The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.

Overall survival analysis of patients enrolled in a randomized phase III trial comparing gefitinib and erlotinib for previously treated advanced lung adenocarcinoma (WJOG5108LFS).

BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.

First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1.

BACKGROUND: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. METHODS: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. RESULTS: At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%-75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. CONCLUSIONS: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.

Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy.

The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).

Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.

Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non-small cell lung cancer patients with asymptomatic brain metastases.

OBJECTIVES: The study was designed to investigate the safety of ramucirumab administered in combination with erlotinib or osimertinib for patients with untreated EGFR-mutated non-small cell lung cancer (NSCLC) and asymptomatic brain metastases, a patient subgroup in which these regimens have remained untested. MATERIALS AND METHODS: This phase 1b study (RELAY-Brain) consisted of two cohorts with three patients each. Patients with asymptomatic brain metastases received ramucirumab every 2 weeks plus either daily oral erlotinib or osimertinib until disease progression or intolerable toxicity. The primary objective was to assess dose-limiting toxicity (DLT), defined as central nervous system (CNS) hemorrhage of grade ≥ 2. RESULTS: Six patients were enrolled. Neither DLT nor serious or unexpected adverse events were observed. One treatment-related adverse event of grade ≥ 3 (hypertension of grade 3) was apparent. Common adverse events were generally manageable. The median number of ramucirumab administrations was 18.5 (range, 13 to 31), and there were no detected episodes of CNS hemorrhage. Five of the six patients showed an objective systemic response. Although only one patient had a measurable CNS lesion at baseline, a confirmed intracranial partial response was observed. CONCLUSION: Ramucirumab in combination with erlotinib or osimertinib showed safety for EGFR-mutated NSCLC with brain metastases.

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.

Plasma screening for the T790M mutation of EGFR and phase 2 study of osimertinib efficacy in plasma T790M-positive non-small cell lung cancer: West Japan Oncology Group 8815L/LPS study.

BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.

Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small cell lung cancer: a phase II clinical trial.

Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2 and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55-85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free survival was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate and median overall survival were 53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no. jRCT1041180081).

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.

The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

[Effectiveness of Nivolumab in Large-Cell Neuroendocrine Carcinoma of the Lung - A Report of Two Cases].

BACKGROUND: The anti-programmed death-1 antibody nivolumab is an important treatment option for non-small-cell lung carcinoma.However, its effectiveness for large-cell neuroendocrine carcinomas(LCNEC)is still controversial.Here, we report 2 cases of LCNECs that responded to nivolumab.Case 1: A 62-year-old man received chemotherapy and radiotherapy for stage III A lung adenocarcinoma.One year later, another lung lesion was observed and diagnosed as LCNEC using surgical lung biopsy.Although he subsequently received some chemotherapy regimens, the patient developed new brain metastasis, expanded mediastinal lesion, and increased levels of the tumor marker pro-gastrin releasing peptide(ProGRP).We started nivolumab as the sixth-line treatment.In response, ProGRP levels significantly decreased and the mediastinal lesion became smaller.Case 2: A 55-year-old man was diagnosed with stage III A LCNEC and received chemotherapy and radiotherapy.The primary lesion was controlled; however, lung metastases developed and chemotherapy was unable to control them.We provided treatment with nivolumab as the third-line therapy.The tumor marker ProGRP decreased and the lung metastases became smaller. CONCLUSION: Nivolumab can be a valuable treatment option for LCNEC.

Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial.

BACKGROUND: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODS: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTS: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded. CONCLUSIONS: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet.

Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial.

BACKGROUND: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. METHODS: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. FINDINGS: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. INTERPRETATION: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. FUNDING: West Japan Oncology Group and Sanofi.

Diagnostic Accuracy of Noninvasive Genotyping of EGFR in Lung Cancer Patients by Deep Sequencing of Plasma Cell-Free DNA.

BACKGROUND: Genotyping of EGFR (epidermal growth factor receptor) mutations is indispensable for making therapeutic decisions regarding whether to use EGFR tyrosine kinase inhibitors (TKIs) for lung cancer. Because some cases might pose challenges for biopsy, noninvasive genotyping of EGFR in circulating tumor DNA (ctDNA) would be beneficial for lung cancer treatment. METHODS: We developed a detection system for EGFR mutations in ctDNA by use of deep sequencing of plasma DNA. Mutations were searched in >100 000 reads obtained from each exon region. Parameters corresponding to the limit of detection and limit of quantification were used as the thresholds for mutation detection. We conducted a multi-institute prospective study to evaluate the detection system, enrolling 288 non-small cell lung cancer (NSCLC) patients. RESULTS: In evaluating the performance of the detection system, we used the genotyping results from biopsy samples as a comparator: diagnostic sensitivity for exon 19 deletions, 50.9% (95% CI 37.9%-63.9%); diagnostic specificity for exon 19 deletions, 98.0% (88.5%-100%); sensitivity for the L858R mutation, 51.9% (38.7%-64.9%); and specificity for L858R, 94.1% (83.5%-98.6%). The overall sensitivities were as follows: all cases, 54.4% (44.8%-63.7%); stages IA-IIIA, 22.2% (11.5%-38.3%); and stages IIIB-IV, 72.7% (60.9%-82.1%). CONCLUSIONS: Deep sequencing of plasma DNA can be used for genotyping of EGFR in lung cancer patients. In particular, the high specificity of the system may enable a direct recommendation for EGFR-TKI on the basis of positive results with plasma DNA. Because sensitivity was low in early-stage NSCLC, the detection system is preferred for stage IIIB-IV NSCLC.

A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib.

Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor.

[Evaluation of recurrence rates on change in hormone receptor and human epidermal growth factor receptor 2 status after neo-adjuvant chemotherapy in breast cancer patients].

BACKGROUND: Neo-adjuvant chemotherapy(NAC)may affect hormone receptor(HR)and human epidermal growth factor receptor 2(HER2)status in breast cancer patients. However, the correlation between recurrence rates and this status change remains unclear. METHODS: We evaluated 70 consecutive breast cancer patients receiving NAC with anthracyclines and taxanes, with or without trastuzumab, between January 2005 and May 2012. Pre-treatment core needle biopsy samples and specimens obtained after surgery were tested to determine HR and HER2 status. The relationship between HR and HER2 status changes and recurrence rates was then assessed. RESULTS: Pathological complete response(pCR)was observed in 13 cases and non-pCR was observed in 57 cases. Of the non-pCR cases, HR-positive status changed to HR-negative status in 6.3% of patients, but a change from negativity to positivity was not observed. HER2-positive status changed to HER2-negative status in 48.0% of patients, and a change from negativity to positivity was observed in 12.5% of cases. The recurrence rate among patients with conversion to a HR-negative status was 0%and that among patients with conversion to a HER2-negative status was 25.0%. CONCLUSION: Recurrence rates were not significantly associated with HR and HER2 status conversion after NAC. Future research is warranted to confirm out results.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.