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Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225). Random assignment was stratified by race (Japanese, Chinese, other East Asian, or non-Asian) and EGFR mutation type. The final OS analysis was conducted with a data cutoff date of February 17, 2017; at that time 220 deaths (48.7%) were observed. Results During a median follow-up time of 31.3 months, 103 (45.4%) and 117 (52.0%) deaths occurred in the dacomitinib and gefitinib arms, respectively. The estimated hazard ratio for OS was 0.760 (95% CI, 0.582 to 0.993; two-sided P = .044). The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib. The OS probabilities at 30 months were 56.2% and 46.3% with dacomitinib and gefitinib, respectively. Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis. Conclusion In patients with advanced NSCLC and EGFR activating mutations, dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) to show significant improvement in OS in a phase III randomized study compared with a standard-of-care TKI. Dacomitinib should be considered one of the standard treatment options for these patients.

Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Introduction:The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations.Methods:We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients.Results:The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42–86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41–639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors.Conclusions:The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets.

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Combination chemotherapy with irinotecan and cisplatin was active in patients with LCNEC, but the RR and the overall survival period among the patients with LCNEC seemed to be inferior to those among the patients with SCLC. Small numbers of patients were a major limitation in this study.

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P ¼ 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.