Japanese Non-small Cell Lung Cancer Research Articles

Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests.

Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

Brain metastases in Japanese NSCLC patients: prognostic assessment and the use of osimertinib and immune checkpoint inhibitors—retrospective study

BackgroundThe Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.MethodsWe retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.ResultsThe median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).ConclusionsWe confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Real-world Efficacy and Safety of Atezolizumab Plus Bevacizumab, Paclitaxel and Carboplatin for First-line Treatment of Japanese Patients With Metastatic Non-squamous Non-small Cell Lung Cancer.

Platinum-doublet chemotherapy plus either programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitors has been reported to improve the survival of patients with advanced non-small cell lung cancer (NSCLC). The IMpower150 study showed significant improvements in progression-free survival and overall survival with atezolizumab in combination with bevacizumab, a humanized anti-VEGF monoclonal antibody, paclitaxel, and carboplatin (ABCP therapy) in chemotherapy-naïve patients with non-squamous NSCLC. We herein report the efficacy and safety of ABCP therapy in Japanese patients with non-squamous NSCLC in clinical practice. We retrospectively evaluated the efficacy and safety of ABCP therapy in 30 patients treated at our hospital from February 2019 to December 2021. The median age of patients was 69 years, 24 (80.0%) patients were male, 29 (96.7%) patients had a performance status of 0 or 1, 28 (93.3%) patients had adenocarcinoma histology, and 7 (23.3%) patients had epidermal growth factor receptor mutations. Evaluation of the PD-L1 tumor proportion score (TPS) showed that 12 (40.0%), 8 (26.7%), and 6 (20.0%) patients had a TPS of ≥50%, 1% to 49%, and <1%, respectively. The objective response rate of the intention-to-treat wild-type population was 73.9%, and the median progression-free survival was 8.3 months. Immune checkpoint inhibitor (ICI)-induced pneumonitis occurred in one (3.3%) patient. ABCP therapy for Japanese non-squamous NSCLC patients in a clinical setting achieved a high response rate with low incidence of ICI-induced pneumonitis equivalent to those observed in IMpower150 study.

Evaluation of factors affecting epidermal growth factor receptor tyrosine kinase inhibitor-induced hepatotoxicity in Japanese patients with non-small cell lung cancer: a two-center retrospective study

BackgroundGefitinib and erlotinib, are epidermal growth factor receptor tyrosine kinase inhibitors, and are currently recommended for non-small cell lung cancer stage IV in the elderly and in patients with decreased performance status in the Japanese Lung Cancer Society Guideline, but they occasionally caused severe hepatotoxicity requiring postponement or modification of treatment. However, little is known about the risk factors for hepatotoxicity in patients receiving gefitinib and erlotinib. In this study, we investigated the factors influencing hepatotoxicity in Japanese non-small cell lung cancer (NSCLC) patients treated with gefitinib or erlotinib monotherapy.MethodsJapanese patients with NSCLC who started gefitinib or erlotinib monotherapy from January 2005 to December 2017 at Kanazawa University Hospital or Kanazawa Medical University Hospital were included in this study. Factors affecting hepatotoxicity were retrospectively investigated by multiple logistic regression analysis.ResultsA total of 102 patients who received gefitinib and 95 patients who received erlotinib were included in the analysis. In the gefitinib group, a body mass index (BMI) ≥ 25 was associated with an increased risk of hepatotoxicity (OR = 4.571, 95% CI = 1.486–14.056, P = 0.008). In the erlotinib group, concomitant use of acid-suppressing medications (AS), namely proton pump inhibitors or histamine-2 receptor antagonists, was associated with a reduced risk of hepatotoxicity (OR = 0.341, 95% CI = 0.129–0.900, P = 0.030).ConclusionsBMI ≥ 25 in patients treated with gefitinib increased the risk of hepatotoxicity. In contrast, AS combination with erlotinib reduced the risk of hepatotoxicity. Thus, because different factors influence the risk of hepatotoxicity, monitoring for adverse events should take into account patient background factors and concomitant medications.

