Pembrolizumab (PEM) Added to ICE Chemotherapy Results in High Complete Metabolic Response Rates in Relapsed/Refractory Classic Hodgkin Lymphoma (cHL): A Multi-Institutional Phase II Trial

Abstract

Introduction: Approximately 30-35% of patients with classic Hodgkin Lymphoma will prove refractory to frontline therapy or relapse subsequently. Traditional second-line chemotherapy regimens including ifosfamide, carboplatin, and etoposide (ICE) result in complete response rates of ~50%. Achievement of complete metabolic response (CMR) assessed by PET/CT imaging prior to autologous hematopoietic stem cell transplant (AHSCT) predicts favorable progression free survival (PFS) and overall survival (OS). PD-1 blockade is a well-established therapeutic strategy for the treatment of cHL. Pembrolizumab (PEM) is a checkpoint inhibitor targeting PD-1 currently FDA approved as monotherapy in relapsed cHL. We hypothesized that PEM in combination with ICE (PEM-ICE) chemotherapy would be a safe and effective regimen that would yield high CMR rates prior to AHSCT. Methods: This single arm, phase II, multi-institutional clinical trial evaluated the addition of PEM to ICE chemotherapy in AHSCT eligible patients with relapsed and refractory cHL (NCT03077828). The regimen consisted of 21 day cycles of PEM 200 mg IV on day 1 with standard ICE including ifosfamide 5 g/m2 with MESNA as a 24hr continuous infusion on day 2, carboplatin AUC 5 IV (max 800 mg) on day 2, and etoposide 100 mg/m2/day IV on days 1 to 3. Two cycles of PEM-ICE were followed by stem cell mobilization/collection. One cycle of PEM 200 mg IV monotherapy was then administered. Our primary endpoint was the rate of CMR on PET/CT (PET2) imaging defined as a Deauville score of ≤ 3. Images were reviewed centrally. An optional third cycle of PEM-ICE was permitted for patients achieving CMR to allow for appropriate timing of AHSCT. Secondary objectives included clinical outcomes (PFS and OS), safety and tolerability, and transplantation related metrics including ability to collect stem cells and time to engraftment. Results: A total of 42 patients were enrolled with 37 patients evaluable for the primary endpoint. Median age was 34 (19-70) with female predominance (n=27, 64%). 16 patients had primary refractory disease. The CMR rate assessed by PET/CT imaging following 2 cycles of PEM-ICE was 86.5% (95% CI, 71.2-95%), meeting our primary endpoint of improvement over historical outcomes to 70%. The PET2 ORR was 97.3% with 11% PR and 2.7% PD. PET2 scores were Deauville 1 in 45% (n=17), Deauville 2 in 27.0% (n=10), Deauville 3 in 8.1% (n=3), Deauville 4 in 13.5% (n=5), and Deauville 5 in 5.4% (n=2). New areas of PET-positivity in two cases were biopsied showing noncaseating granuloma in one case and EBV but no cHL in another. Five patients received the optional third cycle of PEM-ICE chemotherapy with 35 of the 37 evaluable patients proceeding to AHSCT. Seven patients had radiation as part of the conditioning regimen with an additional 4 patients receiving consolidative radiation following transplant. After a median follow up of 27 months, the median PFS was 26.9 months with survival probability at 24 months of 88.2% (Figure 1). Median OS was not reached with too few events but remained 95.1% at 27 months. The addition of PEM to ICE did not impair stem cell mobilization and all patients successfully collected, with 35 (87%) within 2 apheresis sessions (range 1-7). No patients had engraftment delays or failure. Of the 42 patients, all received at least one dose of PEM and were therefore eligible for toxicity analyses. 34 patients (81%) experienced adverse events (AEs) attributed to PEM and 22 patients (52.3%) had grade 3-4 AEs comprised of cytopenias, elevated AST/ALT, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe AEs attributed to PEM which included anemia, back pain, decreased EF, fever, and thrombocytopenia. There were no significant PEM-related autoimmune events that delayed a patient's treatment on protocol. There were two grade 5 toxicities on the protocol including a patient with cardiac arrest during stem cell collection and a patient with acute respiratory distress syndrome attributed to engraftment syndrome. Both were judged "possibly" related to PEM. Conclusions: Pembrolizumab with ICE chemotherapy is a tolerable and efficacious regimen with high CMR rate as assessed by PET/CT. Despite short follow up, patients had excellent PFS and OS in the post-transplant setting. The results support further investigation of PEM-ICE as second-line treatment for AHSCT eligible patients with relapsed and refractory classical Hodgkin lymphoma. Figure 1 Figure 1. Disclosures Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Allen: Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria; Secure Bio: Consultancy, Honoraria. Karmali: Epizyme: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Genentech: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy. OffLabel Disclosure: new combination of study agent with standard of care chemotherapy regimen

