Panitumumab retreatment followed by regorafenib versus the reverse sequence in chemorefractory metastatic colorectal cancer patients with <i>RAS</i> and <i>BRAF</i> wild-type circulating tumor DNA (ctDNA): Results of the phase II randomized PARERE trial by GONO.

Abstract

LBA3515 Background: Retreatment (re-tx) with anti-EGFR monoclonal antibodies offers a promising approach to extend the continuum of care of patients (pts) with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) with no mutations of resistance in their ctDNA at the time of treatment re-exposure. Methods: PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab (pani) and regorafenib (rego) in the chemorefractory setting of RAS and BRAF wt mCRC pts, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA. Eligible pts were randomized 1:1 to receive pani followed by rego after progression (arm A) versus the reverse sequence (arm B). Primary endpoint was overall survival (OS). 155 events were required to detect a hazard ratio (HR) of 0.69 in favor of arm B, using a two-sided unstratified log-rank test, with type I error of 0.15 and 80% power. Secondary endpoints included 1 st and 2 nd objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Results: From December 2020 to December 2024, 428 pts from 37 Italian centers underwent molecular screening, and 213 with RAS and BRAF wt ctDNA were randomized (arm A/B = 106/107). Median age was 61 and 64 years (A/B), most pts had left-sided primary tumors (92/88%, A/B), and had received a median of 2 prior lines of therapy in both tx arms. After a median follow-up of 23.5 months (mos), 194 and 135 1 st and 2 nd disease progression events were recorded, while OS data were not mature yet. Key efficacy outcomes are summarized in the table. Adverse events occurred with the expected frequency and grade in both treatment arms. Conclusions: PARERE is the largest randomized trial demonstrating an ORR and PFS advantage in favor of liquid biopsy-guided anti-EGFR re-tx, compared to regorafenib, in the late-line setting of RAS / BRAF wt mCRC. Clinical trial information: NCT04787341 . ARM A a pani, N = 106 ARM Brego, N = 107 p* p** 1 st PFS, median mos 4.1 2.4 HR: 1.23 (95% CI: 0.93 – 1.64) 0.15 0.12 1 st ORR, % 16.0 1.9 OR: 0.1 (95% CI: 0.01 – 0.44); p &lt; 0.01 1 st DCR, % 59.4 31.8 OR: 0.32 (95% CI: 0.18 – 0.56); p &lt; 0.01 ARM A a rego, N = 75 ARM B pani, N = 70 2 nd PFS, median mos 2.7 3.7 HR: 0.76 (95%CI: 0.54 – 1.07) 0.12 0.07 2 nd ORR, % 0 17.4 OR: NA (95% CI: 3.44 - NA); p &lt; 0.01 2 nd DCR, % 37.3 55.7 OR: 2.17 (95% CI: 1.11 – 4.27); p = 0.02 Per protocol population b 2 nd PFS, median mos 2.7 3.9 HR: 0.71 (95%CI: 0.5 – 1.01) 0.06 0.03 OR, Odds Ratio; CI, confidence interval; NA, not assessable; *Cox proportional hazards model; **stratified log-rank test according to ECOG PS; a reference; b pts actually treated with rego and pani (A/B, N = 68/69).