Brain Metastases in Japanese NSCLC Patients: Prognostic Assessment and the Use of Osimertinib and Immune Checkpoint Inhibitors

<h3>Purpose/Objective(s)</h3> To validate the Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) for Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and assess the factors impacting survival. <h3>Materials/Methods</h3> We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with brain metastases (BM) between 2013 and 2020 and received radiotherapy for BM initially at the Hokkaido Cancer Center. Lung-molGPA items, sequence of therapy, use of osimertinib, expression of PD-L1 (classified as high, low, and no) and use of immune checkpoint inhibitors (ICI) were evaluated for influence. The main outcome measure was survival from the day of diagnosis of BM, and log-rank tests were performed to compare the results. <h3>Results</h3> The median survival times for adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p<0.0001), respectively. The median survival times for non-adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0 and 2.5‒3.0) Group were 3.2, 11.0 and 16.0 months (p=0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome. The median survival times for the group with and without osimertinib treatment were 34.2 and 17.6 months, respectively (p=0.0164). In a comparison of treatment sequences, no significant differences were found between groups; however, patients who received both irradiation and tyrosine-kinase inhibitor for BM had better prognoses than patients with only irradiation for BM (35.8 months vs 14.8 months, p=0.0007). In patients tested for PD-L1 expression, the median survival times after diagnosis of brain metastasis were 5.6, 22.5 and 9.3 months for high-, low- and no-expression groups (p=0.2198), respectively. Also, in patients with high PD-L1 expression, those with ICI had better survival (median OS, 8.6 months) than those without (median OS, 3.6 months). <h3>Conclusion</h3> We conformed that Lung-molGPA successfully classified Japanese NSCLC patients with brain metastasis by prognosis. Osimertinib was shown to extend survival of EGFR-positive NSCLC patients with BM, and ICI proved effective in patients with high PD-L1 expression.

Early change in the clearance of pembrolizumab reflects the survival and therapeutic response: A population pharmacokinetic analysis in real-world non-small cell lung cancer patients

ObjectivesThe dosing pattern of pembrolizumab is based on population pharmacokinetic (Pop-PK) analysis of clinical trials. Data for Japanese patients or patient populations with poor conditions such as cachexia are scarce. In this study, we performed a Pop-PK analysis of Japanese non-small cell lung cancer patients and analyzed the relationship between exposure, treatment effect, and survival. Materials and MethodsA total of 270 blood samples from 76 patients who received 200 mg pembrolizumab every 3 weeks between March 2017 and December 2018 were included. Blood concentrations of pembrolizumab were measured using mass spectrometry, and Pop-PK analysis was conducted using the Phoenix NLME software with a one-compartment model. ResultsThe estimated median of clearance (CL) in this analysis population was 0.104 L/day, about half of the historical data for Western data. Overall, pembrolizumab CL decreased over time, with some populations showing increased CL early in the treatment and others showing decreased CL over time. When the time-varying CL was stratified by quartile, the group with decreasing CL showed significantly better treatment response and survival than the group with increasing CL, even though the group included more patients with cachexia. Detailed analysis suggested that the patient population that responded to pembrolizumab treatment had an improved general condition and reduced protein catabolism, further decreasing CL. ConclusionIn populations that benefit from pembrolizumab treatment, CL may be reduced early in their treatment, which may be a predictive and prognostic factor. However, further prospective validation of our findings is needed.

The relationship between evolving sarcopenia and efficacy of immune checkpoint inhibitor in non-small cell lung cancer patients.

