Background: Improved disease control with continuation of EGFR inhibition beyond progression has been suggested in retrospective/non-randomized studies, however, this has yet to be prospectively evaluated in a randomized trial. LL5 is a randomized trial, which assessed the efficacy of continuation of the irreversible ErbB family blocker, afatinib (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: 202 pts were randomized (A+P, n=134; CT, n=68) and baseline characteristics were well balanced (median age 60 yrs, 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: ContinuedErbB 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. Our data support that tumors progressing on E/G and A continue to depend on signalling through the receptors of the ErbB family and can benefit from continuous ErbB family blockade with A. Clinical trial information: NCT01085136.