cycles of therapy. PET scans were interpreted using the Deauville 5-point scale and a negative scan was defined as Deauville 1-3. Results: Interim data for the first 19 of a planned 30 patients enrolled are presented here. Median age was 32 (range, 18-50), 47% female, 100% stage II disease, 53% with disease bulk by GHSG criteria, 53% elevated ESR, 34% B-symptoms, 37% extranodal involvement, 42% >2 involved lymph node sites. All patients with disease bulk had large anterior mediastinal masses measuring >10cm by CT in transverse plane (range, 10-16.9 cm). There were eight patients enrolled who would be considered to have advanced stage disease by the GHSG classification: 3 with IIBX, 3 with IIBE, and 2 with IIBXE disease. To date, 79% (15/19) and 63% (12/19) have completed interim PET-2 and PET-4 imaging studies, respectively. Ninety-three percent of patients (14/15) achieved a negative PET scan after 2 cycles (6, 8, and 1 patients achieved Deauville score of 2, 3, 4, respectively). All patients with disease bulk were PET-2 negative (10/10). Ninety-two percent of patients achieved a negative PET scan after 4 cycles of therapy (1, 8, 2, and 1 patients achieved Deauville score of 1,2,3,4, respectively). The patient with a positive PET-4 scan had a subsequent positive biopsy and will be treated off study for primary refractory HL. The study treatment has been well-tolerated. No pulmonary toxicity has been observed. Serious adverse events have been documented in two patients: febrile neutropenia and grade 3 hypertension. One patient discontinued protocol treatment due to the development of grade 3 peripheral neuropathy after one treatment with BV+AVD. The four patients who have completed combined modality therapy and an end-of-treatment imaging assessment achieved complete responses and no relapses have occurred to date. Conclusion: The combination of BV+AVD chemotherapy followed by ISRT appears well-tolerated with no early signal of increased pulmonary toxicity. In this interim analysis of 19 newly diagnosed patients with early stage, unfavorable risk HL, over ninety percent of the evaluable patients have achieved negative interim PET scans after 2 and 4 cycles of BV + AVD, suggesting this is a highly active treatment program even in patients with substantial disease bulk. Updated safety and response data will be presented at the meeting. Disclosures Hamlin: Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding; Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol Myers Squibb,: Consultancy; Jannsen: Consultancy. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding.