Continued Afatinib (A) With the Addition of Cetuximab (C) After Progression on Afatinib in Patients With Acquired Resistance (AR) to Gefitinib (G) or Erlotinib (E): Metastatic Non-Small Cell Lung Cancer

Abstract

In a phase 1b trial we demonstrated that combination of A+C induces robust responses (objective response rate (ORR), 29%; progression-free survival (PFS), 4.7 months) in pts with EGFR mutation-positive non-small cell lung cancer (NSCLC) who develop resistance to E/G, regardless of secondary T790M mutation status. A separate cohort in this trial additionally explored sequential use of A then A+C in such pts; we report safety and efficacy in this cohort. Pts with EGFR mutation-positive NSCLC who progressed on E/G received A 40 mg daily oral until progression, followed by A 40 mg daily oral + C 500 mg/m2 IV every 2 weeks. Endpoints included efficacy, safety, and pharmacokinetics (PK) of A+C. Thirty-seven pts received A; baseline characteristics were: median age, 58 years; female, 62%; white, 84%; T790M +/-, 54%/46%. Upon progression 31 transitioned to A+C; 4 additional pts from other A trials meeting enrollment criteria received A+C. ORR, median duration of response (DR), disease control rate (DCR) and median PFS on A alone were 5.4% (2/37 pts), 3.9 months, 56.8% (21/37), and 2.7 months, respectively. Upon progression on A, 3/35 (8.6%) of pts achieved OR (median DR, 3.7 months) and 17/35 (48.6%) of pts achieved DC on subsequent A+C, with a median PFS of 2.7 months. The 3 pts responding to A+C were different from the 2 pts responding to A. Exploratory analyses showed that pts who received A for ≥12 weeks (18/35) tended to have higher ORR (11.1 vs 5.9%), DCR (55.6 vs 41.2%) and PFS (4.8 vs 1.8 months) with A+C than those who received A for <12 weeks (17/35). Median overall exposure to A (A + A+C) for the 31 pts who transitioned from A to A+C was 5.3 months. Most frequent drug-related adverse events (DRAEs) of any grade (G) with A/A+C were diarrhea (70.3%/31.4%), rash (48.6%/71.4%), fatigue (37.8%/22.9%), stomatitis (32.4%/34.3%), nail effect (24.3%/51.4%) and dry skin (13.5%/37.1%). G3 DRAEs with A/A+C occurred in 35.1%/45.7% of pts, the most frequently occurring of which were diarrhea (5.4%/0%), rash (2.7%/20.0%), fatigue (8.1%/0%), headache (5.4%/5.7%), acne/dermatitis acneiform (0%/5.7%) and hypophosphatemia (0%/ 5.7%). Two pts on A+C (5.7%) had G4 DRAEs (hypomagnesaemia, 1 pt; rash, 1 pt). There were no G5 DRAEs. PK parameters, which did not identify a clinically relevant effect of A on exposure to C, or vice versa, will be presented. Sequential EGFR blockade with A then A+C had an acceptable safety profile and was effective, achieving responses and DC in pts with EGFR mutation-positive NSCLC with acquired resistance to E/G. Despite a low ORR, sequential use of A+C was associated with a median PFS of 2.7 months after progression on A, and may offer an alternate, more tolerable approach for treating such pts.