Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance.

Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody-drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.

Initial Therapeutic Approach with Pembrolizumab in Synchronous Multiple Cancers, Including Non-Small Cell Lung Cancer, Highly Positive for Programmed Death-Ligand 1 Expression.

Treatment of synchronous multiple primary cancers is clinically difficult. We report four cases of synchronous primary cancers, including advanced and metastatic non-small cell lung cancer (NSCLCs) highly positive for programmed death ligand-1 (PD-L1) expression and initially treated with pembrolizumab. Pembrolizumab was efficacious in 2 patients with NSCLC lesions, followed by chemoradiotherapy for esophageal cancer (case 1) and chemotherapy for gastric cancer (case 2). Both cancers in case 1 showed a complete response for 3 years, while progression of the accompanying gastric cancer resulted in mortality at 20 months in case 2. Both NSCLC and gastric cancer in case 3 failed to respond to pembrolizumab, but the accompanying laryngeal cancer in case 4 showed a complete response, and cytotoxic chemotherapy for NSCLC was continued for 18.0 months. Our clinical experience suggests that pembrolizumab is a useful therapeutic approach for patients with synchronous cancers, including NSCLC that highly expresses PD-L1.

Clinical Analysis of Extrapulmonary Neuroendocrine Carcinoma: A Retrospective and Single Institution Experience.

INTRODUCTION: Extrapulmonary neuroendocrine carcinoma (EPNEC) is a clinicopathological entity distinct from neuroendocrine carcinoma of the lung. Here, we reviewed the clinical features, treatment modalities, and prognosis of EPNEC patients in a single-institution series. METHODS: We retrospectively reviewed the medical records of EPNEC patients and examined the clinical profiles and treatment outcomes at our hospital between 2013 and 2021. RESULTS: Thirty-one EPNEC patients (21 men and 10 women) with a median age of 65 years were included. The primary sites were as follows: stomach (n = 7); rectum and bladder (n = 3 each); prostate, esophagus, cervix, and pancreas (n = 2 each); maxillary sinus, parotid gland, gallbladder, anal canal, larynx, uterine body, ovary, appendix, anterior mediastinum, and unknown primary lesion (n = 1 each). Thirteen patients had locally advanced stage and 18 cases had distant metastases. Chemotherapy using platinum-combined CPT-11 or VP-16 was mainly performed. Various therapeutic modalities were used, especially in locally advanced cases. Ten patients underwent surgery, including initial surgery in 5 and conversion in 5 after chemotherapy. The response rate to initial chemotherapy was 56.5%, and the median overall survival in all patients was 12.8 (95% CI: 9.6-34.5) months. Survival was significantly longer in patients with locally advanced stage (80.3 months) and receiving surgery (not reached) than in those with metastatic disease (9.9 months) and without surgery (9.6 months). CONCLUSION: EPNEC occurs in various organs and has poor prognosis. Long-term survival may be possible with surgical resection in cases with early-stage disease or tumor shrinkage due to chemotherapy.

Multi-institutional survey of antiemetic therapy in lung cancer patients treated with carboplatin in Hokushin region.

OBJECTIVE: Appropriate monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with prophylactic antiemetics is important for cancer patients. This study was performed to validate the clinical practice of antiemetic use with carboplatin-based chemotherapy in lung cancer patients in the Hokushin region (Toyama, Ishikawa, Fukui, and Nagano prefectures), Japan. METHODS: We surveyed retrospective data of newly diagnosed and registered lung cancer patients initially treated with carboplatin-based chemotherapy in 21 principal hospitals in the Hokushin region linked with health insurance claims data between 2016 and 2017. RESULTS: A total of 1082 lung cancer patients (861 [79.6%] men, 221 [20.4%] women; median age 69.4 years [range, 33-89 years]). All patients received antiemetic therapy, with 613 (56.7%) and 469 patients (43.3%) receiving 5-hydroxytryptamine-3 receptor antagonist/dexamethasone double regimen and 5-hydroxytryptamine-3 receptor antagonist/dexamethasone/neurokinin-1 receptor antagonist triple regimen, respectively. However, the rates of double regimen and use of palonosetron were higher in Toyama and Fukui prefectures. Thirty-nine patients (3.6%) changed from double to triple regimen, while 41 patients (3.8%) changed from triple to double regimen after the second cycle, but six of these returned to triple antiemetics in subsequent cycles. CONCLUSION: Adherence to antiemetic guidelines in clinical practice was high in Hokushin region. However, rates of double and triple antiemetic regimens differed between the four prefectures. Simultaneous analysis of nationwide registry and insurance data was valuable for evaluating and comparing the differences in the status of antiemesis and management.

