Concordance of ALK fusion gene-rearrangement between immunohistochemistry and next-generation sequencing.

BACKGROUND: Although various companion diagnostic tests of ALK fusion gene-rearrangement are approved, few reports have assessed the concordance of ALK fusion gene-rearrangement in two companion diagnostic tests: next-generation sequencing (NGS) testing and immunohistochemistry (IHC). METHODS: The samples evaluated for gene alterations using NGS testing between May 2019 and November 2021 were included in this study. The inclusion criteria were as follows: samples were diagnosed with non-small cell lung cancer; the results of the NGS analysis were informative; and samples had residual specimens for IHC. We performed IHC on the residual specimens and retrospectively collected sample characteristics from medical records. RESULTS: A total of 185 samples were analyzed using NGS. Twenty-six samples were excluded because of failure to analyze gene alterations using NGS, no residual samples, and inadequate IHC. We analyzed 159 samples. The major histological type was adenocarcinoma (115 samples). The number of surgical and transbronchial lung biopsy specimens was 59 and 56, respectively. ALK fusion gene-rearrangement was detected in four samples using NGS, and five were detected using IHC. The sensitivity and specificity of IHC referred to by NGS were 75.0% and 98.7%, respectively. The concordance rate between IHC and NGS was 98.1%. ALK rearrangement was detected in two patients using IHC but not using NGS. In addition, ALK rearrangement was detected in one patient using NGS but not using IHC. CONCLUSION: Our results suggest that IHC and NGS might be complementary tests. In patients suspected of harboring ALK fusion gene-rearrangement, it should be analyzed using another diagnostic method.

Validation of the initial brain metastasis velocity in non-small cell lung cancer at a single cancer center.

PURPOSE: The initial brain metastasis velocity (iBMV) was recently reported as a survival predictor after brain metastases (BM) in patients treated by stereotactic radiosurgery. In this study, we validated whether iBMV is a prognostic tool, regardless of treatment modality, in patients with non-small cell lung cancer (NSCLC) with metachronous BM. METHODS: We retrospectively reviewed consecutive 3,792 new lung cancer cases in which no BM was found on magnetic resonance (MR) screening between February 2014 and December 2019, and enrolled 176 NSCLC patients with subsequent BM. Overall survival (OS) was calculated from the date of MR to identify the time from BM to death. RESULTS: The median iBMV score was 1.9. We used an iBMV score of 2.0 as the cutoff level, as previously reported. An iBMV score ≥ 2.0 was significantly associated with older age, high neutrophil-to-lymphocyte ratio, and Stage IV (P = 0.04, 0.02, and 0.02, respectively). The median OS was 0.92 years. The median OS for patients with iBMV score ≥ 2.0 and < 2.0 were 0.59 years and 1.33 years, respectively (P < 0.001). Multivariate analysis showed that an iBMV score ≥ 2.0, ECOG performance status score of 1-3, Stage IV, and non-adenocarcinoma histology were independent poor prognostic factors (hazard ratio (HR), 1.94; P = 0.0001; HR, 1.53; P = 0.04; HR, 1.45; P = 0.04; and HR, 1.14; P = 0.03, respectively). Patients with iBMV scores of < 2.0 were more likely to undergo craniotomy or stereotactic irradiation. CONCLUSIONS: An iBMV score ≥ 2.0 is an independent predictor of survival in NSCLC patients with metachronous BM, regardless of the treatment modality.

Long-term survival data of patients with limited disease small cell lung cancer: a retrospective analysis.

INTRODUCTION: In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. METHODS: In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. RESULTS: The patients had a median age of 65.5 years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2 months, median OS was 42.5 months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5 months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36 months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan-Meier curve showed disease progression frequently occurred in the first 2 years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2 years, the 5-year survival rate was 83.6%. CONCLUSION: These data suggested that the prognosis of patients with LD-SCLC was improving.

Association between the efficacy and immune-related adverse events of pembrolizumab and chemotherapy in non-small cell lung cancer patients: a retrospective study.

