4017 - Comprehensive biomarker analyses and updated results of PURE-01 study: neoadjuvant pembrolizumab (Pembro) in muscle-invasive urothelial bladder carcinoma (MIBC).

Background

PURE-01 (NCT02736266) is a single-arm, phase 2 study of Pembro preceding radical cystectomy in MIBC. Updated results and exploratory biomarker analyses are presented.

Methods

71 patients (pts) will be enrolled, with cT ≤ 3bN0 MIBC, regardless of cisplatin eligibility. Pembro is given 200mg q3w x3 cycles. Pathologic complete response (pT0) in ITT population is the primary endpoint (EP). The H₁ is pT0 ≥25%, H₀ pT0≤15%. 15/71 pT0 are required. Biomarker analyses include: IHC PD-L1 combined positive score (CPS, Dako 22C3), hybrid-capture based comprehensive genomic profiling (CGP, FoundationONE), and expression of a 22-gene “T-cell inflamed” signature via quantitative PCR (qPCR).

Results

As of 05/2018, 65 pts have been enrolled and all underwent CGP from TURB samples: 42% showed DDR genomic alterations (GA). Median CPS was 21%. CPS and qPCR showed a significant correlation (r = 0.71, p < 0.0001), whereas CPS did not correlate with neither tumor mutational burden (TMB) nor DDR-GA (R=-0.16). 37 pts are evaluable for the primary endpoint. With 15 (40.5%) pT0 responses, the study has already achieved its PE. RB1 and PBRM1 GA were significantly associated with pT0 (p = 0.014 and p = 0.007). pT0 responses were obtained in 10 (52.6%) pts with CPS≥21% and, most noteworthy, in 13 (61.9%) with DDR or RB1 GA. 8/8 pts (100%) with DDR/RB1 GA and CPS≥21% achieved pT0. The 22 gene T-cell inflamed signature also significantly discriminated pT0 from non-pT0 pts (p = 0.0032). 17 pts had matched pre-post Pembro tumor samples analyzed, showing a mean of 51.9% shared GA. Concordant increases in gene expression by qPCR, observed in post- vs pre-Pembro lesions, from at least 5/7 non responding patients, were consistent with promotion of adaptive immunity (IFN-g, CXCL9, CXCR6, CD27, GZMB), being counteracted by strong adaptive resistance mechanisms (CD274, PDCD1, CD276, PDCD1LG2, IDO1).

Conclusions

Pembro has already exceeded the pT0 responses required in this study. Many new observations and the immune-genomic features interplay may contribute identifying those pts who might deserve a bladder-sparing approach. Full results on the entire dataset will be presented.

Clinical trial identification

NCT02736266.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Funding

Merck Inc.

Editorial Acknowledgement

Disclosure

A. Necchi: Consultant and advisor: Merck. R. Madison, J.S. Ross, J. Chung: Employee: Foundation Medicine Inc. S.M. Ali: Employee: Foundation Medicine. All other authors have declared no conflicts of interest.