Epidemiological and therapeutic profiles of lung cancer patients in the Hokushin Region Japan: a retrospective hospital administrative database study.

OBJECTIVE: This study was performed to validate the epidemiology, initial treatment, and clinical practice of lung cancer patients in the Hokushin region, Japan. METHODS: We retrospectively surveyed data of 5503 newly diagnosed and registered lung cancer patients in 22 principal hospital-based cancer registries in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017. RESULTS: The patients consisted of 3677 (66.8%) men and 1826 (33.2%) women with a mean (range) age of 72.2 (27-103) years). Diagnoses were small cell lung cancer (n = 512, 9.4%), squamous cell carcinoma (n = 1083, 19.7%), and non-squamous non-small cell lung cancer (NSCLC; n = 3906, 70.9%). The population with stage I disease in Toyama prefecture (41.1%) was smaller than in the other three prefectures associated with reduced selection of initial surgical therapy and increased frequencies of stage IV disease (33.2%) and best supportive care (18.6%). Initial chemotherapy for stage IV non-squamous NSCLC consisted of tyrosine kinase inhibitors in 39.3% of cases for EGFR and 4% of cases for ALK-positive non-squamous NSCLC, followed by platinum compounds (25.9%) non-platinum compounds (12.9%), and immune checkpoint inhibitors (10.2%). Carboplatin was the commonly prescribed first-line cytotoxic chemotherapeutic agent (65.4% of patients under 75 years and in 96.7% of patients over 75 years). CONCLUSION: This study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan. Simultaneous analysis of nationwide registry and insurance data could provide valuable insights for the development of lung cancer screening and medical treatment strategies. In addition, the comparative data analysis with other lesions or countries will be useful for evaluating the differences in clinical practice of cancer managements.

Factors Affecting Nivolumab Therapy Outcome in Patients with Head and Neck Cancer: A Single-Center Analysis.

BACKGROUND: Nivolumab, a programmed death-1 antibody, is an immune checkpoint inhibitor approved in Japan in March 2017 for the treatment of recurrent or metastatic head and neck cancers (RM-HNCs) after platinum drug administration. This study aimed to evaluate the effectiveness and safety of nivolumab and to determine the prognostic factors affecting the treatment outcome, in a real-world setting in Japanese RM-HNCs. METHODS: Forty-six patients with RM-HNCs treated with nivolumab between April 2017 and April 2021 at Shinshu University Hospital were retrospectively assessed in this cohort study. RESULTS: The overall response rate was 17.4%, and the disease control rate was 41.3%. The median first and second progression-free survival (PFS1 and PFS2) were 2.6 and 10.3 months, respectively. The median overall survival (OS) was 14.8 months. Multivariate analysis showed that performance status (PS) (p = 0.003) and a decrease in neutrophil-lymphocyte ratio (NLR) (p = 0.02) were significantly associated with a better OS, and a decrease in NLR (p = 0.035) was associated with a better PFS2. CONCLUSIONS: This study is the first report of PFS2 in RM-HNCs treated with nivolumab; the long PFS2 may contribute to prolonged OS. We propose that the PS and a decrease in NLR could be useful clinical prognostic markers of nivolumab therapy, which can easily be evaluated in the clinical setting.

Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant.