e21049 Background: Sarcopenia has been receiving attention due to its association with prognoses in patients with cancer. We investigated the association between evolving sarcopenia assessed with computed tomography (CT) and outcome of non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Methods: In this retrospective study, 47 NSCLC patients who received ICIs at our Hirosaki University Hospital were enrolled. Skeletal muscle area at the level of the third lumbar vertebra (L3-SMA) was measured from CT images before and 90 days after the ICI treatment. The factor related to the poor efficacy of ICIs was determined by logistic regression analysis. The prognostic cut-off value was estimated by a receiver operating characteristic (ROC) curve. As covariate factors, age, gender, smoking history, histology, performance status (PS), PD-L1 tumor proportion score (TPS), status of driver mutations, body mass index (BMI), serum protein and albumin levels, and lymphocyte count were included. Results: In the univariate analysis, reduction rate of L3-SMA, PS, BMI, serum protein and albumin levels, and lymphocyte count were significantly associated with efficacy. In the multivariate analysis, only reduction rate of L3-SMA was significant. The cut-off value was estimated to be 6%. The study subjects were divided into two groups by the cut-off value. In both of progression free and overall survival analysis, those with more than 6% of reduction had significantly shorter period being free of events than that of the other. Conclusions: Evolving sarcopenia assessed with CT images is promising as a prognostic factor in Japanese NSCLC patients receiving ICIs.

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p &lt; 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p &lt; 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p &lt; 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

Brigatinib in Japanese ALK positive NSCLC patients previously treated with ALK tyrosine kinase inhibitors: J-ALTA.

9537 Background: Brigatinib is an ALK inhibitor with demonstrated activity against ALK resistance mutations. To evaluate efficacy and safety in Japanese patients with ALK-positive non-small cell lung cancer (NSCLC), a prospective, single-arm, phase 2 study was conducted. We report the efficacy and safety of brigatinib in patients who have progressed on alectinib with or without prior crizotinib and of those who previously received up to two ALK tyrosine kinase inhibitors (TKIs) with or without prior chemotherapy. Methods: A safety evaluation lead-in was followed by an expansion stage of an ALK TKI-naïve and two ALK TKI-refractory cohorts. The refractory cohorts included patients with stage IIIB, IIIC, or IV NSCLC with ALK rearrangements. This report describes efficacy results from the post-alectinib patients in the expansion cohort and safety results from all refractory patients. The primary endpoint was confirmed objective response rate (ORR) assessed by IRC, secondary endpoints included duration of response (DoR), progression-free survival (PFS), disease control rate (DCR), and intracranial ORR (iORR). Brigatinib was administered at 180 mg QD with 90 mg QD lead-in for the first 7 days, and efficacy was evaluated every 8 weeks. Results: A total of 72 patients were enrolled in 28 sites, including a cohort of 47 patients with prior alectinib, with/without crizotinib between January 2018 and September 2019. The primary analysis of brigatinib in this cohort (data cut-off date 26 September 2019) demonstrated an IRC-assessed, confirmed ORR of 30% and a median DoR of 6.1 months. The median PFS was 7.3 months. Clinically meaningful intracranial efficacy was also observed (see table). Grade ≥3 TEAEs included blood creatine phosphokinase increase (18.1%), lipase increase (13.9%), hypertension (11.1%), amylase increase (4.2%), and pneumonitis (1.4%). Brigatinib also showed anti-tumor activity in patients with refractory secondary mutations in the ALK kinase domain, including G1202R, I1171N, V1180L, and L1196M. Conclusions: Brigatinib showed clinically meaningful efficacy in Japanese patients refractory to prior alectinib (first line or post crizotinib), regardless of prior chemotherapy. The safety profile of brigatinib was consistent with prior studies and no new safety findings were identified. Clinical trial information: NCT03410108 . [Table: see text]

Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study).

Background:In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients.Methods:The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients (N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up.Discussion:Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

Abstract B004: Revealing the mechanisms of acquired resistance to osimertinib from re-biopsy specimens in advanced non-small cell lung cancer with EGFR T790M mutation (LOGIK1607)

