A phase II study of alpelisib and capecitabine in patients with previously treated metastatic colorectal cancer (KCSG-CO21-04).

This open-label, single-arm, multi-center phase II study investigated the clinical activity and safety of alpelisib in combination with capecitabine in patients with PIK3CA-mutant metastatic colorectal cancer who had progressed after standard chemotherapy. Patients received oral alpelisib and capecitabine in 21-day cycles, and clinical outcomes and circulating tumor DNA were longitudinally assessed. A total of 26 patients were enrolled across nine institutions. Median progression-free and overall survival were 3.5 and 8.8 months, respectively, with partial responses observed in two patients and disease control achieved in more than half of the cohort. Clinical benefit was more frequently observed in patients without KRAS mutations or liver metastases. Hyperglycemia was the most common adverse event and frequently required treatment interruption or discontinuation. Serial circulating tumor DNA analysis revealed dynamic alterations in oncogenic pathways, including RAS, BRAF, HER2, and PIK3CA, which correlated with changes in tumor burden. Overall, alpelisib combined with capecitabine demonstrated modest antitumor activity in a molecularly selected subset of patients with metastatic colorectal cancer. However, frequent treatment-limiting toxicities may limit the future clinical applicability of this regimen and highlight the need for improved toxicity management and optimized patient selection.