PURPOSE: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. METHODS: Urinary 11ß-hydroxytestosterone (11ß-OHT)/testosterone concentration ratio and plasma 4ß-hydroxycholesterol (4ß-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. RESULTS: The urinary 11ß-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4ß-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4ß-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. CONCLUSION: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

Epidemiology of neuroendocrine neoplasmas in Japan: based on analysis of hospital-based cancer registry data, 2009†-†2015.

PURPOSE: Neuroendocrine neoplasms are rare disease and could originate from throughout the body, however, there have been little epidemiological studies in Japan, especially the organ distribution. This study was to examine the epidemiological information of neuroendocrine neoplasms in the Japanese population using data from a hospital-based cancer registry. METHODS: Using data from the national database of hospital-based cancer registries, we examined the organ distribution, the stage and initial treatment of neuroendocrine neoplasms newly diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. In the present study, neuroendocrine neoplasms consisted of neuroendocrine tumors and carcinoma. RESULTS: A total of 33,215 (17,485 neuroendocrine carcinomas and 15,730 neuroendocrine tumors) cases were diagnosed. The majority in neuroendocrine carcinoma occur in lung (31.1%) followed in decreasing frequency by stomach (12.9%), pancreas (7.5%), rectum (6.7%) and esophagus (5.8%). On the other hand, the half of neuroendocrine tumor originated rectum (50.9%) and followed by pancreas (13.9%), duodenum (9.0%), lung/bronchus (8.9%), and stomach (8.7%). Neuroendocrine carcinoma presented at more advanced stage and higher age than neuroendocrine tumors.　Most cases of neuroendocrine tumors were treated surgically, while half of neuroendocrine carcinomas were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy. CONCLUSIONS: Our results demonstrated that neuroendocrine neoplasms could originate from various organs and the site distribution was different between neuroendocrine carcinoma and tumor. The national database of hospital-based cancer registries in Japan is a valuable source for evaluating the organ distribution of the rare systemic disease.

Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment.

BACKGROUND: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME). METHODS: This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3). RESULTS: The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73-6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = -0.648, p = 0.005, stromal: r = -0.490, p = 0.046). CONCLUSIONS: A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.

A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer.

BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFRm NSCLC was evaluated. METHODS: This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy. RESULTS: From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9-80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5-15.2) and median response duration was 9.2 months (95% CI: 3.7-14.0). CONCLUSIONS: Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFRm NSCLC.

Five-year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non-small-cell lung cancer.

Combination antiprogrammed death 1/programmed death-ligand 1 Ab and platinum-based chemotherapy is standard first-line treatment for advanced non-small-cell lung cancer without targetable oncogene alterations. We describe the long-term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non-small-cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first-line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first-line); arm C, 4-6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first-line); and arm D, docetaxel (second- or third-line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow-up period was 57.9 months. Median progression-free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+-47.8), 11.8 (1.4-65.1+), 40.7 (5.3-60.8+), and 3.2 (1.9-10.9) months, and 5-year progression-free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0-55.4), 28.5 (14.6-66.2+), not reached (24.2-67.4+), and 12.5 (9.8-16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment-related deaths occurred. Nivolumab and platinum-based chemotherapy combinations showed long-term tolerability. A moderate proportion of patients in arm C showed 5-year progression-free and overall survival.

Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer.

The efficacy of immune checkpoint inhibitors (ICIs) in elderly and poor performance status (PS) patients is controversial, because clinical evidence is limited. This study aimed to find a predictive biomarker for the efficacy of anti-programmed cell death 1 (PD-1) antibodies in these patient populations. We retrospectively reviewed medical records of advanced non-small-cell lung cancer (NSCLC) patients who were ≥ 75 years of age or classified as PS 2 and received anti-PD-1 antibody treatment between December 2015 and May 2018. We evaluated the association between the efficacy of the anti-PD-1 antibody in these patients and the clinical variables thought to affect ICI efficacy. A total of 235 patients with advanced NSCLC were treated with anti-PD-1 antibodies, among whom 31 patients were ≥ 75 years of age and 22 were PS 2. A Cox proportional hazard model showed that only high levels of serum vascular endothelial growth factor (VEGF) were significantly associated with a shorter progression-free survival in patients aged ≥ 75 years and those with PS 2. Among these cohorts, the overall response rate to anti-PD-1 treatment tended to be lower when serum VEGF was high compared to patients with low serum VEGF. Our results demonstrate that serum VEGF concentration may be a negative predictive biomarker in elderly and poor PS advanced NSCLC patients receiving anti-PD-1 antibody treatment. This finding may help identify patients who will not benefit from anti-PD-1 antibody therapy.

Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody.

The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.

[Mediastinal Growing Teratoma Syndrome during Chemotherapy, Presenting as a Huge and Inoperable Tumor].

A 22-year-old male was diagnosed with a metastatic nonseminomatous germ cell tumor in the mediastinum with an elevated serum alpha-fetoprotein(AFP)concentration. Histopathological findings following percutaneous biopsy revealed the presence of a mature teratoma. Bleomycin, etoposide, and cisplatin(BEP)chemotherapy resulted decreased his serum AFP. However, the tumor became enlarged and was deemed inoperable due to size. Radiographic examination indicated diffuse calcification of the tumor mass. Growing teratoma syndrome in a patient with a primary mediastinal nonseminomatous germ cell tumor is extremely rare.

Individual optimal dose of amrubicin to prevent severe neutropenia in Japanese patients with lung cancer.

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.

Modified Glasgow Prognostic Score as a Prognostic Factor in Patients with Extensive Disease-Small-Cell Lung Cancer: A Retrospective Study in a Single Institute.

INTRODUCTION: Small-cell lung cancer (SCLC) is a very chemosensitive solid tumor but is characterized by rapid progression. The modified Glasgow prognostic score (mGPS) has been shown to be an independent prognostic factor in various tumors. However, there have been few reports regarding the prognostic value of mGPS in extensive disease (ED)-SCLC. OBJECTIVE: This study was designed to clarify the clinical significance of mGPS focusing on its usefulness as a prognostic indicator for the survival and serial administrations of chemotherapies in patients with ED-SCLC. METHODS: We retrospectively analyzed the clinical records of ED-SCLC patients diagnosed and treated at Shinshu University School of Medicine between January 2005 and December 2018. Overall survival (OS) was compared according to mGPS and we examined whether mGPS could be a prognostic factor in ED-SCLC using the Kaplan-Meier method and univariate and multivariate Cox hazard analyses. RESULTS: Eighty-three patients were enrolled in this study. The median OS of mGPS 0, mGPS 1, and mGPS 2 groups were 13.6, 9.2, and 5.7 months, respectively. The OS of the mGPS 0 group was significantly longer than those of mGPS 1 and mGPS 2 groups (log-rank, p = 0.025 and 0.008, respectively). The rates of second-line chemotherapy administration in mGPS 0, mGPS 1, and mGPS 2 groups were 79.4, 61.9, and 33.3%, respectively. The rate in the mGPS 0 group was significantly higher than that in the mGPS 2 group (p = 0.003). Multivariate analyses indicated that mGPS 2 was an independent unfavorable prognostic factor in addition to old age (≥75 years), poor performance status (2-3), and elevated serum lactate dehydrogenase level (≥223 IU/L). CONCLUSION: In ED-SCLC patients, mGPS was useful as a prognostic indicator for OS.

Effect of sequential chemoradiotherapy in patients with limited-disease small-cell lung cancer who were ineligible for concurrent therapy: a retrospective study at two institutions.

