Background: Cetuximab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is given alone or in combination with chemotherapy in the 60% of mCRC that are KRAS WT. Unfortunately, resistance inevitably develops, which may be related to downstream upregulation of the extracellular-signal-regulated kinase (ERK) pathway. Rechallenge with anti-EGFR mAb may be effective in patients previously benefiting from anti-EGFR therapy, but median progression-free survival is < 4 months, indicating need for novel more effective combinations for rechallenge. Co-inhibition of EGFR and downstream cyclin-dependent kinases 4/6 (CDK4/6) may overcome ERK pathway reactivation. We hypothesized that the addition of the CDK4/6 inhibitor palbociclib to cetuximab would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. Methods: LCCC1717 was a multicenter, single-arm, Simon’s two stage phase II study of cetuximab and palbociclib in KRAS WT mCRC treated with ≥2 prior regimens (NCT03446157). Eligible pts were enrolled to one of two cohorts depending on previous anti-EGFR mAb therapy; we report here on cohort B, which enrolled pts who had disease control for at least 4 months with anti-EGFR therapy. Cohort B was designed to initially enroll 10 evaluable pts; if ≥ 4 pts had disease control at least 4 months, then 11 more pts would be enrolled. Treatment included cetuximab 400 mg/m² followed by 250 mg/m² weekly, plus palbociclib 125 mg daily on days 1-21 of a 28-day cycle until progression, toxicity, or withdrawal. Primary endpoint was disease control rate (DCR) at 4 months by RECIST 1.1. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: In cohort B, 10 evaluable pts were enrolled from 2/2018-8/2020 (1 additional pt withdrew after an infusion reaction with first dose of cetuximab). Median age 59, 70% male, 90% left-sided primary. The 4-mo DCR was 2/10 (20%; 95% CI 5-52%). Given this, enrollment in this cohort was halted after first stage. Median PFS was 1.8 mo (95% CI: 1.7, NE) and median OS was 6.6 mo (95% CI: 3.6, NE). No pts had a complete or partial response; 3 pts (30%) had stable disease (SD), including 1 patient with SD for 24.7 months. The regimen was well tolerated; most common treatment-related grade 3-4 adverse events were lymphopenia (27%) and leukopenia (18%). While 55% of pts had acneiform rash, none were grade 3-4. Conclusions: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify pts likely to respond to palbociclib + cetuximab rechallenge. This emphasizes the need for screening using circulating tumor (ct) DNA of known resistance mutations to select pts for anti-EGFR rechallenge approaches. Translational work assessing ctDNA in this study is planned. Cohort A with anti-EGFR naïve patients continues enrollment. Clinical trial information: NCT03446157.