Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study

Abstract

BackgroundFew data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available.MethodsThis multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR).ResultsAt the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts.ConclusionAmong the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

Multicenter, single‐arm, phase II study of the continuous use of panitumumab in combination with FOLFIRI after FOLFOX for RAS wild‐type metastatic colorectal cancer: Exploratory sequential examination of acquired mutations in circulating cell‐free DNA

“…Another relevant study is a retrospective report that evaluates the role of the maintenance treatment after cetuximab plus cytotoxic doublet treatment for left-sided RAS/BRAF wild-type mCRC. 25 The data from 686 consecutive patients suggested that the patients treated with 5FU/LV plus anti-EGFR showed better PFS and OS than those for whom the initial treatment was continued. These results should be interpreted in terms of the possibility that clinicians tend to choose not to de-escalate antitumor treatment in patients with higher tumor burden (more advanced status).…”

“…Another relevant study is a retrospective report that evaluates the role of the maintenance treatment after cetuximab plus cytotoxic doublet treatment for left‐sided RAS/BRAF wild‐type mCRC 25 . The data from 686 consecutive patients suggested that the patients treated with 5FU/LV plus anti‐EGFR showed better PFS and OS than those for whom the initial treatment was continued.…”

The Role of Anti-EGFR Monoclonal Antibody in mCRC Maintenance Therapy

“…In addition, in a multicenter retrospective study of maintenance therapy after the first-line anti-EGFR mAb combined with two drug schemes in 355 left-sided RAS/BRAF wild-type mCRC patients, the mPFS in the 5FU/LV + anti-EGFR mAb, anti-EGFR mAb monotherapy, 5FU/LV, and nonmaintenance cohorts was 16.0 months (95% CI = 14.3–17.7, 86 events), 13.0 months (95% CI = 11.4–14.5, 56 events), 14.0 months (95% CI 8.1–20.0, 8 events), and 10.1 months (95% CI = 9.0–11.2, 136 events) ( p < 0.001), respectively ( Parisi et al, 2021 ). This study provides a realistic clinical strategy for clinicians regarding maintenance therapy after receiving two-drug first-line induction therapy based on anti-EGFR, but the retrospective nature of the study, inherent selection bias, untargeted data collection, and small sample size of the cohort are some limitations that may have influenced the results of this study.…”