BACKGROUND: The combination of immune-checkpoint inhibitors with chemotherapy has become the standard of treatment for non-small cell lung cancer (NSCLC) patients. However, the association between therapeutic efficacy and the development of immune-related adverse events (irAEs) remains unclear in patients treated with combination therapy. We aimed to investigate the frequency of irAEs, and the association between therapeutic efficacy and the development of irAEs in patients with NSCLC. MATERIALS AND METHODS: We retrospectively surveyed patients with chemo-naïve advanced NSCLC who received pembrolizumab plus platinum-based chemotherapy or pembrolizumab monotherapy at Juntendo University Hospital, Japan, between February 2017 and May 2021. RESULTS: Among 148 patients (median [range] age, 68 (33-85) years; 107 men [72.3%] and 41 women [27.7%]), 74 each received pembrolizumab plus chemotherapy and pembrolizumab monotherapy. IrAEs were observed in 46 (62.2%) and 41 patients (55.4%) in the combination therapy and monotherapy group, respectively. Patients with irAEs showed significantly longer progression-free survival (PFS) than those without irAEs in the combination therapy group (8.9 vs. 5.7 months; Hazard Ratio [HR], 0.53; 95% CI, 0.29-0.98; P = 0.041) and monotherapy group (11.7 vs. 5.0 months; HR, 0.40; 95% CI, 0.22-0.70; P = 0.001). In the multivariable analysis, development of irAEs was positively associated with PFS in both the groups (HR, 0.48; 95% CI, 0.26-0.89; P = 0.019 and HR, 0.38; 95% CI, 0.21-0.68; P < 0.01). In the inverse probability of treatment weighting adjusted analysis, development of irAEs was significantly associated with combination therapy (OR, 0.56; 95% CI, 0.34-0.91; P = 0.019). CONCLUSION: Our study demonstrated that the incidence of irAEs was associated with favorable efficacy in patients treated with pembrolizumab plus chemotherapy, as well as pembrolizumab monotherapy. Also, the addition of chemotherapy to pembrolizumab significantly increased the incidence of irAEs.

Association between oligo-residual disease and patterns of failure during EGFR-TKI treatment in EGFR-mutated non-small cell lung cancer: a retrospective study.

BACKGROUND: Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI. METHODS: Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 - 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated. RESULTS: A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites. CONCLUSIONS: This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.

A randomized phase 3 study of maintenance therapy with S-1 plus best supportive care versus best supportive care after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell carcinoma of the lung (WJOG7512L).

BACKGROUND: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival. RESULTS: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe. CONCLUSIONS: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.

Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

Phase II study of nab-paclitaxel + carboplatin for patients with non-small-cell lung cancer and interstitial lung disease.

The prognosis of non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is poor, and 5%-20% of those receiving chemotherapy experience ILD exacerbation. To evaluate the safety and efficacy of nab-paclitaxel plus carboplatin for NSCLC patients with ILD, we undertook a multicenter phase II study. Chemotherapy-naïve patients with advanced NSCLC and mild or moderate ILD received nab-paclitaxel (100 mg/m2 , days 1, 8, and 15) plus carboplatin (area under the curve = 6, day 1) every 3 weeks for 4 cycles (maximum, 6 cycles). Interstitial lung diseases were diagnosed based on criteria for fibrosing interstitial pneumonia. The primary endpoint was the prevalence of exacerbation-free ILD 28 days after completion of protocol treatment. Secondary endpoints were response rate, progression-free survival, overall survival, prevalence of exacerbation-free ILD, and toxicity. Ninety-four patients were enrolled, and 92 patients received any protocol treatment. Median age was 70 years, and 58% had nonsquamous histology. In the primary analysis, the prevalence of exacerbation-free ILD 28 days after protocol treatment was 95.7% (88/92; 90% confidence interval, 90.3-98.5), which met the primary endpoint. Response rate was 51% (95% confidence interval, 40%-62%). At the time of data cut-off, median progression-free survival was 6.2 months, and median overall survival was 15.4 months. The most common grade 3/4 adverse events were neutropenia (75%), leukopenia (53%), anemia (48%), and thrombocytopenia (20%). Two treatment-related deaths (1 each of pulmonary infection and ILD exacerbation) were observed. This study showed that a combination of nab-paclitaxel with carboplatin was tolerable in NSCLC patients with mild or moderate ILD in terms of safety. This study is registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN 000012989).

