Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with ErbB alterations: Results of a phase II trial.

Abstract

459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.