Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma

Afatinib, an oral irreversible ErbB family blocker, has demonstrated efficacy in patients with epidermal growth factor receptor (. EGFR) mutation-positive advanced lung adenocarcinoma. Other potential biomarkers predicting response to afatinib, such as human epidermal growth factor receptor-2 (. HER2) mutations and EGFR gene amplification, have not been validated yet. This phase II study investigated whether afatinib conferred clinical benefit in cohorts of adenocarcinoma patients with: (1) EGFR mutation and failing on erlotinib/gefitinib; or (2) increased copy number of EGFR by fluorescence in situ hybridization (FISH); or (3) HER2 mutation. Materials and methods: Patients started daily afatinib 50mg monotherapy. Upon disease progression, patients could continue, at the investigator's discretion, afatinib (40mg) with the addition of paclitaxel (80mg/m² weekly for 3 weeks/4-week cycle). Endpoints included confirmed objective response (OR), progression-free survival (PFS), disease control, and safety. Results: Of 41 patients treated (cohort 1: n=. 32; cohort 2: n=. 2; cohort 3: n=. 7), 33 received afatinib monotherapy; eight subsequently received afatinib plus paclitaxel. With afatinib monotherapy, one patient achieved a confirmed OR (partial response [PR]; cohort 2). Two further patients achieved unconfirmed PRs (one each in cohort 1 and cohort 3). Disease control was achieved by 17/32 (53%), 2/2 (100%) and 5/7 (71%) patients in cohorts 1, 2 and 3, respectively. In patients receiving combination therapy (median PFS: 6.7 weeks), one (cohort 3) had confirmed PR of 41.9 weeks. The most common afatinib-related adverse events were diarrhea (95%) and rash/acne (80%). Conclusion: Afatinib demonstrated signs of clinical activity in heavily pretreated patients with activating HER2 or EGFR mutations or EGFR FISH-positive tumors.