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown. METHODS: We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2-4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017. RESULTS: Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39-89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36-70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3-13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.

Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter.

Circulating tumor cells (CTCs) are a tumor-derived material utilized for liquid-based biopsy; however, capturing rare CTCs for further molecular analysis remains technically challenging, especially in non-small-cell lung cancer. Here, we report the results of a clinical evaluation of On-chip Sort, a disposable microfluidic chip-based cell sorter, for capture and molecular analysis of CTCs from patients with lung adenocarcinoma. Peripheral blood was collected from 30 metastatic lung adenocarcinoma patients to enumerate CTCs using both On-chip Sort and CellSearch in a blind manner. Captured cells by On-chip Sort were subjected to further molecular analysis. Peripheral blood samples were also used for detection of EGFR mutations in plasma using droplet digital PCR. Significantly more CTCs were detected by On-chip Sort (22/30; median 5; range, 0-18 cells/5 mL blood) than by CellSearch (9/30; median, 0; range, 0-12 cells/7.5 mL) (P < 0.01). Thirteen of 30 patients who had a negative CTC count by CellSearch had a positive CTC count by On-chip Sort. EGFR mutations in CTCs captured by On-chip Sort were observed in 40.0% (8/20) of patients with EGFR-mutated primary tumor. EGFR mutations were often observed in 53.3% (8/15) of patients detected in plasma DNA. Expressions of EGFR and vimentin protein on CTCs were also successfully assessed using On-chip Sort. These results suggest that On-chip Sort is an efficient method to detect and capture rare CTCs from patients with lung adenocarcinoma that are undetectable with CellSearch. Mutation detection using isolated CTCs remains to be further tackled (UMIN000012488).

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

Dasatinib Suppresses TGFß-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis.

PURPOSE: Transforming growth factor ß (TGFß)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFß1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. METHODS: TGFß1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM). RESULTS: A549 and BEAS-2B cells exposed to TGFß1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFß1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model. CONCLUSIONS: These findings suggest that DAS inhibited TGFß-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFß/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Surfactant protein-D predicts prognosis of interstitial lung disease induced by anticancer agents in advanced lung cancer: a case control study.

BACKGROUND: Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. METHODS: Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. RESULTS: Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. CONCLUSIONS: This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients.

BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs. We analyzed 27 practicable samples using a tumor genotyping panel to assess 23 hot-spot sites of genetic alterations in nine genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene copy number of EGFR, MET, PIK3CA, FGFR1, and FGFR2, and ALK, ROS1, and RET fusions. Additionally, 34 samples were analyzed by commercially available EGFR mutation tests. RESULTS: Sixty-one patients underwent rebiopsy. Twenty-seven samples were analyzed using our tumor genotyping panel, and 34 samples were analyzed for EGFR mutations only by commercial clinical laboratories. Twenty-one patients (34 %) had EGFR T790M mutation. Using our tumor genotyping panel, MET gene copy number gain was observed in two of 27 (7 %) samples. Twenty patients received continuous treatment with EGFR-TKIs even after disease progression, and 11 of these patients had T790M mutation in rebiopsy samples. In contrast, only 10 of 41 patients who finished EGFR-TKI treatment at disease progression had T790M mutation. The frequency of T790M mutation in patients who received continuous treatment with EGFR-TKIs after disease progression was significantly higher than that in patients who finished EGFR-TKI treatment at disease progression (55 % versus 24 %, p = 0.018). CONCLUSIONS: The frequency of T790M mutation in this study was lower than that in previous reports examining western patients. These results suggest that continuous treatment with EGFR-TKI after disease progression may enhance the frequency of EGFR T790M mutation in rebiopsy samples.

