Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.

Abstract

312 Background: Platinum-refractory 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 targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.