All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.

PURPOSE: Lazertinib is a potent, CNS-penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This global, phase III study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were 18 years and older with no previous systemic anticancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomly assigned 1:1 to lazertinib 240 mg once daily orally or gefitinib 250 mg once daily orally, stratified by mutation status and race. The primary end point was investigator-assessed progression-free survival (PFS) by RECIST v1.1. RESULTS: Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 v 9.7 months; hazard ratio [HR], 0.45; 95% CI, 0.34 to 0.58; P < .001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P = .116). Observed safety of both treatments was consistent with their previously reported safety profiles. CONCLUSION: Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.

Adenoid cystic carcinoma (ACC) is an uncommon tumor, constituting approximately 10% of all head and neck tumors. Classically, ACC has been described as a tumor with indolent, but persistent and recurrent, growth and late onset of metastases, leading eventually to death. This study assessed the prognostic factors affecting the clinical outcome in patients with ACC in the head and neck region. We performed a retrospective study of 42 patients who underwent primary tumor resection or radiotherapy with curative intent and evaluated the clinical parameters, treatment and clinical outcomes. Forty-two patients (18 males and 24 females with a median age of 65 years) received curative treatment. The overall 3- and 5-year survival was 87.4% and 55.3%, respectively, whereas the 3- and 5-year disease-free survival was 64.3% and 36.1%, respectively. Of the 32 patients in whom recurrence could be evaluated, 18 (56.3%) developed distant metastases, with the lung (72.2%) being the most common site. Perivascular invasion influenced metastasis to the lung with borderline significance (P = 0.053). The recurrence rate was higher (P = 0.045) in patients with high-grade tumor. The status of lymph node metastasis was significantly associated with overall survival (P = 0.030). High tumor grade and lymph node involvement were predictive of recurrence and overall survival, respectively. Despite aggressive treatment, it seems to be impossible to prevent the development of distant metastasis. Therefore, more research is needed to identify molecular biomarkers that predict the clinical outcome and to develop effective treatment for patients with ACC.

To assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration NCT02105636.

As EBV-associated gastric cancer has unique features that are different from EBV (-) gastric cancer, EBV is considered to have a key role in gastric carcinogenesis. It has been reported that viral latent membrane protein 2A (LMP2A) in EBV-transformed tumor cells activates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which provides a survival signal and chemo-resistance to cytotoxic anti-cancer drugs. This study was to evaluate anti-proliferative effect and cell cycle change when 5-FU and LY294002 (LY), a selective inhibitor of PI3K, were treated separately or combined with different schedules in EBV positive gastric cancer cell line, SNU-719.

In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival and pathological complete response (primary endpoints; modified ITT [mITT] population, which excluded patients with known EGFR/ALK aberrations) with a manageable safety profile in patients with resectable (R)-NSCLC. Here, we report surgical outcomes from AEGEAN. Patients with treatment-naïve R-NSCLC (stage II-IIIB[N2]) and ECOG PS 0/1 were randomized (1:1) to platinum-based chemotherapy plus durvalumab or placebo IV (Q3W, 4 cycles) before surgery, followed by durvalumab or placebo (Q4W, 12 cycles). Surgical outcomes were summarized for the mITT population using descriptive statistics. 737/740 mITT patients received treatment, 366 and 371 in the durvalumab and placebo arms, respectively; 80.6% and 80.7% underwent surgery, 77.6% and 76.7% completed surgery, and, of the 295 and 302 patients who underwent surgery, 17.3% and 22.2% had delayed surgery. Median time from last neoadjuvant dose to surgery was 34.0 days in both arms. Of patients who underwent surgery, similar proportions had open (49.2% vs 50.7%) and minimally invasive (49.2% vs 47.0%) procedures; lobectomy was the most common procedure (88.1% vs 85.4%). R0 resection rates were numerically higher in the durvalumab versus placebo arm (94.7% vs 91.3%). Median time from surgery to first adjuvant dose was 50.0 versus 52.0 days. In exploratory analyses, a numerically higher proportion of patients in the durvalumab versus placebo arm with baseline N2 nodal status had downstaging from N2 to N0 (47.3% vs 40.2%) or, with baseline N1 nodal status, from N1 to N0 (53.6% vs 46.2%) after surgery. Similar proportions had surgical complication(s) (59.1% vs 60.1%), primarily grade 1/2 (53.0% vs 51.8%, modified safety analysis set). The addition of durvalumab to neoadjuvant chemotherapy had no detrimental effect on the feasibility, approach, type, or timing of surgery and was associated with a tolerable surgical safety profile, versus neoadjuvant chemotherapy alone. NCT03800134.