Regorafenib or trifluridine-tipiracil is used after failure of 2 lines of therapy, 1, 2 with modest benefit in overall survival and progression-free survival (PFS). ![]() ![]() 7 In fact, the genetic landscape of cancer cell clones is continuously evolving for the selective pressure of different therapies. 6 After anti-EGFR treatment is stopped, RAS mutant clones decay with a half-life of approximately 4 months, whereas RAS WT clones increase. A subsequent treatment, such as chemotherapy plus antiangiogenic drugs, could cause the disappearance of RAS mutant clones and potentially restore sensitivity to anti-EGFR drugs. 3, 4 Whereas the majority of RAS WT cancer cells are killed by chemotherapy plus cetuximab or panitumumab, a genetic selection of RAS mutant cancer cells occurs with tumor progression. 1, 2 Despite initial efficacy, acquired resistance mechanisms, including KRAS or NRAS alterations, 3 - 5 are associated with treatment failure in all patients. Trial Registration Identifier: NCT05468892Īnti–epidermal growth factor receptor (EGFR) monoclonal antibodies plus cytotoxic drugs are the treatment cornerstone for RAS wild-type (WT) metastatic colorectal cancer (MCRC). The findings support the clinical utility of liquid biopsy–guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC. Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.Ĭonclusions and Relevance In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio, 0.48 95% CI, 0.28-0.82 P = .007). Results Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 male median age, 65 years ) and 31 received trifluridine-tipiracil alone (17 male median age, 66 years ). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients. Main Outcomes and Measures The primary end point was progression-free survival (PFS). Interventions Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug–free interval of 4 or more months during second-line therapy were included. Objective To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.ĭesign, Setting, and Participants This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients. Importance Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. ![]() Shared Decision Making and Communication.Scientific Discovery and the Future of Medicine.Health Care Economics, Insurance, Payment.Clinical Implications of Basic Neuroscience.Challenges in Clinical Electrocardiography.
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