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This article proposes an automotive safety integrity level (ASIL) D, which is the highest automotive integrity level specified in ISO 26262, and a target application processor for driving automation systems with a high convolutional neural network (CNN) processing performance of 60.4 trillion operations per second (TOPS) with high power efficiency of 13.8 TOPS/W. To achieve both performance and power efficiency, a stream processing architecture specialized for CNN hardware module is adopted to implement many low-power arithmetic units. In addition, 6 MB of local memories are implemented to reduce data transfers between dynamic random access memory (DRAM) and the CNN hardware, thereby improving the execution efficiency of the arithmetic units and saving power consumption caused by the data transfer. In order to support high safety integrity level with power efficiency, we provide safety mechanisms with high failure detection rates only for the hardware used in applications that require ASIL D support. The configuration of two CNN modules can switch between lockstep and single operation depending on the use case, thus achieving a tradeoff between performance and ASIL while maintaining power efficiency. In addition, the freedom from interference (FFI) concept defined in ISO 26262 is achieved by providing mechanisms to prevent low safety level tasks from interfering with high safety level tasks running concurrently inside the processor.

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. Whole-transcriptome sequencing of a subset of 75 non-small-cell lung cancer specimens in a multi-institutional genome screening study identified a fusion of the CLIP1 and LTK genes with transformational potential due to constitutive LTK kinase activity.

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., The mutation identification success rate for all four genes was 80.1%. Surgical resection was associated with the highest success rate. Multivariate analysis showed a significant difference for surgical resection alone.

Background NJLCG1402 was a phase I/II trial investigating biweekly nanoparticle albumin‐bound paclitaxel (nab‐PTX) in patients with advanced non‐small cell lung cancer (NSCLC). Methods The study included patients aged ≥20 years with previously treated NSCLC. Nab‐PTX (100–150 mg/m2) was administered biweekly in a 28‐day cycle. The phase I portion was performed to determine the recommended phase II dose of nab‐PTX. In the phase II portion, the primary endpoint was the objective response rate. Secondary endpoints were disease control rate, progression‐free survival, overall survival, and safety. Results A total of 15 patients received biweekly nab‐PTX (100–150 mg/m2) and 12 patients in phase II were treated with 150 mg/m2. In the phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2, the objective response rate was 22%, and the median progression‐free and overall survival was 3.6 and 11.2 months, respectively. Adverse events grade ≥3 were observed in 39% of patients. Conclusions Biweekly nab‐PTX monotherapy was well tolerated and exhibited favorable antitumor activity in patients with previously treated NSCLC., We conducted the first prospective multicenter phase I/II trial to evaluate the efficacy and safety of biweekly nab‐PTX treatment in patients with previously treated advanced NSCLC. In phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2, the objective response rate was 22%; median progression‐free and overall survival was 3.6 and 11.2 months, respectively.

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1–73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9–23.9) months. The median overall survival was not reached (95% confidence interval 24.6–not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Background Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. Methods Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. Results Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. Conclusion Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Objectives Immune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. Materials and methods This multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. Results The results of 22C3 and 28–8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87–0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11–0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. Conclusion Comprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non–small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation–positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.

Background A cisplatin plus irinotecan (CPT‐11) regimen is used for patients with extensive disease small cell lung cancer (ED‐SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open‐label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED‐SCLC who responded to induction therapy. Methods Patients with histologically‐ or cytologically‐confirmed ED‐SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT‐11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT‐11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1–3) every three weeks. Results A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT‐11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6–11.8), and the median overall survival was 20.1 months (95% CI: 13.7–not reached). No statistically significant difference in progression‐free survival (PFS) were noted between patients treated with CPT‐11 and those treated with AMR. There were no treatment‐related deaths in this study. Conclusions Maintenance therapy with CPT‐11 or AMR after induction therapy might be effective in some patients., There were some patients who achieved long disease control. Maintenance therapy with CPT‐11 or AMR after induction therapy could have potential for treating ED‐SCLC.