Abstract Background: Although treatment with osimertinib confers survival benefits in the second-line treatment of epidermal growth factor receptor (EGFR)-mutated lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib has not been well understood. Here, we planned a multicenter, prospective observational study in order to clarify the possible acquired resistance mechanisms to second-line treatment using osimertinib in Japanese non-small cell lung cancer patients. Methods: EGFR T790M positive advanced non-small cell lung cancer patients were included in this study. We excluded EGFR tyrosine kinase inhibitor naïve patients, patients whose EGFR T790M proved only by liquid biopsy, and patients whose tumor specimens were not adequate for targeted resequencing analysis. Re-biopsy was planned after the patient developed acquired resistance to osimertinib under written informed consent. Nucleic acids were extracted from formalin-fixed paraffin embedded tumor sections and targeted resequencing was performed using a panel consisting of 143 genes (Oncomine Comprehensive Assay, OCA, ThermoFisher Scientific, USA) in a CLIA-certified laboratory (SRL Inc., Japan), and then analyzed using IonReporter software (ThermoFisher Scientific, USA). Results: Between November 2016 and February 2019, 86 patients from 25 institutions were screened. Among 71 patients who were eligible, 31 patients were still on osimertinib and 33 patients developed acquired resistance. Among the 33 patients who developed acquired resistance, 16 patients proceeded to re-biopsy (4 males, 8 Del19 and 7 L858R EGFR mutations). 15/16 samples from re-biopsies and 9/16 samples from pre-osimertinib biopsies proceeded to OCA analyses. Others were excluded because of low quality of extracted nucleic acids. The acquired resistance mechanisms were as follows: T790M maintained in 10 patients with EGFR G796S being found in 1 patient. T790M loss observed in 5 patients with 1 patient having copy number gain in growth-arrest specific gene 6 (GAS6). Another patient possibly had copy number alterations in cell cycle genes. All patients had equal or reduced mutation counts during the therapeutic course, suggesting clonal selections by the therapies. Conclusions: EGFR C797S mutation was not observed in this series. Copy number alteration in GAS6-AXL pathway and cell cycle pathway could be targets of therapy. Citation Format: Atsushi Osoegawa, Masafumi Yamaguchi, Tomomi Nakamura, Ryotaro Morinaga, Kentaro Tanaka, Kosuke Kashiwabara, Kenichi Taguchi, Kazuki Nabeshima, Junji Kishimoto, Kenji Sugio. Revealing the mechanisms of acquired resistance to osimertinib from re-biopsy specimens in advanced non-small cell lung cancer with EGFR T790M mutation (LOGIK1607) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B004. doi:10.1158/1535-7163.TARG-19-B004

Retrospective cohort study on the safety and efficacy of docetaxel in Japanese non-small cell lung cancer patients with nondialysis chronic kidney disease stage 3b or higher.

BackgroundIt has been reported that 20% of lung cancer patients have renal impairment caused by chronic kidney disease (CKD). Since docetaxel is predominantly excreted by the hepatobiliary system, it is administered to non‐small cell lung cancer (NSCLC) patients with renal impairment. However, few clinical data are available on the toxicity and efficacy of docetaxel for patients with nondialysis renal impairment. Furthermore, some cases of tubular nephrotoxicity caused by docetaxel in NSCLC patients have been reported. Therefore, a retrospective cohort study was conducted to assess the influence of nondialysis CKD on the toxicity and efficacy of docetaxel in NSCLC patients.MethodsNSCLC patients who received docetaxel were assessed for renal function, occurrence of adverse events and treatment efficacy.ResultsA total of 34 NSCLC patients who received docetaxel were studied. Eight (23.5%) patients had nondialysis CKD stage 3b or higher, with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. Although the differences were not statistically significant, the starting dose of docetaxel (mg/m2) was lower (60 mg/m2; 37.5% vs. 69.2%) in patients with an eGFR <45 than that in patients with an eGFR ≥45. No significant association was observed between pretreatment eGFR and hematological and nonhematological toxicities. No significant difference was observed in the disease control rate (62.5% vs. 65.4%, P = 1.000) or in the median overall survival (10.7 vs. 11.7, P = 0.735) between patients with an eGFR <45 and those with an eGFR ≥45.ConclusionDocetaxel is a reasonable option for NSCLC patients with nondialysis CKD stage 3b or higher. Dose reduction of docetaxel is also a possibility for NSCLC patients with CKD stage 3b or higher.

Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations

SummaryPurpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer

Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3weeks) or docetaxel (60 mg/m2 on day 1 every 3weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0months; P = 0.54) and overall survival (14.6 versus 13.5months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. NCT01207011 (ClinicalTrials.gov).

Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism.

Crizotinib is a standard treatment for advanced ALK‐positive non‐small‐cell lung cancer (NSCLC). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non‐hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK‐positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4–61.0 kg). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration–time curve from 0–12 h (AUC 0–12) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT‐2677TT‐3435TT genotype was an outlier, with an AUC 0–12 and peak concentrations on day 15 of 2.84× and 2.61× the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese NSCLC patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors.

Promoter Methylation of the &amp;lt;i&amp;gt;CADM&amp;lt;/i&amp;gt;1 and 4.1&amp;lt;i&amp;gt;B&amp;lt;/i&amp;gt; Genes Occurs Independently of the &amp;lt;i&amp;gt;EGFR&amp;lt;/i&amp;gt; or the &amp;lt;i&amp;gt;KRAS&amp;lt;/i&amp;gt;2 Mutation in Non-Small Cell Lung Cancer

Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent approach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI varies in individual cases even among tumors carrying the same EGFR mutation, suggesting the involvement of modifying factors. To characterize possible modifiers, we examined mutation state of the EGFR and the KRAS genes in Japanese NSCLC and compared them with the methylation state of lung tumor suppressors, the CADM1 and 4.1B, whose products have potentials to modify the functions of EGFR or KRAS. Materials and methods: A total of 103 Japanese NSCLC and 11 NSCLC cell lines were examined. Genomic DNA of exons 18–21 of the EGFR and exons 1 and 2 of the KRAS were amplified by polymerase chain reaction (PCR), followed by single-strand conformation polymorphism analysis and direct sequencing. Methylation status of gene promoters in NSCLC cells were examined by methylation-specific PCR. Results: Mutations of the EGFR and KRAS were detected mutually exclusively in 27 and 11 out of 103 NSCLC cases, respectively. EGFR mutations were observed exclusively in adenocarcinoma (27 of 69, 41%) and preferentially in tumors from female and non-smokers (p EGFR and 4 (36%) and 8 (73%) of 11 tumors carrying mutated KRAS showed methylation of the CADM1 and 4.1B, respectively. EGFR-mutated tumors with methylation of either CADM1 or 4.1B showed more malignant features than those with unmethylated CADM1 and 4.1B (p CADM1 and 4.1B are independent of the mutation status of the EGFR or KRAS but play roles in the malignant progression of NSCLC. Integration of epigenetic information would be useful for identifying possible modifiers to predict the response or recurrence of lung adenocarcinoma to the EGFR-TKI therapy.

APOBEC3B gene overexpression in non-small-cell lung cancer.

Recent study results have demonstrated that a subclass of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminase may induce mutation clusters in various types of cancer. From the Cancer Genome Altas, an APOBEC mutation pattern was identified in bladder, cervical, breast, head and neck and lung cancers. In the present study, APOBEC3B mRNA expression was investigated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay using LightCycler in surgically treated non-small-cell lung cancer (NSCLC) cases. Additionally, 88 surgically removed Japanese NSCLC cases were analyzed for mRNA level. The results showed that APOBEC3B/β-actin mRNA levels were significantly higher in lung cancer (1,598.481±6,465.781) when compared to adjacent normal lung tissues (2,116.639±8,337.331, P=0.5453). The tumor/normal (T/N) ratio of APOBEC3B/β-actin mRNA levels was not different within the gender, age, smoking status and pathological stages. The T/N ratio of APOBEC3B/β-actin mRNA levels was not significantly different in epidermal growth factor receptor (EGFR) or Kras mutation-positive cases as compared to the wild-type cases.

Impact of the new EGF receptor and ALK testing guideline on personalized lung cancer medicine.

