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Ref Type Journal Article
PMID (27044931)
Authors Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL, Karrison T, Stadler WM, Nakamura Y, O'Donnell PH
Title Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34 18 2016 Jun 20 2165-71 J Clin Oncol
URL
Abstract Text Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response.In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted.The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations (P < .001).Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB3 R103G missense unknown ERBB3 (HER3) R103G lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). R103G has been identified in the scientific literature (PMID: 27044931), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Apr 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 G284R urinary bladder cancer sensitive Afatinib Case Reports/Case Series Actionable In a Phase II clinical trial, a patient with ERBB3 G284R mutant urothelial carcinoma had improved progression free survival when treated with Gilotrif (afatinib), and median PFS was 6.6 months for patients with ERBB2 or ERBB3 alterations relative to 1.4 months for patients lacking alterations (PMID: 27044931). 27044931
ERBB3 V104M urinary bladder cancer predicted - sensitive Afatinib Case Reports/Case Series Actionable In a Phase II clinical trial, a patient with ERBB3 V104M mutant urothelial carcinoma had improved progression free survival when treated with Gilotrif (afatinib), and median PFS was 6.6 months for patients with ERBB2 or ERBB3 alterations relative to 1.4 months for patients lacking alterations (PMID: 27044931). 27044931