A single-arm, phase II study of autophagy modulation using hydroxychloroquine in addition to encorafenib and cetuximab or panitumumab in metastatic BRAF-mutated colorectal cancer refractory to standard therapy.

TPS262 Background: BRAF mutations drive 5-10% of colon cancers. BRAF + EGFR inhibition with encorafenib + cetuximab is standard second-line therapy, per the BEACON trial, but responses are short-lived. Autophagy induction is implicated as a mechanism for this acquired resistance to therapy. Preclinical models have shown that BRAF inhibition leads to increased ATF4 phosphorylation and an overreliance on oxidative phosphorylation, both markers of autophagy induction. Use of hydroxychloroquine (HCQ), an antimalarial agent with anti-autophagy activity, reduces such markers and improves the cellular metabolic profile. This was confirmed clinically in the BAMM trial, a phase I/II study in which patients with advanced BRAF-mutated melanoma received dabrafenib, trametinib and HCQ (Mehnert JM et al, Clin Cancer Res 2022). This study asks a similar question in advanced, BRAF-mutated colon cancer, of whether autophagy inhibition overcomes acquired resistance to BRAF inhibition. Methods: This is a Phase II, single-arm, open-label study to be conducted at Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL. The study was approved by the Northwestern University Institutional Review Board on 9/22/22 (IRB #: STU00217727); clinicaltrials.gov listing is pending. Key eligibility criteria: BRAF-mutated, stage IV colon cancer, with at least one line of therapy; ECOG PS 0/1, preserved organ function, and measurable disease at baseline. Key exclusion criteria: prior treatment with BRAF/MEK inhibitors; history of acute/chronic pancreatitis, psoriasis, or porphyria. Patients will receive standard of care encorafenib 300 mg daily and cetuximab IV weekly (panitumumab IV q 2 weeks can be used per investigator discretion). After a 14-day lead-in, HCQ 400 mg BID will be added. Each cycle is 28 days. CT scans will be done every 2 cycles, and blood will be taken every 2 weeks during the first 2 cycles for metabolomics analysis. The trial utilizes a Simon 2-stage admissible design. 14 patients will be enrolled in stage 1; if 4 or more responses are observed, the trial will continue to Stage 2 in which an additional 24 patients will be enrolled for a total sample size of 38 patients. The primary endpoint is objective response rate (ORR). Secondary endpoints are safety/efficacy, progression-free survival, overall survival and duration of response/stable disease. The exploratory endpoint is changes in markers of autophagy over time. The null hypothesis is an ORR of 20% (per the BEACON trial), and the alternative hypothesis is an ORR of 40%. This is the first trial exploring autophagy modulation in advanced, BRAF-mutated colon cancer. This study aims to show that autophagy inhibition with HCQ circumvents acquired resistance to BRAF + EGFR inhibition in advanced colon cancer.