Continuation of afatinib (A) beyond progression: results of a randomized, open-label, phase III trial of A plus paclitaxel (P) versus investigator's choice chemotherapy (CT) in patients (pts) with metastatic non-small-cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and A: LUX-Lung 5 (LL5)
Background: Continuation of EGFR inhibition beyond progression has been associated with improved disease control in case reports and retrospective/non-randomized studies. LL5 is a randomized trial, which assessed the efficacy of continuation of the irreversible ErbB family blocker, A, beyond progression with the addition of P in NSCLC pts with prior benefit from reversible EGFR tyrosine kinase inhibitors (E/G) and A.
Methods: In this open-label, global phase III trial, pts with NSCLC who had failed ≥1 line of CT and E/G (after ≥12 wks treatment) were treated with A (50 mg/day) in Part A (n= 1154). Upon progression, those with ≥12 wks on A were eligible to be randomized 2:1 to A+P (40 mg/day; 80 mg/m2/week) or single agent investigator's choice CT in Part B. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.
Results: In part B 202 pts were randomized (A+P, n= 134; CT, n= 68). Baseline characteristics were well balanced (median age 60yrs, females 49%, ECOG PS 0 – 1 91% overall). A statistically significant improvement in PFS was observed on A + P vs CT arm (median 5.6 vs 2.8 months, hazard ratio (HR) 0.60 (95% CI 0.43, 0.85; p = 0.003). ORR was also significantly higher in A+P arm vs CT (32.1% vs 13.2%; p = 0.005). OS was similar in both arms 12.2 vs. 12.2 months, HR 1.00 (95% CI 0.70, 1.43; p = 0.994). Most common related adverse events (AEs) with A+P vs CT were diarrhea (53.8% vs 6.7%), alopecia (32.6% vs 15.0%) and asthenia (27.3% vs 28.3%).
Conclusions: Continued ErbB family blockade with A with the addition of P significantly improved PFS and ORR vs CT alone in heavily pretreated pts with acquired resistance to E/G and progression on A monotherapy. AEs were considered manageable. This is the first prospective clinical validation that tumors progressing on E/G and A continue to depend on ErbB family signalling and can benefit from continuous ErbB family blockade with A.