Yuichiro Ohe

Bio: Yuichiro Ohe is an academic researcher from Juntendo University. The author has contributed to research in topics: Lung cancer & Medicine. The author has an hindex of 63, co-authored 528 publications receiving 24406 citations. Previous affiliations of Yuichiro Ohe include Jikei University School of Medicine & National Cancer Research Institute.

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

Abstract: METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

Abstract: BackgroundOsimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). MethodsIn this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. ResultsThe median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confi...

AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer

Abstract: Background The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Methods We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. Results A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. Conclusions AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).

Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC

Abstract: Background Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing ...

Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer

Abstract: Purpose To evaluate epidermal growth factor receptor (EGFR) mutations and copy number as predictors of clinical outcome in patients with non–small-cell lung cancer (NSCLC) receiving gefitinib. Patients and Methods Sixty-six patients with NSCLC who experienced relapse after surgery and received gefitinib were included. Direct sequencing of exons 18 to 24 of EGFR and exons 18 to 24 of ERBB2 was performed using DNA extracted from surgical specimens. Pyrosequencing and quantitative real-time polymerase chain reaction were performed to analyze the allelic pattern and copy number of EGFR. Results Thirty-nine patients (59%) had EGFR mutations; 20 patients had deletional mutations in exon 19, 17 patients had missense mutations (L858R) in exon 21, and two patients had missense mutations (G719S or G719C) in exon 18. No mutations were identified in ERBB2. Response rate (82% [32 of 39 patients] v 11% [three of 27 patients]; P < .0001), time to progression (TTP; median, 12.6 v 1.7 months; P < .0001), and overall survi...

Pembrolizumab for the treatment of non-small cell lung cancer

Abstract: BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR

Abstract: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated amino transferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

Abstract: Summary Background Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m 2 on day 1 plus docetaxel (75 mg/m 2 on day 1) or gemcitabine (1250 mg/m 2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m 2 or AUC 5 with gemcitabine 1000 mg/m 2 ) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Findings Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Tematica de Investigacion Cooperativa en Cancer.