# Phase Ia/Ib Study of Afatinib with Capecitabine in Patients with Refractory Solid Tumors and Pancreaticobiliary Cancers

## TL;DR

A clinical trial found that combining afatinib and capecitabine is safe but not effective for treating advanced pancreatic and biliary cancers.

## Contribution

The study identifies KRAS wild-type status as a potential biomarker for better outcomes with anti-EGFR therapies in these cancers.

## Key findings

- Afatinib plus capecitabine showed tolerable safety but no significant clinical benefit in refractory pancreatic and biliary cancers.
- KRAS wild-type cancers had better disease control and longer survival compared to KRAS-mutated cancers.
- Future research should focus on novel anti-EGFR therapies in KRAS wild-type cancers with comprehensive molecular profiling.

## Abstract

The epidermal growth factor receptor (EGFR) is overactive in many solid tumors. Afatinib, an EGFR/HER2/HER3 inhibitor, synergizes with capecitabine in preclinical models. This phase Ia/Ib trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma, biliary cancers, and other solid tumors. Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory pancreatico-biliary cancers. Numerically better disease control rates (50% vs. 20%) and median survival (5.8 months vs. 3.9 months) were observed for KRAS wild-type (WT) vs. KRAS-mutated (MUT) pancreatic cancers. Similarly, better disease control (40% vs. 20%) and median survival (5 months vs. 3.1 months) were observed for KRASWT vs. KRASMUT biliary cancers. Future studies should test novel anti-EGFR therapies in KRASWT cancers, further selected with a complete molecular profile.

Background: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. Patients and Methods: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m2 twice daily on days 1–14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). Results: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRASWT PDA, and 5.0 months (95% CI 1.6, 6.1) for KRASWT BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRASMUT PDA and 3.1 months (95% CI 1.0, 22.8) for KRASMUT BTC, respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRASWT cancers further selected with a comprehensive molecular profile.