Kalakonda, Nagesh

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

Abstract Background: The pivotal phase 3 ECHELON-1 study demonstrated superior efficacy of brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with previously untreated advanced stage classical Hodgkin lymphoma (cHL) with a 2-year modified progression-free survival (mPFS) of 82.1% in the A+AVD group versus 77.2% in the ABVD group (Hazard Ratio=0.77; 95% confidence interval [CI] 0.60, 0.98; p=0.04). PN is a known toxicity associated with anti-mitotic agents, including vinblastine and the MMAE component of brentuximab vedotin. In the ECHELON-1 study, the incidence of any-grade PN events was 67% (442 of 662 patients) and 43% (286 of 659 patients) in the A+AVD and ABVD arms, respectively; the incidence of grade ≥3 PN was 11% and 2%, respectively. At the time of the initial analysis, 67% of A+AVD-treated patients had either resolution (43%) or improvement (24%) of PN events. A total of the 92% of ongoing PN events were grade 1 (64%) or grade 2 (29%). Here, we report rates of PN resolution and improvement in patients participating in the ECHELON-1 study after long-term follow-up. Methods: Patients with Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670). Pre-existing PN was an exclusion factor at study entry. Peripheral neuropathy was determined on the basis of a standardized MedDRA query; patients who developed PN were monitored throughout the study and those with ongoing PN at end of treatment were followed for resolution or improvement during the post-treatment follow-up period; follow-up visits were scheduled for every 12 weeks ±1 week until 36 months, then every 6 months until study closure. PN resolution was defined as completely resolved and improvement was defined as improved by ≥1 grade from worst grade as of the latest assessment. Results: At the time of the primary analysis, 51% (226/442) and 61% (174/286) of patients in the A+AVD and ABVD arms, respectively, had resolution or improvement of PN events at EOT. Upon continued follow-up (~10 additional months) for approximately 30 months (range 0-78.5) after end of treatment, 76% (335/442) of patients with PN in the A+AVD arm had either complete resolution (59%, 260/442) or improvement (17%, 75/442) of their PN events compared with 82% (234/286) with either resolution (72%) or improvement (10%) in the ABVD arm. In the A+AVD arm, 90% of ongoing PN cases (n=182) were grade 1/2; grade 1=58% (n=106), grade 2=32% (n=58). Residual grade 3 PN was reported in 9% (n=17) of patients (1 patient with grade 4 PN died before resolution). In the ABVD arm, residual PN (n=81) was grade 1 (65%; n=53), grade 2 (30%; n=24), and grade 3 (5%; n=4). For the subset of patients with PN that had not resolved by end of treatment, the median time to resolution of all PN events from AE start date was 28 weeks for A+AVD and 14 weeks for ABVD, the median time to improvement of PN was 39 weeks for A+AVD and 18.5 weeks for ABVD. Conclusions: After approximately 2.5 years of continued follow-up, PN continues to resolve and improve for patients who were treated with A+AVD or ABVD in the ECHELON-1 study. In both study arms, the majority of ongoing PN cases are grade 1 or grade 2. Further follow-up is ongoing. Disclosures Radford: Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership. Connors:Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Roche Canada: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Janssen: Research Funding; Bayer Healthcare: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Merck: Research Funding; F Hoffmann-La Roche: Research Funding; Amgen: Research Funding; Lilly: Research Funding. Younes:Astra Zeneca: Research Funding; J&J: Research Funding; Curis: Research Funding; BMS: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Gallamini:Takeda: Consultancy, Speakers Bureau. Ansell:Affimed: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding. Gopal:Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Merck: Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; Teva: Research Funding; Asana: Consultancy. Flinn:Trillium: Research Funding; Calithera: Research Funding; Forma: Research Funding; Portola: Research Funding; Verastem: Research Funding; Janssen: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Merck: Research Funding; Curis: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Agios: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; TG Therapeutics: Research Funding; Kite: Research Funding; BeiGene: Research Funding. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria. Dlugosz-Danecka:Servier: Consultancy; Roche: Consultancy. Engley:Seattle Genetics: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Purevjal:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kuruvilla:Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Merck: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding.

TPS7573 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells and may provide an effective target for enhancing anticancer immune response. In DLBCL, high PD-L1 expression has been identified as a negative prognostic factor for overall survival. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and preliminary preclinical and clinical activity support the study of durvalumab in high-risk DLBCL subtypes. The primary study objective is to explore the clinical activity of durvalumab with R-CHOP in non-activated B-cell–like (non-ABC) and durvalumab with lenalidomide + R-CHOP (R2-CHOP) in ABC previously untreated DLBCL; secondary objectives are to evaluate safety and identify biomarkers predictive of clinical response. Methods: This is a phase II, two-arm, open-label, global, multicenter study of durvalumab combinations in patients with previously untreated, high-risk DLBCL (MEDI4736-DLBCL-001; EUDRA CT 2015-005173-20; NCT03003520). High risk was defined as Ann Arbor stage III/IV or II with bulky disease (≥7.0 cm), along with intermediate-high/high IPI ≥3 or NCCN-IPI ≥4; patients must also have CD20+ DLBCL, ECOG PS 0-2, and no prior antilymphoma therapy. All patients receive durvalumab + R-CHOP21 in induction cycle 1 simultaneous to cell-of-origin (COO) analysis by gene expression profiling with NanoString technology. Beginning with cycle 2, Arm A (non-ABC) receives durvalumab 1125 mg IV on day 1 with 6 or 8 cycles of R-CHOP21; Arm B (ABC) receives the same durvalumab + R-CHOP21 doses with oral lenalidomide 15 mg/day on days 1-14. Both arms receive durvalumab consolidation 1500 mg IV on day 1 q28d for ≤12 months from induction cycle 1, day 1. The primary endpoint is 2-y progression-free survival (PFS); secondary endpoints include clinical response to treatment in biomarker-defined subpopulations (tumor and peripheral blood) and safety as assessed per NCI CTCAE v4.03 criteria. Exploratory endpoints include PFS at 12 mo, complete response, and PK/PD. Recruitment is ongoing, with a target enrollment of 120 patients. Clinical trial information: NCT03003520.