Phase III CR-SEQUENCE trial of FOLFOX+panitumumab followed by FOLFIRI+bevacizumab (SEQ1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (SEQ2) in previously untreated RAS wild-type, left-sided, unresectable metastatic colorectal cancer

3512 Background: The optimal sequencing of systemic therapy for patients with RAS wild-type, left-sided metastatic colorectal cancer (mCRC) remains under debate. This study evaluates whether starting with SEQ1 improves the 36-months progression-free survival rate (PFSR) versus SEQ2. Methods: Adult patients were randomized (1:1) to SEQ1 or SEQ2 and treated until second-line progression or unacceptable toxicity. Key inclusion criteria were untreated left-sided and wild type RAS (per local test) primary mCRC, ECOG-PS<2, measurable disease (RECIST 1.1), and adequate organ function. Primary endpoint was 36-month PFSR in ITT. Secondary endpoints included overall survival (OS), total PFS, objective response rate (ORR), PFS1, PFS2, and safety. Results: A total of 418 patients were analyzed (SEQ1=210; SEQ2=208); 54.76% and 70.19% of randomized patients received 2L treatment in SEQ1 and SEQ2 arms, respectively. The median follow-up was 62.2 months (95%CI 55.2 – 65.5). SEQ1 yielded a higher 1st-line ORR (80.95% vs 64.25%, p <0.01) and significantly improved median PFS1 (14.09 vs 12.39 months, p=0.03). In second line, SEQ2 (FOLFIRI + panitumumab) resulted in a higher ORR (40.43% vs 27.27%, p=0.03). There was no significant difference in 36-months PFS rate (28.57% vs. 22.36%; p=0.224). Median total PFS and OS were 22.93 vs 21.39 months (p=0.2241) and 36.57 vs 31.74 months (p=0.2949), respectively. Longer follow-up for PFS and OS is ongoing. Curative intent procedures were performed in 22.86% (SEQ1) and 19.23% (SEQ2) of patients, respectively. Rescue surgery improved PFS and OS across both sequences. Common related G3-4 adverse events included neutropenia (42%), rash (15.7%), diarrhea (13%), peripheral neuropathy (12%), and fatigue (12.3%). Conclusions: SEQ1 did not improve the 36-month PFSR versus SEQ2. However, starting with SEQ1 yielded superior early efficacy (higher ORR and longer PFS1), which may be clinically relevant in a subset of patients. Molecular profiling and genomic correlation analyses are ongoing to identify biologically defined clusters that may improve selection of sequential treatment strategies. Longer follow-up for clinically relevant secondary endpoints (total PFS and OS) is ongoing. Clinical trial information: 2024-510967-41-00. Baseline characteristic by treatment arm. Characteristic SEQ 1 (n=210) SEQ 2 (n=208) Age, median (IQR*), years 63 (57-71) 63 (57-71) Sex, n (%) FemaleMale 53 (25.2)157(74.8) 58(27.9)150 (72.1) ECOG-PS, n (%) 01 112 (53.3)98 (46.7) 118 (56.7)90 (43.3) Metastasis per organ, median (range) 2 (1-6) 2(1-7) Baseline CEA, median (IQR), ng/mL 40.7 (11.6 – 364.3) 74.5 (11.8 – 643.9) Prior therapies Adjuvant chemoRadiationPrimary tumor resection 27 (12.9)23 (10.9)56 (26.7) 24 (11.5)18 (8.6)72 (34.6) *IQR: interquartile range.