Randomized phase 3 study of intermittent or continuous Panitumumab plus FOLFIRI for first-line treatment of patients with unresectable left-sided RAS/BRAF wild-type metastatic colorectal cancer: the IMPROVE-2 trial

Background Despite significant advances in the diagnosis and treatment of metastatic colorectal cancer (mCRC), five-year survival rates remain poor. Patients with left-sided, wild-type RAS and BRAF mCRC have shown clear benefits from anti-EGFR-based regimens. Following an induction phase, maintenance treatment with the combination of 5-fluorouracil and folinic acid (5FU/FA) with anti-EGFR monoclonal antibodies (cetuximab and panitumumab) is currently recommended. However, persistent skin toxicity and the emergence of resistance to anti-EGFR therapies pose significant challenges to both treatment adherence and efficacy. Consequently, the optimal strategy for post-induction treatment remains unclear. Findings from the phase II IMPROVE trial suggest that adopting an intermittent treatment approach after a four-month induction period may prolong the effectiveness of anti-EGFR therapy by delaying tumor progression and reducing skin toxicity. Therefore, this strategy has the potential to enhance patients' quality of life without compromising overall survival. Methods and design: IMPROVE-2 is a multicenter, open-label, academic, randomized non-inferiority phase-3 study designed to enroll 500 treatment-naive patients with unresectable left-sided RAS/BRAF wild-type mCRC across 49 Italian centers. Upon enrollment, patients will be randomized in a 1:1 ratio to receive one of the two treatment strategies following induction therapy with eight cycles of panitumumab plus FOLFIRI. In the absence of disease progression, patients will either continue treatment until progression or follow an intermittent regimen with treatment-free intervals until progression during therapy. The primary endpoint is time to treatment failure (TTF). Secondary endpoints include objective response rate, disease control rate, depth of response, progression-free survival, overall survival, toxicity, and quality of life. Correlative studies will explore prognostic and predictive biomarkers through next-generation sequencing of liquid biopsies and serum metabolomic profiling. Discussion IMPROVE-2 study aims to optimize anti-EGFR therapy in combination with chemotherapy in untreated left-side RAS/BRAF wild-type unresectable mCRC patients, through an intermittent approach, easily implementable in healthcare systems. Correlative studies could add new insights into the dynamic evolution of tumors in response to therapy, paving the way for better refining anti-EGFR therapy. This study is ongoing, with enrollment started in June 2024. Trial registration: EudraCT number 2023-509551-14-00; ClinicalTrials.gov identifier NCT06509126, registration date 2024-07-10