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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.

42 Background: Diet may be associated with survival and health-related quality of life (HRQOL) among CRC survivors. Behavioral interventions using web and mobile technology are feasible and acceptable approaches to modify dietary behavior. Little is known about the effect of web-based dietary interventions on HRQOL among CRC survivors. Methods: The Survivor Choices for Eating and Drinking study (SUCCEED) was a pilot randomized wait-list controlled trial designed to determine the feasibility and acceptability of a 12-week (wk) web-based dietary intervention with daily text messages. In this secondary analysis, we estimated the effect of the intervention on HRQOL. Between 2017-2018, 50 CRC survivors were randomized (1:1) to intervention or control. Participants in the intervention arm received the intervention in wk 1-12 and were followed from wks 12-24. Participants assigned to the control arm for 1-12 wks had the option to receive the intervention in wks 13-24. In both arms, HRQOL and sleep quality were assessed using the EORTC QLQ–C30 and CR29 and the Pittsburgh Sleep Quality Index at 0, 12, and 24 wks. Within- and between-group mean changes in HRQOL from enrollment to 12 and 24 wks were evaluated using independent t-test and paired t-test. Results: Follow-up was 88% complete at 12 and 24 wks in the intervention arm and 92% and 80% complete at 12 and 24 wks in controls. Participants mean age was 56 ± 9 y; 34% were men, 70% identified as non-Latinx White, 12% identified as Latinx, and 70% had stage III cancer. Between 0 and 12 wks, an increase in emotional functioning was observed in the intervention arm [mean change: 9.1; 95% confidence interval (CI): 2.2,16.0], while a decrease in emotional functioning was observed in controls (mean change: -5.1; 95%CI: -14.5,4.1; between-group mean difference: 14.3; 95%CI: 3.0,25.6). Between 0 and 24 wks, an increase in social functioning (mean change in intervention: 12.1; 95%CI: 2.1,22.1; between-group mean difference: 13.8; 95%CI: 2.1,25.5) and a decrease in fatigue (mean change in intervention: -9.1; 95%CI: -17.1,-1.1; between-group mean difference: -4.1; 95% CI: -15.8,7.6) was observed in the intervention arm. No other measures of HRQOL or sleep quality differed within or between arms. Conclusions: A web-based dietary intervention with daily text messages may improve emotional and social functioning among CRC survivors. Further study to evaluate the effect of web-based interventions on HRQOL among CRC survivors in larger studies may be merited. Clinical trial information: NCT02965521.

552 Background: Over half of patients (pts) with oligometastatic CRC treated with definitive surgery or radiotherapy experience cancer recurrence. Early detection of ctDNA could identify high risk pts for additional intervention to eliminate micrometastatic disease. Here we report interim results of a prospective study aiming to determine ctDNA detection rates using a sensitive multigene assay and to correlate post-procedure ctDNA detection with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at a single site. ctDNA was collected pre-procedure, 3 weeks (wks) post-procedure, and at multiple follow-up timepoints. ctDNA detection utilizing a multi-gene sequencing panel (Guardant Health) included somatic variant and epigenetic assessments. A novel variant classifier was applied to differentiate tumor derived versus non-tumor derived alterations. A Simon’s two-stage design with planned interim analysis to assess 3wk post-procedure ctDNA detection rate was employed. Results: Of 25 pts enrolled, 21 (84%) had evaluable paired pre- and post-procedure samples. In these 21 pts, the 3 wks post-procedure sample was collected after surgery (N = 20) or radiation (N = 1) to address liver (N = 17), lung (N = 3), or ovarian (N = 1) metastases ± colon resection (N = 6). ctDNA was detected (+) in 15/21 (71%) pre- and 11/21 (52%) post-procedure samples. ctDNA was (+) in 8/12 (67%) pre- and 8/17 (47%) post-procedure samples with carcinoembryonic antigen < 5 ng/ml. Conclusions: In this interim analysis of pts with mCRC undergoing curative intent procedures, the post-procedure ctDNA detection rate was 52%. The similarity between the observed post-procedure ctDNA detection and expected recurrence rate suggests promise for recurrence prediction using this approach. Given post-procedure ctDNA was (+) in > 3 pts, the study will continue to enroll, and pts are being followed for future correlation of ctDNA with radiographic recurrence. [Table: see text]

