Background: The irreversible ErbB family blocker, afatinib, has demonstrated acceptable tolerability and promising efficacy when combined with cytotoxic agents. Methods: In an open-label, 3+3 dose escalation study, we evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of afatinib in combination with carboplatin (regimen A) or carboplatin + paclitaxel (regimen B). The starting dose was afatinib 20 mg/day + carboplatin AUC6 (Day 1 of a 3-weekly cycle) in both regimens. Paclitaxel 175 mg/m² was given on Day 1 of each cycle in regimen B. Carboplatin was reduced to AUC5 in case of toxicity. Afatinib was to be escalated from 20 to 40 mg then 50 mg; if ≥2/6 pts experienced dose-limiting toxicity (DLT) at 40 mg, an intermediate dose of 30 mg was assessed. Results: 12 pts were treated in regimen A (8 male; median age 58 years) and 26 in regimen B (13 male; median age 61 years). The table shows dose cohorts and DLTs in both regimens. Although MTD was not reached for regimen A, it was decided not to escalate the dose further. Overall, the most frequent (any grade) drug-related adverse events (AEs) were rash/acne (75%), fatigue (67%) and diarrhea (58%) in regimen A and diarrhea (88%), rash/acne (73%) and fatigue (69%) in regimen B. Afatinib did not appear to alter carboplatin or paclitaxel PK. Partial response was reported in 3 pts (25%) in regimen A and 5 (19%) in regimen B. Conclusions: MTD was not reached for regimen A but the recommended phase 2 dose (RP2D) was afatinib 40 mg + carboplatin AUC6. MTD/RP2D for regimen B was afatinib 20 mg + carboplatin AUC5 + paclitaxel 175 mg/m². At RP2D, AEs were manageable with antitumor activity observed. Clinical trial information: NCT00809133

* No DLT in first 3 pts; cohort expanded to 6 pts after 40 and 30 mg dose exceeded MTD.