Phase I/Ib study of afatinib with capecitabine in patients with refractory solid tumors and pancreaticobiliary cancers.

594 Background: The epidermal growth factor receptor (EGFR) and ErbB2/HER2 signaling is overactive in many solid tumors. Afatinib, an irreversible inhibitor of ErbB signaling, downregulates thymidine synthase and synergizes with capecitabine in preclinical models. This phase I trial evaluated the safety, maximum tolerated dose (MTD) and preliminary efficacy of afatinib plus capecitabine in patients (pts) with refractory solid tumors and pancreatic ductal adenocarcinoma (PDA) and biliary tract cancers (BTC). Methods: The phase I study had a 3+3 design with capecitabine 1000 mg/m 2 twice daily (BID) on days 1-14 and afatinib 20 mg, 30 mg or 40 mg daily (QD) in 21-day cycles. In phase Ib, 15 pts each with PDA and BTC were treated at MTD. Results: 41 pts enrolled from November 2016 to October 2021, who received a median of 2 (range 1-5) prior therapies. No dose-limiting toxicities were observed. The MTD was 40 mg afatinib QD plus 1000 mg/m 2 capecitabine BID. Grade 3 treatment related adverse events were diarrhea (12.2%) and nausea (4.9%). Among 36 response evaluable pts, best response was 1 partial response (PR, 3%) in a pt with KRAS wild type (WT)/EGFR amplified BTC, and 8 stable diseases (SD, 22%), with disease control rate (DCR) of 25%. PDA pts (n=20) had DCR of 24%, median progression-free (PFS) and overall survival (OS) of 1.9 months (95% CI 1.05, 2.03) and 3.2 months (95% CI 2.01, 5.82) respectively. BTC pts (n=18) had DCR of 31%, median PFS and OS of 1.9 months (95% CI 1.55, 3.39) and 4.6 months (95% CI 1.88, 6.09), respectively. Eight pts with cancers with EGFR/HER2/HER3 pathway alterations, most KRAS WT (n=6), had DCR of 29%, and median PFS and OS of 2.1 months (95% CI 1.05, 4.14) and 3.5 months (95% CI 1.64, 6.09), respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have significant efficacy in pts with refractory PDA/BTC, including in KRAS WT cancers with EGFR/HER2/HER3 alterations. Clinical trial information: NCT02451553 .