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3565 Background: MSS mCRC rarely responds to pembrolizumab monotherapy, but capecitabine and bevacizumab may induce immune-stimulatory effects. This study evaluates the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in MSS mCRC. Methods: Single-center, phase 2 trial with safety lead-in to confirm the recommended phase 2 dose (RP2D) for capecitabine and expansion cohorts (NCT03396926). Key eligibility: MSS mCRC with stable disease (SD) or progressive disease (PD) on prior fluoropyrimidine-based therapy. Treatment: Capecitabine 1000 mg/m2 PO BID D1-14 Q21 days (confirmed RP2D) plus pembrolizumab 200 mg IV D1 Q21 days and bevacizumab 7.5 mg/kg IV D1 Q21 days. Endpoints: Primary: Objective response rate (ORR) by RECIST 1.1. Key secondary: Safety, duration of response (DOR), progression-free survival (PFS), overall survival (OS). Results: From 04/2018-10/2021, 44 patients (pts) were enrolled. Overall: Median age 53 years (range 28-79); female 50%; Caucasian 61%. Liver metastases at enrollment 80%. Prior therapies: median prior lines of therapy 2 (range 1-5); PD on fluoropyrimidine-containing regimens 91%; prior exposure to bevacizumab 86%. Complete toxicity data are available for 36 off-treatment pts. Grade ≥ 3 treatment-related (tr)AEs occurred in 10 (28%) pts, including grade 3 immune-related AEs in 4 (11%) pts. All-cause serious (s)AEs occurred in 13 (36%) pts and trSAEs in 5 (14%) pts. (tr)AEs leading to dose interruptions, reductions, or delays occurred in 21 (58%) pts, most commonly palmar-plantar erythrodysesthesia syndrome in 17 (47%) pts. Disposition: of 44 pts enrolled, 35 were removed for PD and 1 was removed for treatment noncompliance; 8 treatment ongoing. ORR in 40 evaluable pts was 5% (95% CI: 0.6,16.9). Best response by RECIST 1.1: partial response (PR) in 2 (5%); SD in 26 (65%); PD in 12 (30%). 2 responders: DOR 12 and 15 months, both with liver metastases. Median follow up was 7 months (range 1-45), with median PFS 4.3 months (95% CI: 3.9, 6.1), PFS at 6 months 31.1% (95% CI: 19.2%, 50.4%), and median OS 9.6 months (95% CI: 6.2, 13). Median time on treatment was 5 months (range 1-26). Single cell RNA sequencing on a subset of paired pre- and on-treatment biopsies demonstrated changes in the frequency of dendritic cells. Conclusions: The combination of pembrolizumab with capecitabine and bevacizumab was found to be tolerable with an expected toxicity profile in MSS mCRC pts. The ORR of 5% did not meet the prespecified target of ≥ 15%, however nearly a third of pts had PFS > 6 months. Immune profiling of tumor biopsies and peripheral blood is ongoing. Clinical trial information: NCT03396926.

444 Background: Immune checkpoint inhibitors (ICI) have limited activity as monotherapy in unselected patients with ABC; the objective response rate (ORR) of PEM was 5.8% in the multicenter phase 2 KEYNOTE-158 trial. GM-CSF modulates immune cells including monocytes and the innate immune response and has demonstrated safety and prolonged survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial was designed to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Single-center, phase 2 trial with Simon’s 2-stage design and expansion cohort (EC) (NCT02703714). Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior ICI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 and EC) or in cycles 1 and 2 (Stage 2). Primary endpoint was objective response rate (ORR) by RECIST 1.1, H0 5% vs. H1 20%. Key secondary endpoints were safety, progression-free survival (PFS), OS, PD-L1 expression. Exploratory endpoints included relationship between efficacy outcomes and anatomic subsite, risk factors, and tumor genotype. Results: Overall, 42 patients enrolled between 5/2016-12/2019: n = 9 in Stage 1, n = 18 in Stage 2, and n = 15 in EC. Overall: median age 61; female 67%; intrahepatic (ICC) 67%, extrahepatic (ECC) 26%, gallbladder (GBC) 7%; stage IV 90%; hepatitis B/C virus positive (HBV/HCV+) 24%; microsatellite instability (MSI-H)/stable (MSS)/unknown n = 1/35/6. Immune-related (ir)AE occurred in 69%, grade 3/4 treatment-related (tr)AE in 10%, all-cause serious (S)AE in 36%, and trSAE in 7%. ORR was 12% (95% CI: 4, 26), with median PFS of 63 days (95% CI: 55, 125), PFS at 6 months in 27% (95% CI: 14, 43), and median OS 3of 93 days (95% CI: 243, 573). There was no significant difference in ORR, PFS, or OS by anatomic subsite or tumor PD-L1 expression; HBV/HCV+ showed trends toward higher ORR (30% vs 6%, p = 0.08) and longer median PFS (276 vs 63 days, p = 0.06) and OS (1033 vs 323 days, p = 0.052). Conclusions: The combination of PEM plus GM-CSF was safe and well-tolerated with higher ORR than expected for PEM monotherapy in a predominantly MSS ABC population but did not meet target ORR threshold for efficacy. ORR and median PFS and OS were highest in patients with underlying HBV or HCV infection. Immune profiling of on-treatment biopsies and peripheral blood are ongoing to ascertain influence of both PEM and GM-CSF on circulating and tumor immune microenvironment. Clinical trial information: NCT02703714.