All advanced-stage lung adenocarcinoma patients should be tested for EGF receptor (EGFR) mutations and for EML4–ALK translocations as a guide for selecting them for tyrosine kinase inhibitor (TKI) therapy. The new EGFR and ALK guideline provides useful recommendations for appropriate testing [1]. Lung tumors are the leading cause of cancerrelated mortality worldwide [2]. Almost 80% of cases are non-small-cell lung cancer (NSCLC) and extensive disease is present at the time of diagnosis in the majority of patients. Systemic treatment with chemotherapy has reached a plateau of 10–20% response rates and 4–5 months of progression-free survival (PFS), and has not improved in more than a decade [3–5]. A first milestone in a new era of targeted therapy for this disease was reached with the discovery of a subset of tumors carrying activating mutations of EGFR, which can be selectively blocked with TKIs such as erlotinib and gefitinib. Numerous clinical studies have demonstrated the efficacy of these TKIs in the treatment of EGFR-mutated lung tumors, with 55–83% response rates and 9–13 month PFS [6,7]. A second milestone was the discovery, in 2007, of the EML4–ALK translocation in 6.7% of Japanese NSCLC patients [8]. The translocation was later found in 4–7% of Chinese [9], European [10] and US patients [11]. When treated with a novel ALK inhibitor, crizotinib, these patients showed response rates of 57% with a PFS greater than 6 months [12]. As a result of these new developments, many laboratories worldwide are currently testing lung tumor samples for EGFR mutations and EML4–ALK fusions. In an effort to standardize testing practices, the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology constituted writing and advisory panels, presided by three cochairs, to

Gene expression analysis in Merkel cell polyomavirus‐positive non‐small cell lung cancer from Japanese patients

We read with great interest the recent article by Lasithiotaki et al. entitled “The presence of Merkel cell polyomavirus is associated with deregulated expression of BRAF and Bcl-2 genes in non-small cell lung cancer.”1 This very interesting report gives a new insight into the currently important issue of the infectious causes of cancer. The analysis presented in this study was based on 110 patients with non-small cell lung cancer (NSCLC) in Crete, Greece. The authors found that 9.1% (10/110) of NSCLC specimens were positive for the presence of Merkel cell polyomavirus (MCPyV), identified by polymerase chain reaction (PCR). The article also provided interesting data on the expression patterns of seven cellular genes in the MCPyV-positive NSCLC specimens by comparing 6 MCPyV-positive and 10 MCPyV-negative samples. Around the same time, we reported on our analysis of 112 Japanese NSCLC patients with an MCPyV detection rate of 17.9% (20/112).2 The viral prevalence rate was higher in these Japanese NSCLC patients than in the Greek patients reported by Lasithiotaki et al. In our study, MCPyV was detected more frequently in never smokers than in smokers, although Lasithiotaki et al. showed a positive trend for smoking status. Recent studies have indicated that the increase in the incidence of lung cancer in never smokers is higher in East Asia, including Japan, than in the United States and European countries.3-5 Thus, the incidence of lung cancer in never smokers seems to vary between geographic locations or ethnic groups; the higher prevalence in Asia may account for the discordance between our study and that by Lasithiotaki et al. Japanese ethnicity compared with Caucasian ethnicity and never-smoker status are independent favorable prognostic factors for overall survival in NSCLC patients.6 In addition, Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced by gene polymorphisms and genome-wide association studies. For example, East Asian patients with NSCLC have a much higher prevalence of mutation of the “epidermal growth factor receptor” gene and a lower prevalence of mutation of the K-ras gene. These clinical and genetic differences between East Asians and Caucasians prompted us to investigate the gene-expression patterns in MCPyV-positive NSCLC samples from Japanese patients and to compare the results with those reported by Lasithiotaki et al. Our study included 27 surgically resected frozen tumors from Japanese NSCLC patients, including 12 squamous cell carcinomas (SCCs) and 15 adenocarcinomas. Nine samples (four SCCs and five adenocarcinomas) were positive for MCPyV and 18 samples (8 SCCs and 10 adenocarcinomas) were negative. Total RNA was extracted with the High Pure RNA Tissue Kit (Roche Diagnostics, Tokyo, Japan). The extracted RNA was treated with DNase to avoid amplification of DNA. One microgram of RNA was reverse transcribed using the SuperScript III First-Strand Synthesis System (Life Technologies, Tokyo, Japan). The transcript levels of the K-ras, BRAF, RKIP, p53, RB1, Bcl-2, and Bax genes were measured using the StepOne Plus real-time PCR system with SYBER Green PCR Master Mix (Life Technologies). Primer sequences and PCR conditions were the same as those used by Lasithiotaki et al. All reactions were run in triplicate. mRNA of the housekeeping gene GAPDH was used as an internal control to normalize mRNA expression levels. Relative gene expression was calculated by the 2–ΔΔCt method, as described.1, 7 The gene expression levels were first evaluated by the F-test to determine whether they followed a normal distribution pattern. Depending on the results, the Aspin–Welch's t test or Student's t test was used to compare the gene expression levels between MCPyV-positive and MCPyV-negative samples. A p-value less than 0.05 was considered significant. This study was approved by the Ethics Committee of Kochi Medical School, Kochi University. As shown in Table 1, the transcript levels of the K-ras, BRAF, RKIP, p53, RB1, Bcl-2, and Bax genes did not differ statistically between MCPyV-positive and MCPyV-negative NSCLC samples. However, we found a trend toward higher expression levels of the Bcl-2 gene in MCPyV-positive samples than in negative samples (p = 0.073). This trend was noticeable in MCPyV-positive adenocarcinoma (p = 0.012). Considering the antiapoptotic effect of the Bcl-2 gene, it is conceivable that this proto-oncogene might be associated, at least partially, with the pathogenesis of MCPyV-infected NSCLC in a subset of Japanese patients. Our results did not match exactly the findings of Lasithiotaki et al., who found downregulation of the Bcl-2 gene and upregulation of the BRAF gene in MCPyV-positive patients. These two reports clearly illustrate the need for further worldwide large-scale studies to elaborate on possible ethnic differences in the genetic pathogenecity of MCPyV-associated NSCLC. Yours sincerely, Yumiko Hashida, Masayuki Imajoh, and Masanori Daibata

