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Background: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development.

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12 Background: Encorafenib (E) and cetuximab (C) offers short-lived response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p= percentage of pts with radiographic response) was employed using a one-sided α=.05 and β=.20. In the first stage, ≥ 4/15 responses were needed in order for the trial to enroll 11 additional pts. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: All 26 pts have been enrolled - 23 patients treated, and 21 evaluable for response so far. Median age is 59 years (range, 32-85), and 14 (54%) are female. No dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events (AE) occurred in 4/22 (18%) patients. Grade 3 AEs included colitis, maculopapular rash, leukocytosis, and elevated amylase/lipase (all N=1). Grade 4 AEs in a single patient were myositis/myocarditis. Overall response rate is 45% (95% CI, 23-68), and disease control rate is 95% (95% CI, 75-100). Median PFS is 7.3 months (95% CI, 5.5-NA). Median OS is 11.4 months (95% CI, 7.6-NA). For the 9 pts thus far with responses, median duration of response is 8.1 months (95% CI, 7.3-NA). Updated results will be presented. Conclusions: E + C + N is effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. The E+C+N regimen met its predefined efficacy endpoint and suggests a role for immunotherapy as a novel combination approach for this specific subpopulation of MSS metastatic CRC. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in early 2022. Clinical trial information: NCT04017650.

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.