Clinical activity, safety, and biomarkers of MPDL3280A in metastatic urothelial bladder cancer: Additional analysis from phase IA study.

Abstract

297 Background: Metastatic urothelial bladder cancer (UBC) is a mutationally-complex disease in which PD-L1 expression in the tumor microenvironment may inhibit immune-mediated antitumor responses. MPDL3280A is a PD-L1-targeting antibody with an engineered Fc domain that disrupts PD-L1/PD-1 and PD-L1/B7.1 signaling. Methods: MPDL3280A was studied in a phase Ia metastatic UBC expansion cohort. UBC pts received MPDL3280A 15 mg/kg IV q3w for ≤16 cycles. Efficacy-evaluable pts were dosed by January 27, 2014 (≥12 week follow-up) with a data cutoff of April 21, 2014. RECIST v1.1 was used to assess ORR. PD-L1 expression (by immune cell IHC) was centrally evaluated from archival biopsies. In-tumor gene expression and peripheral biomarker analyses were done on pts dosed by Nov 20, 2013, with a cutoff of January 1, 2014. Results: In the UBC cohort, 33 IHC 2/3 pts, 36 IHC 0/1 pts, and 1 PD-L1 pt with unknown IHC were efficacy-evaluable. Median pt age was 65 y (36-89), and 73% were male. Visceral and liver metastases were present in 74% and 33% of pts, respectively. 73% had ≥2 prior therapies, and 91% had prior platinum. The unconfirmed ORR was 52% (95% CI, 34-69; 3 CRs, 14 PRs) in IHC 2/3 pts and 14% (95% CI, 6-28; 5 PRs) in IHC 0/1 pts. The median DOR was not yet reached (0.1+ to 42+ w in IHC 2/3 pts, n=17; 6+ to 19+ w in IHC 0/1 pts, n=5). 19/22 responding pts had ongoing responses. Median PFS was 24 w in IHC 2/3 pts (5 to 50+ w, n=33) and 8 w in IHC 0/1 pts (0.1+ to 30+ w, n=36). Of 74 pts evaluable for safety, all grade treatment-related AEs occurred in 65%, most often fatigue, decreased appetite and nausea. 5% had treatment-related G3-4 AEs. No treatment-related deaths were seen. The median follow-up was 5.4 mos (1+ to 12 mos, n=70). IHC 2/3 tumors had low expression of a baseline myeloid marker gene signature, including IL8 and IL1B, which was associated with MPLD3280A response. Additionally, circulating inflammatory markers (e.g., CRP) and tumor burden markers (e.g., HCG) decreased in responders by cycle 2. Updated data will be presented. Conclusions: MPDL3280A was well tolerated in UBC pts. Rapid and durable responses were seen and correlated with PD-L1 IHC status on immune cells. Biomarkers suggest a potential role for myeloid biology in primary resistance to MPDL3280A. Clinical trial information: NCT01375842.