Identification of actionable mutations in surgically resected tumor specimens from Japanese patients with non-small cell lung cancer by ultra-deep targeted sequencing.

7572 Background: Detection of tumor genetic alterations is critically needed for lung cancer clinic as well as for the development of molecular targeted therapeutics. Here we report the results of a broad spectrum of genetic alterations identified in Japanese non-small cell lung cancer (NSCLC) patients by ultra-deep targeted sequencing. Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens. TruSeq amplicon cancer panel was used for the detection of somatic mutations in 48 cancer related genes followed by ultra-deep sequencing (Illumina) at an average coverage of approximately 2800x. ALK, ROS1 and RET traslocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications were also detected by multiplex RT-PCR and quantitative PCR, respectively. Results: The demographics of 204 consecutive patients enrolled in this prospective study at Shizuoka Cancer Center between July 2011 and November 2012: median age 69 years (range: 38-92); male 66%; never smoker 25.5%; histology: adenocarcinoma 68.6%, squamous cell carcinoma (SQ) 27.0%, others 4.4%; tumor stage: I 53.9%, II 28.4%, III 12.7%, IV 4.9%. TP53 mutation was most frequently detected (44.4%) in all patients, particularly in SQ (67.9%). Mutations in genes such as MLH1 (4.9%), STK11 (6.3%), CTNNB1 (5.6%), SMAD4 (1.4%), VHL1 (1.4%), PTPN11 (0.7%) and GNAS (0.7%) were detected besides major mutations in genes such as EGFR (43.0%), KRAS (17.6%) and PIK3CA (14.1%) in adenocarcinoma. PIK3CA (21.4%), MLH1 (5.4%), APC (3.6%), STK11 (3.6%), FGFR2 (1.8%) and VHL (1.8%) mutations were identified in SQ and notably, 48.2% of SQ patients harbored simultaneous gene mutations, suggesting the genetic complexity of this histology. FGFR1 amplification was found in 8.9 % of SQ, suggesting lower frequency in Asian population than in Caucasian population. Conclusions: We managed to detect a wide range of genetic alterations and identified additional actionable mutations besides popular driver mutations. This approach may facilitate elucidation of detailed molecular characteristics of NSCLC, thereby implementing personalized cancer medicine.