Open-label phase Ib/II study of cetuximab (CET) plus LY3214996 with or without abemaciclib in patients (pts) with anti-EGFR-refractory metastatic colorectal cancer (mCRC).

3534 Background: Acquired resistance limits the efficacy of anti-EGFR (EGFRi) therapy in RAS wild-type (WT) mCRC, often through MAPK reactivation driven by secondary RAS mutations or other genomic alterations. Preclinical studies on EGFRi-refractory models led by our group showed that LY3214996, a potent ERK1/2 inhibitor, combined with CET suppresses MAPK signaling and reduces tumor growth, while the addition of Abemaciclib further enhances anti-tumor activity by synergistically inhibiting cell cycle and survival pathways. Methods: In this open-label, phase Ib/II study, RAS/BRAF/EGFR/MEK1 WT mCRC pts who progressed on prior EGFRi-based therapy and ≥1 chemotherapy were treated with CET + LY3214996 (Arm A) or CET + LY3214996 + Abemaciclib (Arm B). Phase Ib employed a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase II followed a two-stage design with cohort expansion to assess ORR by RECIST v1.1 as the primary endpoint. Secondary endpoints included PFS and OS. Results: Of 44 pts treated on trial, 2 did not meet inclusion criteria; 39 were evaluable for activity, and 34 for efficacy. The RP2D was 200 mg LY3214996 p.o. daily + 500 mg/m² CET i.v. biweekly in Arm A with the addition of 150 mg Abemaciclib p.o. twice daily in Arm B. Median age was 53.0 years (IQR 47.0 – 63.8), and 59.1% (26/44) were male. Most pts (95.5%, 42/44) had a left-sided or rectal primary, and all were pMMR/MSS. Prior EGFRi-based rechallenge, retreatment/reintroduction, or both were noted in 9.1% (4/44), 25.0% (11/44), and 4.5% (2/44), respectively. ORR, DCR, median PFS and OS were 5.3% (1/19), 36.8% (7/19), 1.8 months (95% CI 1.5 – 4.8) and 7.0 months (95% CI 5.0 – 22.0) for the doublet and 15.0% (3/20), 65.0% (13/20), 3.6 months (95% CI 2.5 – 4.5), and 14.0 months (95% CI 5.9 – 21.0) for the triplet, respectively. Longer time elapsed from last EGFRi was associated with higher predicted probability of response after adjustment for trial regimen (OR 1.35, 95% CI 1.06 – 1.94, p = 0.038). Baseline ctDNA profiling drawn prior to rechallenge revealed acquired RAS mutations in two responders, one per arm. Grade 3 TRAEs occurred in 31.8% (14/44), with acneiform rash (9.1%, 4/44), diarrhea (9.1%, 4/44), thrombocytopenia (6.8%, 3/44), fatigue (4.5%, 2/44), and anemia (4.5%, 2/44) being the most frequent while one Grade 4 TRAE (thrombocytopenia, 2.3%) was reported. Conclusions: CET + LY3214996 ± Abemaciclib had a manageable safety profile with no unexpected adverse events. Although activity was modest, this study is the first to report objective responses to an EGFRi-based regimen in pts harboring acquired RAS mutations in pre-rechallenge ctDNA. Translational efforts are ongoing. Clinical trial information: NCT04616183 .