3505 Background: Metastatic colorectal cancer (mCRC) patients (pts) with BRAFV600 mutations have poor outcomes with standard of care chemotherapy and rarely respond to the BRAF inhibitor vemurafenib. In preclinical models, blockade of BRAFV600 by vemurafenib (V) causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab (C) with anti-tumor activity augmented by irinotecan (I). Methods: Pts with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Eligible pts had ECOG PS ≤1, and had received 1 or 2 prior regimens with no prior anti-EGFR agents. Randomization was stratified for prior irinotecan. Crossover from the control arm (IC) to the experimental arm (VIC) was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 pts were enrolled (99 eligible, 49 in the experimental arm) from 12/2014 to 4/2016, with median age 62 years, 59% female, and 39% with prior irinotecan therapy. PFS was improved with the addition of vemurafenib (HR 0.42, 95% confidence interval [CI] 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI 3.6 – 5.7) mos vs 2.0 (95% CI 1.8 – 2.1) months. Response rate was 16% vs 4% (P = 0.08), with disease control rate of 67% vs 22%. In pts with no prior irinotecan, median PFS was 5.7 (95% CI 3.0-6.1) months in the VIC arm vs 1.9 (95% CI 1.7 – 2.1) months in the IC arm. Grade 3/4 adverse events higher in the VIC arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. 23 pts (46%) in the IC arm crossed over at the time of progression, with median PFS from crossover of 6.0 months (95% CI 3.7 – 7.4). Overall survival (OS) data will be mature for ASCO 2017. Conclusions: These results demonstrate the clinical benefits of the VIC triplet (vemurafenib, cetuximab, and irinotecan) in pts with treatment-refractory BRAFV600 mutated mCRC, and support VIC as a potential new treatment option in this molecular subset. Clinical trial information: NCT02164916.

520 Background: BRAF V600 mutations are associated with rare objective responses to the mutated BRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. In murine models of BRAFV600 mCRC, the combination of irinotecan, cetuximab, and vemurafenib leads to greater anti-tumor activity, as suggested by a prior Phase 1B study. Methods: Patients (pts) with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Patients had received 1 or 2 prior regimens, with no prior anti-EGFR agents, although prior irinotecan was allowed. Crossover from the control arm to the experimental arm was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 patients were enrolled (54 in the experimental arm) from 12/2014 to 4/2016, with ECOG PS ≤ 1. Median age of 62 years, 59% female, and prior irinotecan therapy in 39%. PFS was improved with the addition of vemurafenib (HR = 0.42, 95% confidence interval [CI] of 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI: 3.6 – 5.7) months vs 2.0 (95% CI: 1.8 – 2.1). Response rate was 16% vs 4% (P = 0.09), with disease control rate of 67% vs 22% (P < 0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. No new safety signal was observed. Approximately 50% of patients in the control aim crossed over at the time of progression. Overall survival and efficacy at cross-over data remain immature. Conclusions: The addition of vemurafenib to the combination of cetuximab and irinotecan resulted in a prolongation of progression-free survival and a higher disease control rate, indicating that simultaneous EGFR and BRAF inhibition is effective in BRAFV600 mutated CRC. Clinical trial information: NCT02164916.

452 Background: The p53 tumor suppressor gene is frequently mutated in colorectal cancer, but reports on the effect of p53 mutations on response to adjuvant chemotherapy and survival are inconclusive. This study investigates whether p53 mutational status (wild-type, zinc or non-zinc binding mutations) impacts survival following adjuvant therapy containing fluorouracil/leucovorin with or without irinotecan (5FU/LV or IFL) in women and men with stage III colon cancer. Methods: As part of a retrospective analysis of prospectively accrued data, p53 mutational status was determined for 609 patients with stage III colon cancer who were randomized on CALGB 89803, a phase III adjuvant chemotherapy trial. p53 exons 5-8 were analyzed by direct sequencing or sequencing by hybridization. p53 mutations were identified in 276 tumors (45%), of which 134 were in the zinc binding and 142 were in the non-zinc binding regions of the core domain. Cox regression was used to study the impact of p53 mutational status, sex, and adjuvant chemotherapy on disease-free (DFS) and overall survival (OS). Results: p53 mutational status did not predict differential survival or response to adjuvant therapy among the 609 patients assessed. However, a significant sex by treatment interaction was observed for both DFS (Pinteraction=0.008) and OS (Pinteraction=0.002). Significant differences in DFS by p53 mutational status were observed among women (logrank P = 0.009). No such differences were observed among men (logrank P = 0.33). Similar results were observed for OS. There was marginal evidence of a treatment-related impact on the interaction between sex and p53 mutational status for both DFS and OS (DFS Pinteraction = 0.07; OS Pinteraction = 0.11). There was a trend toward improved OS when women with zinc binding mutations received IFL versus 5FU/LV (P = 0.08) and toward worse DFS when women with non-zinc binding mutations were treated with IFL versus 5FU/LV (P =0.08). Conclusions: This exploratory subset analysis suggests that p53 mutational status may be used to predict prognosis in a sex- and potentially chemotherapeutic regimen-specific manner.