Safety and efficacy of neoadjuvant pembrolizumab in mismatch repair deficient localized/locally advanced solid tumors.
Authors: Ludford Kaysia , Raghav Kanwal Pratap Singh , Blum Murphy Mariela A. , Fleming Nicole D. , Nelson Douglas A. , Lee Michael Sangmin , Smaglo Brandon George , You Y. Nancy , Tillman Matthew Murray , Kamiya-Matsuoka Carlos , Thirumurthi Selvi , Messick Craig , Johnson Benny , Vilar Sanchez Eduardo , Dasari Arvind , Thomas Jane V , Foo Wai Chin , Qiao Wei , Kopetz Scott , Overman Michael J. 
Published: June 2021

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Background: Pembrolizumab (Pembro), anti-PD1 therapy, is FDA approved for refractory microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) advanced/metastatic solid tumors. The robust activity of anti-PD1 therapy in these tumors argues for a neoadjuvant organ-sparing approach. However, the role of anti-PD1 monotherapy in the neoadjuvant setting is unknown. Methods: This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease per RECISTv1.1 and ECOG PS 0/1. Treatment is Pembro 200mg every 3 wks for 8 cycles (6 months) followed by surgical resection with option to continue therapy for 18 cycles (12 months) 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 [highest variant allele frequency (VAF) baseline mutation]. 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 12/2019 and 2/2021, 32 pts were enrolled and treated. Enrolment goal of 35 anticipated to be met by 4/2021. Baseline characteristics included 13 females, median age of 63 yrs (range 26 - 91), Lynch syndrome in 12 pts, BRAF V600E mutation in 11 pts. Tumor type included 24 CRC and 8 non-CRC (1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, 2 pancreatic). At baseline disease was resectable in 23 (72%). Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1). Only one pt progressed after initial SD of -18%. Median follow-up is 6.1 months (range 0.1 - 14). Among the 6 (20%) pts who underwent surgery, pCR was seen in 3 (50%). A non-operative approach (pembro for 12 months) has been chosen in 15 pts and 1-year organ-sparing was seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events (TRAE) were seen in 3 (9%) pts: grade 3 immune hepatitis (2) and grade 3 type 1 diabetes (1). Baseline ctDNA was positive in 17 (53%) pts with a median of 4 mutations per pt (1 - 35) and median highest VAF of 0.9% (range 0.3% to 38.2%). Among 26 pts with successful tumor tissue testing, median tumor mutations were 10.5, range 1 to 21 (Oncomine 134 gene panel). ctDNA decline at 3 weeks was seen in 14/17 (82%) patients. Luminal disease was present in 24 pts with endoscopic response of: CR in 13 (54%), major response 1, pending follow-up evaluation 6, not evaluated 3, and no response in 1. Conclusions: Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation. Clinical trial information: NCT04082572.