Activity of Afatinib in Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations in Lux-Lung 3, A Phase III Trial of Afatinib or Cisplatin/Pemetrexed in EGFR Mutation-Positive Lung Cancer

ABSTRACT Background Afatinib (A) is an irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 with in vitro activity against activating and resistant EGFR mutations. LUX-Lung 3 demonstrated superiority of A vs cisplatin/pemetrexed (CP) in 345 treatment-naive pts with EGFR mutation-positive NSCLC; median progression-free survival (PFS) 11.1 vs 6.9 mo, HR 0.58, p = 0.0004 (ITT cohort) and 13.6 vs 6.9 mo, HR = 0.47, p  Methods All pts (n = 345) were stratified according to mutation (Del19, L858R, other) and randomized 2:1 to oral A 40 mg daily or IV CP (75 mg/m2 + 500 mg/m2 q21 days up to 6 cycles) until progression. Other mutations were categorized into 5 groups: T790M, G719X, S768I, exon 20 insertions, L861Q; the first 3 groups included double mutant pts. PFS, best overall response and tumour shrinkage by independent review were described per pt within these 5 groups. Results Uncommon mutations comprised 10.7% (n = 37, A: 26, CP: 11) of the trial population. Breakdown into the 5 groups was: de novo T790M (A:11, CP:2), exon 20 insertions (A:6, CP:3), G719X (A:3, CP:3), L861Q (A:3, CP:3), S768I (A:3, CP:0). Baseline imbalances between the A and CP arms were noted for smoking status (never smoker 65% vs 82%, respectively) and presence of brain (27% vs 0%) and liver metastases (27% vs 18%). Of 32 pts with target lesions, 19/23 on A and 8/9 on CP had measurable shrinkage. The small size of the uncommon mutation cohort, its molecular heterogeneity and numeric imbalances within genetic subgroups limited formal statistical analyses. Tumour response and prolonged PFS were noted in A-treated pts with L858R + T790M (1PR, 11.0 mo; 3SD, 9.6+ mo, 8.5 mo and 6.7 mo); L861Q (1SD, 8.3 mo); G719X (1PR, 10.8 mo); S768I + L858R (1PR, 13.8+ mo); S768I (1PR, 19.2+ mo). Conclusions RECIST responses and prolonged disease control were observed in pts with most types of uncommon EGFR mutations. The efficacy of A in uncommon EGFR mutations should be explored in larger cohorts in future studies. Disclosure J.C. Yang: James Chih-Hsin Yang has received honorarium for speech and advisory roles from Astrazeneca, Roche, Pfizer, OSI. He was the advisor for Boehringer Ingelheim and Eli Lilly without payment. M. Schuler: Paid consultancy/advisory relationship with: Boehringer Ingelheim; Research funding from: Boehringer Ingelheim; Travel support from: Lilly. K.J. O'Byrne: Paid consultancy/advisory relationship with: Boehringer Ingelheim, Lilly Oncology; Honoraria from Boehringer Ingelheim, Lilly Oncology; Research funding from Boehringer Ingelheim; Other remuneration from Boehringer Ingelheim, Lilly Oncology. V. Hirsh: Honoraria from the Boehringer Ingelheim Advisory Board. T.S.K. Mok: Paid consultancy/advisory relationship with and honoraria from: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiko, Boehringer Ingelheim; Research funding from: AstraZeneca. D. Massey: Employee of Boehringer Ingelheim. V. Zazulina: Employee of Boehringer Ingelheim. M. Shahidi: Employee of Boehringer Ingelheim. L.V. Sequist: Paid consultancy/advisory relationship with: Boehringer Ingelheim, Daiichi-Sankyo, Merrimack, Clovis and Celgene; Research funding from: Boehringer Ingelheim. All other authors have declared no conflicts of interest.