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Summary: Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18–21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient. [Copyright &y& Elsevier]

• Bevacizumab did not improve PFS of EGFR mutated NSCLC patients receiving afatinib. • Proteinuria was frequently observed and bevacizumab was discontinued in many patients. • In the group receiving both afatinib and bevacizumab, no adverse events of grade 4 or higher were recorded. • Pneumonitis was observed infrequently in both groups. Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment. Untreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group. Between August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group. This study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Objective In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. Materials and methods Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40 mg/day (level 0) and 30 mg/day (level −1), were evaluated in combination with 15 mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. Results Nineteen patients were enrolled (level 0:5, level −1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level −1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level −1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. Conclusion Afatinib plus bevacizumab (level −1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

• We evaluated treatment practices and outcomes of Japanese stage III NSCLC patients. • Chemoradiotherapy was the commonest first-line treatment (46.1% of 744 patients). • Median OS and the 3-year OS rate in all patients were 25.4 months and 38.7%. To evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. Patients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. The study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18–20 and 12–14 weeks in the CRT and RT cohorts, respectively. Patients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC. [ABSTRACT FROM AUTHOR]

• Follow-up data from the REMORA study showed median overall survival of 28.3 months. • Higher relative dose intensity at 8 weeks may be associated with improved outcomes. • Median overall survival was higher at ≥ 75 % relative dose intensity at 8 weeks. • No new safety concerns or treatment-related deaths were reported for lenvatinib. The main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented. The single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777). The updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1–34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %–49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2–not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4–26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22–0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile. This follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes. [ABSTRACT FROM AUTHOR]

• The ideal predictive biomarker for EGFR-TKI is yet to be developed. • Prospectively collected data of 356 patients with EGFR-mutant NSCLC were analyzed. • HER2 expression in EGFR-mutant NSCLC may negatively impact the TTF of EGFR-TKI. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076–2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510–20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899–2.298) (p interaction = 0.015). In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent. [ABSTRACT FROM AUTHOR]

• Largest real-world study of nivolumab for Japanese NSCLC revealed treatment patterns. • Nivolumab effectiveness and safety were consistent with previous clinical trials. • Effectiveness was associated with PS, EGFR mutation, smoking status, and PD-L1. • Discontinuation of treatment was associated with types of irAEs. To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab. [ABSTRACT FROM AUTHOR]

• Final PFS data and second pre-planned interim analysis of OS and safety from J-ALEX. • Sustained improvement in IRF-assessed PFS demonstrated with alectinib. • Superiority of alectinib to crizotinib not concluded at second interim OS analysis. • Fewer alectinib-treated patients experienced grade ≥3 adverse events. • Alectinib continued to demonstrate superiority in IRF-assessed PFS vs crizotinib. The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK -positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26–0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35–1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK -positive NSCLC, with a favorable safety profile. OS follow-up continues. [ABSTRACT FROM AUTHOR]

Background Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective. Methods In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40 mg/m 2 on days 1, 8, 29 and 36) and S-1 (80 mg/m 2 on days 1–14 and 29–42) and TRT (60 Gy). The primary endpoint was the response rate. Results A partial response was observed in 37 patients (77%; 95% confidence interval: 63–88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis. Conclusions This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). This phase II, single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC. Methods: Eligible patients received erlotinib 150mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival (PFS) and safety. Results: A high degree of concordance was observed between different mutation testing methodologies, suggesting feasibility of early, rapid detection of EGFR mutations. Median PFS was 11.8 months (95% confidence interval [CI]: 9.7–15.3) at data cut-off (1 June 2012) (n =102). Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations; T790M mutations were tentatively linked with shorter PFS. The safety profile was as expected: rash (any grade; 83%) and diarrhea (any grade; 81%) were most common. Six interstitial lung disease (ILD)-like cases were reported, and 5 were confirmed as ILD-like events by the extramural committee. Two patients died of treatment-related pneumonitis (JAPIC Clinical Trials Information number: Japic CTI-101085). Conclusion: Erlotinib should be considered for first-line treatment in this subset of Japanese patients, with close monitoring for ILD-like events. [Copyright &y& Elsevier]

Summary: Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1cm, 1–2cm, and ≥2cm in diameter, respectively, were analyzed. Of the 24 tumors ≤2cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p <0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p =0.017). In the tumors ≤2cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p =0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n =17) and 82% of the wild-type tumors (n =33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued. [Copyright &y& Elsevier]

Background: Gefitinib (‘Iressa’, ZD1839), an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), has shown antitumor activity in refractory patients with non-small-cell lung cancer (NSCLC) in clinical trials. We have retrospectively analyzed the efficacy and tolerability of gefitinib in patients with advanced NSCLC treated at Okayama University Hospital.Methods: We reviewed the clinical records of 57 patients with advanced NSCLC who had received 250 mg/day gefitinib at our hospital between November 2000 and May 2003. Correlations between the sensitivity of brain metastases and extracranial disease following treatment with gefitinib were also investigated.Results: Extracranial objective responses were observed in 15 (27%; 95% confidence interval 15.8–40.3%) patients. Fourteen out of 57 patients had brain metastases; six experienced objective responses (one complete response, CR and five partial responses, PR) and eight had stable disease (SD) in the brain. Seven out of 14 patients with brain metastases experienced objective responses in their extracranial tumors and, interestingly, objective responses in the brain were observed in six (86%) of these patients. Multivariate analysis found that advanced age (≥70 years) and the presence of brain metastases were associated with clinical response to gefitinib (P = 0.01 and 0.05, respectively), and that female patients were more likely to respond. Median survival and median duration of response were 9.1 and 7.7 months, respectively. The majority of adverse events (AEs) were mild and reversible skin and gastrointestinal disorders, with grade 3 adverse events observed in six (11%) patients.Conclusions: This retrospective analysis has found that gefitinib is effective and well tolerated in patients with refractory NSCLC, confirming previous phase II trial data. Interestingly, gefitinib appeared to be effective for brain metastases as well as extracranial tumors. Further prospective trials are warranted to evaluate the efficacy of gefitinib in elderly patients and in patients with brain metastases. [Copyright &y& Elsevier]

Purpose: To determine the maximum-tolerated dose (MTD) of irinotecan and paclitaxel in this two-drug combination, and to investigate a sequence-dependent effect in the pharmacokinetics of these drugs, we conducted a phase I study in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Patients with stage IIIB/IV NSCLC were enrolled in this study. Both irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3 weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially administered and followed by paclitaxel infusion, while the sequence of drug administration was reversed in the second cycle. Blood samples for pharmacokinetic analysis were obtained on day 1 of the first and second cycles. Results: Nine patients received a total of 12 cycles, which were evaluated for toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3 or more neutropenia was observed in 67% of cycles at dose level 2. The main non-hematological toxicities were grade 3 febrile neutropenia, supraventricular arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum concentration of paclitaxel was elevated in a dose-dependent manner. There was a trend toward elevation of the area under the plasma concentration–time curve (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan (r=0.894,P<0.0001). The objective response was not observed in the nine patients. Conclusion: The combination of irinotecan and paclitaxel with this schedule produced considerable toxicities without any antitumor effect for advanced NSCLC. The different schedule of administration or other combinations should be investigated. [Copyright &y& Elsevier]