524P - A phase II study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with metastatic colorectal cancer who failed two prior standard chemotherapies

Background

The objective of this open-label, single-arm, multi-center, phase II trial was to evaluate the efficacy and safety of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with PIK3CA mutant metastatic colorectal cancer (CRC) who failed two prior standard chemotherapies.

Methods

Patients were administered oral alpelisib 300mg once daily and capecitabine 1,250mg/m² twice daily, days 1–14 every 3 weeks as recommended phase II dose (RP2D) of ALCAP phase IB study. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS), disease control rate, and safety. Exploratory endpoints included serial biomarker analysis from circulating tumor DNA (ctDNA).

Results

Twenty-six patients were enrolled at 9 institutions between October 2021 and June 2023. The median PFS was 3.5 months (range 0.7-9.3 months), and the median OS was 3.9 months. Of 26 enrolled patients, 2 (7.7%) achieved partial response (PR), 13 (50.0%) achieved stable disease, and 15 (57.7%) achieved disease control. The patients who showed clinical benefit (i.e., PR, or SD for at least 15 weeks; n=10) had only PIK3CA mutation without KRAS mutation and without liver metastasis, compared to those who did not (n=16) [HR 0.50 (95% CI, 0.09-2.73), HR 0.78 (95% CI, 0.13–4.53), respectively, p=0.42, 0.78]. The most common adverse effect (AE) was grade 1-4 hyperglycemia (62%), the main cause of treatment discontinuation. Grade 3/4 toxicity was observed in 10 of 26 patients (38.5%) with hyperglycemia and 6 of 26 patients (23.1%) with oral mucositis. Serial ctDNA monitoring showed emerging oncogenic alterations in RAS, BRAF, HER2, and PIK3CA with treatment. ctDNA variant allele frequency (VAF) was associated with tumor disease burden for patients with CRC.

Conclusions

This is the first prospective study of alpelisib and capecitabine in patients with metastatic colorectal cancer. While PFS improvement was not attained, the study identified that patients without KRAS and PIK3CA co-mutations and liver metastasis showed longer PFS and PR rates. Detailed analysis of serial ctDNA will be performed, and further research is needed in patient groups with clinical benefits.

Clinical trial identification

NCT04753203.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.