Abstract A006: Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, durva) + tremelimumab (treme) in patients with advanced solid tumors
Authors: Callahan Margaret K. , Odunsi Kunle , Sznol Mario , Nemunaitis John , Ott Patrick A. , Dillon Patrick , Schneider Reva , Park Andrew , Schwarzenberger Paul , Ricciardi Toni , Macri Mary , Ryan Aileen , Venhaus Ralph , Wolchok Jedd D. 
Published: February 2019

Abstract
Durvalumab (durva) is a human IgG1 monoclonal antibody (mAb) that blocks programmed cell death ligand-1 (PD-L1). Tremelimumab (treme) is a human IgG2 mAb inhibitor of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for durva and treme are non-redundant, providing sound rationale for clinical testing of the combination.This is an ongoing phase 1, multicenter, open-label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), or ovarian (OC) cancer are included in the expansion phase. The protocol excludes patients who had prior exposure to anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. Primary objectives are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response, progression-free survival (PFS), and overall survival (OS). The intent-to treat (ITT) analysis set includes all patients who received at least one dose of durva or treme and had the baseline and at least one post-baseline tumor assessment.As of 11 May 2018, 104 patients were treated (73.1% female; median age: 56 (30 to 80) years. Durva 1500 mg every 4 weeks (Q4W) X 12 and treme 75 mg Q4W X 4 was the regimen used for opening the expansion phase (n = 82 patients). The majority of treatment-related adverse events (TRAEs) for all patients were Grades 1 and 2. TRAEs ≥ Grade 3 were reported in 17 (16.3%) patients; the majority were diarrhea/colitis (n = 6) and abnormal liver function tests (n = 4) and responded to established treatment algorithms. There was 1 Grade 5 TRAE: multi-organ failure. Fifteen (14.4%) patients experienced TRAEs leading to treatment discontinuation; the majority were diarrhea/colitis (n = 6) and abnormal liver function tests (n = 5). No new toxicities were identified. Tumor response by immune-related Response Criteria (irRC) was assessed by tumor type in the ITT analysis set for all cohorts included in the expansion phase; the follow-up period was at least 12 months. Best overall responses (complete response (irCR), partial response (irPR) and stable disease (irSD)) are presented by tumor type. For OC (n = 27): irCR = 0, irPR = 2 (7.4%), irSD = 10 (37%); for CRC (n = 18): irCR = 1 (5.6%), irPR = 1 (5.6%), irSD = 2 (11.1%); for NTNBC (n = 16): irCR = 0, irPR = 1 (6.3%), irSD = 2 (12.5%); for RCC (n = 19): irCR = 0, irPR = 3 (15.8%), irSD = 11 (57.9%); and for CC (n = 16): irCR = 1 (6.3%), irPR = 3 (18.8%), irSD = 4 (25%) patients. PD-L1 status is not yet available. MSI status was collected retrospectively for patients with CRC; in this group, the patient with irPR had MSI-high status, and the MSI status of the patient with irCR is unknown. PFS and OS rates will be presented at the meeting. In conclusion, the durva and treme combination has a manageable safety profile, with evidence of clinical activity. These data support continued study of the combination therapy.
Citation Format: Margaret K. Callahan, Kunle Odunsi, Mario Sznol, John Nemunaitis, Patrick A. Ott, Patrick Dillon, Reva Schneider, Andrew Park, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Ralph Venhaus, Jedd D. Wolchok. Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, durva) + tremelimumab (treme) in patients with advanced solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A006.