PD-13 Plasma RAS dynamics and efficacy of anti-EGFR rechallenge in patients with RAS/BRAF wild-type metastatic colorectal cancer: REMARRY and PURSUIT trials

Assessment of plasma RAS (pRAS) mutations in circulating-tumor DNA at ‘just before’ rechallenge with anti-EGFR monoclonal antibody (EGFR mAb) may predict efficacy for the rechallenge therapy in patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). However, the clinical impact of pRAS status at progression on prior EGFR mAb for the rechallenge therapy is unknown. The REMARRY trial is a prospective longitudinal study to investigate the pRAS dynamics, and PURSUIT trial is a phase II trial to investigate the efficacy of EGFR mAb rechallenge in patients with pRAS wild-type just before rechallenge therapy. Eligibility criteria of REMARRY included RAS/BRAF V600E wild-type mCRC; ECOG PS 0-1; CR or PR during prior EGFR mAb; and progressed ≤ 2 months from the last administration of EGFR mAb. pRAS status by the BEAMing method (OncoBEAM RAS CRC Kit) was prospectively monitored at timepoints of progression on EGFR mAb and each subsequent therapy. Among participants of the REMARRY, patients who satisfied the following eligibility criteria were enrolled in PURSUIT; pRAS wild-type within 28 days prior to enrollment in PURSUIT; being refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; and ≥ 4 months of EGFR mAb-free interval. Study treatment was rechallenge with panitumumab 6 mg/kg + irinotecan 150 mg/m2q2wks. Primary endpoint of PURSUIT was a confirmed objective response rate (ORR) according to RECIST v1.1. Biomarker analysis was performed for blood samples after disease progression on prior EGFR mAb, immediately prior to PURSUIT, and after disease progression in PURSUIT using plasma next generation sequencing (Guardant360). Plasma RAS, BRAF V600E, and EGFR extracellular domain mutations were defined as acquired resistances for EGFR mAb. Between May 2019 and May 2021, 183 patients were enrolled in REMARRY from 27 institutions, and 50 patients were enrolled in PURSUIT; median age, 68 years; left-sided primary, 44 patients; and prior EGFR mAb, 1st/2nd/≥3rd lines in 28/6/16 patients. Confirmed ORR and disease control rate were 14% (90% CI, 7.8%–23.9%) and 80% (95% CI, 67.0%–88.8%), respectively. In addition, 4 patients showed an unconfirmed PR. Median progression-free survival (PFS) was 3.6 months (95% CI, 3.0–4.7 months). Among 31 patients with biomarker results after disease progression on prior EGFR mAb, ORR occurred in 5 of 21 patients (23.8%) with pRAS/BRAF/EGFR wild-type, whereas no responses occurred in patients whose tumors harbored any pRAS/BRAF/EGFR mutations (0/10) (p=0.092). Median PFS was 4.2 months and 2.8 months in patients without vs with pRAS/BRAF/EGFR mutations, respectively (p=0.06). In terms of pRAS/BRAF/EGFRstatus immediately prior to PURSUIT, 4 of 22 patients with wild-type responded to the study treatment (ORR, 18.2%), while one patient harboring pKRAS/EGFR co-mutations in 9 patients with any mutations also responded (ORR, 11.1%) (p=0.63). No trend in PFS was observed between the groups; median, 3.1 month and 3.3 months in patients with wild-type and those with any mutations (p=0.62). Plasma RAS/BRAF/EGFR mutational status after progression on prior EGFR mAb may identify patients with RAS/BRAF V600E wild-type mCRC who could benefit from rechallenge with EGFR mAb.