Treatments and outcomes of advanced/recurrent non-small cell lung cancer harboring the EGFR T790M mutation: a retrospective observational study of 141 patients in Japan.

BACKGROUND: The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC. METHODS: We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities. RESULTS: Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations. CONCLUSIONS: This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.

The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

BACKGROUND: It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR). METHODS: We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation. RESULTS: A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p < 0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p < 0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival. CONCLUSIONS: PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

Suitability of frozen cell pellets from cytology specimens for the Amoy 9-in-1 assay in patients with non-small cell lung cancer.

BACKGROUND: The AmoyDx Pan lung cancer PCR panel (AmoyDx PLC panel) has been approved as a companion diagnostic tool for multiple anticancer agents in patients with non-small cell lung cancer (NSCLC). However, the suitability of cytology specimens as samples for the AmoyDx PLC panel remains unclear. We evaluated the performance of frozen cell pellets from cytology specimens (FCPs) in the Amoy 9-in-1 assay, a preapproval assay of the AmoyDx PLC panel. METHODS: We retrospectively collected data of NSCLC patients enrolled in LC-SCRUM-Asia from the Shizuoka Cancer Center between September 2019 and May 2021. RESULTS: A total of 49 cases submitted FCPs for evaluation of oncogenic driver alterations and were assessed using Amoy 9-in-1 and next-generation sequencing (NGS) assays. The success rates of DNA and RNA analyses using the Amoy 9-in-1 were both 100%, compared with 86% and 45%, respectively, using NGS assays. Oncogenic driver alterations were detected in 27 (55%) and 23 (47%) patients using Amoy 9-in-1 and NGS, respectively. No inconsistent results were observed among 19 cases in which both assays showed successful detection. In the remaining 30 cases, 10 had inconsistent results: nine oncogenic driver alterations (3 MET, 2 ALK, 2 ROS1, and 2 KRAS) were detectable only in Amoy 9-in-1, and one epidermal growth factor receptor (EGFR) mutation was detectable only in NGS. CONCLUSION: FCPs can be successfully used in the AmoyDx PLC panel, with higher success rate compared with the NGS assay. The AmoyDx PLC panel may be an option in cases when insufficient tissue sample is available for the NGS assay.

Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Relationship between patterns of immunohistochemical conventional neuroendocrine markers and efficacy of immune check point inhibitors in patients with extensive disease small cell lung cancer.

BACKGROUND: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)-SCLC, to assess whether conventional NE markers are predictive of ICIs. METHODS: Patients with untreated ED-SCLC who received first-line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first-line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI-chemo group) and with chemotherapy alone (chemo group). RESULTS: A total of 227 patients were included in the ICI-chemo and chemo groups, respectively. The progression-free survival (PFS) tended to be better in patients in the ICI-chemo group than those treated with chemotherapy alone in patients with NE marker-positive SCLC. In particular, it was statistically significant in patients with chromogranin A-positive SCLC (p = 0.036). In patients with NE marker-negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. CONCLUSION: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker-negative SCLC.

Continuous vs. Fixed 2-year Duration Immune Checkpoint Inhibitor Treatment of Patients With Non-Small Cell Lung Cancer: A Single Institution Database Analysis.

INTRODUCTION/BACKGROUND: The proper duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains unclear. Previously, sponsor-initiated clinical trials have more often used either a maximum 2-year fixed duration of ICI treatment or continuous treatment until documented disease progression. The study aimed to evaluate the association between ICI treatment duration (2-year fixed or continuous) and prognosis in patients with advanced NSCLC. PATIENTS AND METHODS: The medical records of 425 patients with NSCLC who received ICI before August 31, 2019 were retrospectively reviewed. RESULTS: No differences in time to treatment failure > 24 months (TTF-24) were detected between patients who underwent ICI treatment for > 2 years and patients who stopped ICI treatment at 2 years. Treatment-related adverse events tended to be higher in the patients with ICI treatment > 2 years. CONCLUSION: ICI treatment > 2 years did not significantly prolong the TTF compared with ICI treatment = 2 years, but it did increase the incidence of treatment-related adverse events.