Checkpoint inhibitor‐based salvage regimens prior to autologous stem cell transplant improve event‐free survival in relapsed/refractory classic Hodgkin lymphoma

“…16,18,[24][25][26][27] However, the comparative efficacy of CPI-based salvage regimens versus conventional chemotherapy and BV-based regimens has not yet been previously established in a clinical trial or in a real-world cohort. [16][17][18][19] Our study is the largest multicenter real-world experience to evaluate the efficacy of novel CPI-based regimens compared to conventional chemotherapy and BV-based regimens in R/R cHL. Our data suggest that the impact of CPI-based regimens before ASCT may be substantial with significant improvements in EFS and PFS compared to other salvage regimens.…”

“…15 In two independent single arm phase 2 trials, pembrolizumab leads to response rates of about 97.3 and 100% in combination with platinum-based and gemcitabine-based chemotherapy, respectively, with 24-month progression-free survival (PFS) of 88% and 100%, respectively. 16,17 In a single-arm phase 2 trial of 91 patients with recurrent cHL, salvage BV plus nivolumab leads to CR rate of 67% and 2 year PFS of 91%. 18 In an ongoing phase 2 study of 39 patients, the efficacy of sequential treatment with Nivolumab followed by ICE was studied.…”

Autologous Stem Cell Transplantation in Hodgkin Lymphoma—Latest Advances in the Era of Novel Therapies

“…Preliminary results of pembro with ICE were presented at the American Society of Hematology (ASH) meeting in 2021: 42 patients were enrolled, and 37 patients were evaluable for efficacy, for whom the CR rate was 86.5% and the 24-month PFS was 88.2%. Notably, one patient died of cardiac arrest during stem cell collection, and another patient succumbed to acute respiratory failure early post-autoHCT, attributed to engraftment syndrome [ 19 ].…”

“…Given the strong clinical activity of these agents, there has been ongoing interest in exploring their role in the second-line setting and especially in the context of autoHCT, either as pre-autoHCT salvage, post-autoHCT consolidation, or both. While 2L treatment has historically consisted of cytotoxic chemotherapy, BV monotherapy [ 13 ], BV with concurrent chemotherapy [ 14 , 15 ], BV with nivo [ 16 ], nivo monotherapy [ 17 ], and nivo/pembro + chemotherapy [ 17 , 18 , 19 ] have all been tested as 2L treatments and used successfully to bridge patients to curative intent autoHCT. In fact, the long-standing dogma that chemosensitivity is an absolute requirement prior to autoHCT has been challenged given the success of CPI-based salvage followed by autoHCT, even in previously chemorefractory patients [ 20 ].…”

Updates in the Role of Checkpoint Inhibitor Immunotherapy in Classical Hodgkin’s Lymphoma

“…Other small studies evaluating combination of immunotherapy with standard regimens as bridge to ASCT, including pembrolizumab combined with ICE or gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), showed similarly high CR rates of 86–95% [ 36 ]. The active investigation of other anti-PD-1 mAb combination regimens via a PET-adapted approach using anti-PD1 mAb with GVD are underway to assess efficacy with less toxic or chemotherapy-sparing therapies ( Table 2 ).…”