Aberrant expression of ErbB receptors and multiple defects in their signaling pathways are implicated in the pathobiology of SCC of the lung, providing rationale for ErbB inhibitors in this setting of major unmet medical need. Primary analysis of LUX-Lung 8 (LL8; 2nd-line afatinib [A], an irreversible ErbB family blocker vs erlotinib [E], a reversible EGFR tyrosine kinase inhibitor in pts with SCC of the lung) showed significantly better progression-free survival (PFS) with A. Here we report overall survival (OS), updated PFS and exploratory molecular analysis of tumor samples.
Pts with stage IIIB/IV disease were randomized 1:1 to A (40 mg/day) or E (150 mg/day) until progression. Primary endpoint: PFS; key secondary endpoint: OS; other endpoints: objective response (ORR), disease control (DCR), safety. Archived tumor samples from selected pts – with PFS >2 mos (presumed treatment benefit; n = 144) and a control group with PFS ≤2 mos (treatment refractory; n = 94) – were retrospectively analyzed using the FoundationOneâ¢ next-generation sequencing (NGS) platform.
OS was significantly better with A (n = 398) vs E (n = 397); median 7.9 vs 6.8 mos, HR 0.81 [95% CI, 0.69–0.95], p = 0.008. PFS (median 2.6 vs 1.9 mos, HR 0.81 [95% CI, 0.69–0.96], p = 0.010); ORR (5.5 vs 2.8%; p = 0.055) and DCR (50.5 vs 39.5%; p = 0.002) were better for A vs E. Prespecified subgroup analyses for PFS and OS favored A. Grade ≥3 adverse events were similar with A and E (57.1 vs 57.5%). Preliminary NGS results (A: 130; E: 108 samples) focused on genomic alterations of EGFR. Only 14 EGFR short variants (A: 8; E: 6; 10 novel with unknown clinical significance) were detected. EGFR gene amplification frequency was also low (A: 9; E: 6). No correlation of EGFR aberrations with PFS/OS was observed. NGS analyses are ongoing.
OS was significantly improved with A vs E in pts with SCC of the lung in a 2nd-line setting. PFS and DCR were also significantly better. The improvements were not driven by the presence of EGFR short variants or amplifications and may relate to afatinib's ability to inactivate multiple ErbB signaling cascades. Based on LL8, A should be preferred over E in these pts.
Clinical trial identification
EudraCT No.: 2011-002380-24
K. Park: employment by Samsung Medical Center, and uncompensated advisory board participation for Boehringer Ingelheim. E. Felip: advisory board participation for Eli Lilly, Pfizer, Roche, Boehringer Ingelheim and MSD; and honoraria for lectures from AstraZeneca, Bristol-Myers Squibb and Novartis. G.D. Goss: advisory board participation for AstraZeneca, Boehringer Ingelheim and Bristol-Myers Squibb. J.-C. Soria: advisory board participation for Bayer, Bristol-Meyers Squibb, Sanofi, Roche and BiB. N. KrÃ¤mer: consultant to Boehringer Ingelheim Pharma GmBH & Co. KG, Biberach, Germany and receives compensation for these services. V.K. Chand, F. Solca: employment by Boehringer Ingelheim. All other authors have declared no conflicts of interest.