BACKGROUND: The standard treatment for limited-disease small-cell lung cancer (LD-SCLC) is a combination of chemotherapy and concurrent thoracic radiotherapy. In selected cases, sequential radiotherapy is preferred because of the need for a large irradiation field, patient age, comorbidities or performance status. Nevertheless, the efficacy of sequential chemoradiotherapy in patients in whom concurrent chemoradiotherapy is contraindicated is not well known. METHODS: We retrospectively analyzed 286 patients with LD-SCLC at two institutions in Japan between 2000 and 2014. We compared the clinical characteristics and treatment outcomes of patients undergoing sequential radiotherapy with those undergoing concurrent radiotherapy. RESULTS: One hundred and seventy-five patients received concurrent chemoradiotherapy, 33 received sequential chemoradiotherapy and 46 received chemotherapy only. The median patient age was 64 years (range, 18-82 years) for the concurrent group and 71 years (49-82 years) for the sequential group. Conventional radiotherapy was selected more frequently than accelerated hyperfractionated radiotherapy (27 patients [82%] with conventional radiotherapy, and six patients [18%] with hyperfractionated radiotherapy). The major reasons for the selection of sequential radiotherapy were advanced age (12 patients) and a large irradiation field (11 patients). The median overall survival time was 41.1 months for the sequential group and 38.1 months for the concurrent group. The 5-year survival rates were 36.0% for the sequential group and 41.6% for the concurrent group. CONCLUSIONS: In clinical situation, since the treatment outcomes for patients with sequential radiotherapy were comparable to those receiving concurrent radiotherapy, sequential chemoradiotherapy can be a choice for the treatment of patients who are not candidates for concurrent chemoradiotherapy.

Efficacy and safety of osimertinib in a Japanese compassionate use program.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan. METHODS: Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital. We examined the efficacy and safety of osimertinib in a compassionate use program. RESULTS: All patients had been previously treated with both cytotoxic chemotherapy and EGFR TKIs. Overall response rate was 62.5% (95% confidence interval (CI): 35.9-89.1%). Among the six patients pretreated with a third-generation EGFR TKI, two (33%) responded to osimertinib. On administration with osimertinib, median progression-free and overall survival rates at six months were 66.7% (95% CI: 44.9-88.5) and 88.9% (95% CI: 74.4-100), respectively. Although the toxicity of osimertinib was mild in most patients, three patients had severe adverse events: two developed interstitial lung disease (ILD) and one developed Grade 3 hepatotoxicity. Among these, two (33%) of the six patients who received osimertinib following nivolumab treatment developed severe adverse events, with one each developing Grade 3 hepatotoxicity and Grade 3 ILD. Only one patient visited our hospital seeking to participate in the compassionate program from another hospital. CONCLUSION: Osimertinib demonstrated efficacy even in patients with heavily pretreated NSCLC harboring the T790M mutation. Some patients pretreated with another third-generation EGFR TKI also responded to osimertinib.

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 (AUC0-12 ) 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 AUC0-12 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.

Sensitive cytometry based system for enumeration, capture and analysis of gene mutations of circulating tumor cells.

Methods for the enumeration and molecular characterization of circulating tumor cells (CTC) have been actively investigated. However, such methods are still technically challenging. We have developed a novel epithelial cell adhesion molecule independent CTC enumeration system integrated with a sorting system using a microfluidics chip. We compared the number of CTC detected using our system with those detected using the CellSearch system in 46 patients with various cancers. We also evaluated epidermal growth factor receptor (EGFR) and PIK3CA mutations of captured CTC in a study of 4 lung cancer and 4 breast cancer patients. The percentage of samples with detected CTC was significantly higher with our system (65.2%) than with CellSearch (28.3%). The number of detected CTC per patient using our system was statistically higher than that using CellSearch (median 5, 0; P = 0.000172, Wilcoxon test). In the mutation analysis study, the number of detected CTC per patient was low (median for lung, 4.5; median for breast, 5.5); however, it was easy to detect EGFR and PIK3CA mutations in the CTC of 2 lung and 1 breast cancer patient, respectively, using a commercially available kit. Our system is more sensitive than CellSearch in CTC enumeration of various cancers and is also capable of detecting EGFR and PIK3CA mutations in the CTC of lung and breast cancer patients, respectively.