Pneumologie 2015; 69 - V54
DOI: 10.1055/s-0035-1544761

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)

M Schuler 1, D Planchard 2, JC Yang 3, F De Marinis 4, J Bennouna 5, JH Kim 6, C Chouaid 7, R Wiewrodt 8, F Grossi 9, J Feng 10, J Strausz 11, S Lu 12, DW Kim 13, X Liu 14, YM Chen 15, C Zhou 16, B Wang 17, VK Chand 17, K Park 18
  • 1Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum, Universitätsklinikum Essen
  • 2Gustave Roussy, Villejuif
  • 3National Taiwan University, Taipei
  • 41st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome; European Institute of Oncology, Milan
  • 5Institut de Cancérologie de l'Ouest, Nantes
  • 6Yonsei University College of Medicine, Seoul
  • 7CHI Creteil
  • 8Schwerpunkt Pneumologie, Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster
  • 9National Institute for Cancer Research, Genoa
  • 10Jiangsu Province Cancer Hospital, Nanjing
  • 11Koranyi National Institute for Pulmonology, Budapest
  • 12Shanghai Chest Hospital, Shanghai Jiao Tong University
  • 13Seoul National University Hospital
  • 14Affiliated Hospital of Academy of Military Medical Science, Beijing
  • 15National Yang-Ming University School of Medicine, Taipei
  • 16Tongji University Medical School Cancer Institute, Shanghai
  • 17Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield
  • 18Samsung Medical Center Seoul

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.