510MO - Long-term survival and organ preservation with pembrolizumab in localized MSI-H/dMMR solid tumors

Background

We previously demonstrated safety and high rates of radiographic and pathologic response to pembrolizumab (pembro) in treatment-naïve patients (pts) with localized MSI-H/dMMR cancers. Here, we report updated organ preservation rates and oncologic outcomes after 3 years (yrs) of follow-up.

Methods

This was a phase 2 open-label, single-center trial. Treatment was pembro 200mg every 3 weeks for 6 months (mo) followed by surgical resection, or 1 yr of pembro and non-operative management. In addition to standard imaging, we performed a 70-gene tumor-agnostic ctDNA assay to detect somatic mutations at baseline and serially. Co-primary endpoints were safety and pathological complete response. Secondary endpoints were objective response rate (ORR), organ preservation, disease-free (DFS), and overall survival (OS). An exploratory objective was the predictive ability of ctDNA changes for efficacy endpoints.

Results

Between 10/2019 and 3/2021, 35 pts were enrolled. Seventeen were managed operatively and 18 non-operatively. Median follow-up was 2.9 yrs (range 0-3.8). The 3-year DFS and OS rates for all patients were 80% (95% CI 66-93) and 94% (95% CI 86-100) respectively. Best ORR remained at 82%, but 3 additional pts converted from partial responses (PR) to complete responses (CR): 13 (39%) CRs and 14 (42%) PRs, observed at a median of 33 mo (range 31-33). Of 13 non-operatively managed pts with follow up, 12 were alive with affected organ intact. There was a trend towards longer DFS (p 0.002) and OS (p 0.002) rates in pts whose ctDNA cleared compared to not. No additional progressive events beyond the 6 pts identified in our initial report occurred. Of these 6 pts, 4 underwent planned resection and continue to show no radiographic evidence of disease >30 mo after last pembro, one patient died from disease progression, and one was lost to follow up.

Conclusions

Updated analysis shows ongoing radiographic response and long-term organ preservation in pts managed non-operatively. With three-year follow-up, both DFS and OS in surgically and non-operatively managed pts receiving pembro remains high. Clearance of ctDNA appears to predict prolonged DFS and OS and warrants further exploration.

Clinical trial identification

NCT04082572.

Editorial acknowledgement

Legal entity responsible for the study

University of Texas MD Anderson Cancer Center.

Funding

Supported by CCSG P30 CA016672, SPORE P50CA221707, Merck and Kavanagh Family Foundation.

Disclosure

S. Kopetz: Financial Interests, Personal, Advisory Board, Consultant: Roche, Merck, Bayer, Pfizer, Genentech, Lutris, Aveo, Tachyon Therapeutics, Agenus, Revolution Medicines, Kestrel Therapeutics, Regeneron; Financial Interests, Personal, Advisory Board: Mirati, Flame, Carina; Financial Interests, Personal, Other, Consultant: Frontier Medicines, Replimune, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Harbinger Oncology, Zentalis; Financial Interests, Personal, Other, Research: Sanofi, Guardant Health, Genentech/Roche, EMD Serono, MedImmune, Novartis; Financial Interests, Personal, Advisory Board, Research: Amgen, Lilly, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, BridgeBio, Cardiff, Jazz, Zentalis, Mirati; Financial Interests, Personal, Stocks/Shares: Lutris, Navire; Financial Interests, Personal, Ownership Interest: Frontier Medicines. M.J. Overman: Financial Interests, Personal, Advisory Board: Roche, BMS, Medimmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone, Nouscom, Atreca, Bayer, Summit, Agenus, Regeneron, Astellas; Financial Interests, Institutional, Coordinating PI: Roche, Lilly, Merck, Bms, Phanes, Nouscom. All other authors have declared no conflicts of interest.