1758O - Neoadjuvant pembrolizumab in localized/locally advanced solid tumors with mismatch repair deficiency

Background

Pembrolizumab (pembro) significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors. This study evaluates pembro in the neoadjuvant space with the potential for an organ-sparing approach.

Methods

This is a phase 2 open-label, single center trial of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease. Treatment is Pembro 200mg every 3 wks for 8 cycles followed by surgical resection with option to continue therapy for 18 cycles followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery.

Results

Between 10/2019 and 3/2021, 35 pts were enrolled and study has completed enrollment. Tumor types included 27 CRC and 8 non-CRC: endometrial, gastric, meningioma, 2 duodenal, ampullary and 2 pancreatic. Median follow-up was 9 months (range 0.1 - 17). Among 32 evaluable pts, best ORR was 75% (CR 25% , PR 50%), SD 22% and PD 3%. Luminal endoscopic response was seen in 17/19 (89%) pts. Among 8 (23%) pts who underwent surgery, pCR was seen in 4. At present non-operative approach was chosen by 8 (23%) pts with 1-year organ-sparing seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events were seen in 3 (9%) pts (transaminitis, diarrhea and type 1 diabetes). Baseline ctDNA mutations were present in 20 (57%) pts and at 3 weeks declined in 15 (75%), unchanged in 1, no paired 3 week sample in 1, and increased in 3. Tumor microenvironment immune analysis is ongoing and will be presented.

Conclusions

Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of radiographic and endoscopic response which has implications for organ-sparing strategies. Non-operative management of dMMR/MSI-H localized solid tumors should be further investigated.

Clinical trial identification

NCT04082572.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Merck.

Disclosure

All authors have declared no conflicts of interest.