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A phase Ia study of MPDL3280A (anti-PDL1): Updated response and survival data in urothelial bladder cancer (UBC).
Background: PD-L1 may contribute to immune escape in UBC, a disease of high mutational complexity and immunogenicity. MPDL3280A was designed to restore T cell–mediated antitumor activity by blocking PD-L1 binding to PD-1 and B7.1 receptors. Methods: Previously treated, metastatic UBC pts were enrolled in an expansion cohort and received 15 mg/kg or 1200 mg IV MPDL3280A q3w. Efficacy-evaluable pts had ≥ 12 wk of follow-up (dosed by Jun 9, 2014; Sep 2, 2014 cutoff). ORR was assessed by RECIST v1.1 (unconfirmed), and archival biopsies were centrally evaluated for PD-L1 tumor-infiltrating immune cell (IC) expression by IHC. In-tumor gene expression and peripheral biomarkers were assessed as exploratory analyses in a subset of pts. Results: Updated analyses include 85 efficacy-evaluable, selectively enrolled UBC pts; 46 were PD-L1 IHC 2/3, 38 were IHC 0/1 and 1 had unknown IHC status. Median age was 66 y (36-89 y), and 75% were male. Baseline visceral mets were present in 77% of pts; 98% received ≥ 1 prior therapy (eg platinum in 93%). The ORR for IHC 2/3 pts was 46% (95% CI 31-61%; 6 CRs, 15 PRs), and for IHC 0/1 pts was 16% (95% CI 6-31%; 6 PRs) with median response durations not yet reached (IHC 2/3 pts, 0+ to 54+ wk; IHC 0/1 pts, 4+ to 33+ wk). Median PFS was 24 wk (95% CI 12-NE) for IHC 2/3 pts and 8 wk (95% CI 6-12 wk) for IHC 0/1 pts. 24-wk OS rates for IHC 2/3 and 0/1 pts were 85% (95% CI 74-96%) and 71% (95% CI 54-88%), respectively, with the medians not yet reached (3 to 72+ wk and 2+ to 51+ wk, respectively). Pts with visceral mets had ORRs of 32% (IHC 2/3: 3 CRs, 7 PRs; n = 31) and 12% (IHC 0/1: 4 PRs; n = 33). Median safety follow-up was 16 wk (3-73 wk). Drug-related AEs occurred in 64% of 87 safety-evaluable pts (most often fatigue, asthenia, nausea); 8% had a related G3-4 AE. 12% of pts had an immune-related AE. No related deaths were seen. Responders had lower myeloid gene expression at baseline (eg Cox-2, IL8; IL1B) and decreased circulating inflammatory and tumor markers (eg CRP; HCG, CA 19-9, CA-125) by cycle 2. Conclusions: MPDL3280A was well tolerated and had durable activity in UBC pts. Response, PFS and OS data are promising for IHC 2/3 and IHC 0/1 UBC pts vs historic controls. Response also correlated with in-tumor and blood-based biomarkers. Clinical trial information: NCT01375842
Abstracts by Daniel Peter Petrylak:
Changes in T cell immunity in patients with metastatic castration resistant prostate treated with Radium-223 treatment.Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 295
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC).Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 355
Sipuleucel-T (sip-T)–induced proliferative CD8+ T-cell responses to immunizing and secondary antigens.Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 165