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Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17–0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3–not estimated) and was 10·2 months (8·2–12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. Chugai Pharmaceutical Co, Ltd.

ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Analysis of cell‐free DNA (cfDNA) provides a noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion‐positive NSCLC. The results of cfRNA‐based assays were compared with tissue biopsy and cfDNA‐based liquid biopsy (Guardant360 plasma next‐generation sequencing [NGS] assay). The overall sensitivity of the cfRNA‐based assay was 26.7% (8/30) and that of cfDNA‐based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo‐naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA‐based assay was 77.8% (7/9) and that of cfDNA‐based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first‐line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second‐line treatments. cfRNA‐ and cfDNA‐based assays are evaluated in 20 cases of fusion‐positive NSCLC. cfRNA assay was superior to cfDNA assay for the detection of gene fusions. The results of the cfRNA assay were consistent with the therapeutic effect.

The efficacy of gefitinib for patients with non‐adenocarcinoma non‐small‐cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non‐adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non‐adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty‐seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large‐cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty‐one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression‐free survival (mPFS) was 27%, 67–70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non‐adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67–70%vs 92–93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non‐adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. (Cancer Sci 2011; 102: 1032–1037)

This study provides the benchmark statistics on medically treated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy‐based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3‐year survival rates of 62.9%, 47.3%, 40.0%, 27.8%, 37.5%, 26.5%, and 18.2% for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV, respectively. Among 6158 patients with NSCLC treated with chemotherapy, the 3‐year survival rate was 33.4% in patients receiving epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) at some point in their clinical course, whereas it was 17.4% in patients who did not. The 3‐year survival rate of SCLC was only 15.9%. In conclusion, approximately two‐thirds of the patients were diagnosed as stage IV at the initial diagnosis. Use of EGFR‐TKIs significantly improved the survival of patients with NSCLC. This study provides the benchmark statistics on medically treated patients with lung cancer in Japan. Here, 3‐year survival rates of patients treated with concurrent chemoradiotherapy (n = 1689), sequential chemoradiotherapy (n = 221), thoracic radiotherapy alone (n = 662), chemotherapy alone (n = 7790) and palliative care alone (n = 1952) were 43.6%, 29.1%, 40.0%, 19.9%, and 0.3.4%, respectively.

Alectinib, an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is the recommended first‐line treatment for ALK‐positive non‐small‐cell lung cancer (NSCLC) in Japan. Lorlatinib was approved as a subsequent therapeutic option after progression while receiving ALK TKI treatment. However, data on the use of lorlatinib in the second‐ or third‐line setting after alectinib failure are limited in Japanese patients. This retrospective real‐world observational study investigated the clinical effectiveness of lorlatinib in second‐ or later‐line settings after alectinib failure in Japanese patients. Clinical and demographic data collected in the Japan Medical Data Vision (MDV) database between December 2015 and March 2021 were used. Patients diagnosed with lung cancer who received lorlatinib following alectinib failure after the November 2018 marketing approval of lorlatinib in Japan were included. Of 1954 patients treated with alectinib, 221 were identified from the MDV database as receiving lorlatinib after November 2018. The median age of these patients was 62 years. Second‐line lorlatinib treatment was reported for 154 patients (70%); third‐ or later‐line lorlatinib treatment was reported for 67 patients (30%). The median duration of treatment (DOT) for all lorlatinib‐treated patients was 161 days (95% confidence interval [CI], 126–248), and 83 patients (37.6%) continued treatment after data cut‐off (March 31, 2021). Median DOTs of 147 days (95% CI, 113–242) and 244 days (95% CI, 109 to not reached) were reported with second‐line and third‐ or later‐line treatment, respectively. Consistent with clinical trial data, this real‐world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients. Of 1954 patients treated with alectinib, 221 were identified from the Japan Medical Data Vision database as receiving lorlatinib; 70% received lorlatinib as a second‐line therapy and 30% received lorlatinib as a third‐ or later‐line therapy. The median duration of treatment for all lorlatinib‐treated patients was 161 days. This real‐world observational study supports data suggesting the effectiveness of lorlatinib after alectinib failure in Japanese patients with ALK‐positive non‐small‐cell lung cancer.

Background Cancer cachexia is a syndrome that does not fully recover with nutritional support and causes appetite loss and body weight loss. It worsens a patient's quality of life and prognosis. In this study, the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy response rate and prognosis were examined using the national database of the Japan Lung Cancer Society. Understanding these things related to cancer cachexia is important as a starting point in overcoming cancer cachexia in patients with lung cancer. Methods In 2012, 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (Japanese Lung Cancer Registry Study). Of these, data on body weight loss within 6 months were available for 8489 patients. We defined the patients with body weight loss ≥ 5% within 6 months, which is one of the three criteria listed in the 2011 international consensus definition of cancer cachexia, as cachectic in this study. Results Approximately 20.4% of the 8489 patients had cancer cachexia. Sex, age, smoking history, emphysema, performance status, superior vena cava syndrome, clinical stage, site of metastasis, histology, epidermal growth factor receptor (EGFR) mutation status, primary treatment method and serum albumin levels were significantly different between patients with and without cachexia. Logistic analyses showed that smoking history, emphysema, clinical stage, site of metastasis, histology, EGFR mutation, serum calcium and albumin levels were significantly associated with cancer cachexia. The response to initial therapy, including chemotherapy, chemoradiotherapy or radiotherapy, was significantly poorer in the patients with cachexia than in those without cachexia (response rate: 49.7% vs. 41.5%, P < 0.001). Overall survival was significantly shorter in the patients with cachexia than in those without cachexia in both univariate and multivariable analyses (1‐year survival rate: 60.7% vs. 37.6%, Cox proportional hazards model, hazard ratio: 1.369, 95% confidence interval: 1.274–1.470, P < 0.001). Conclusions Cancer cachexia was seen in approximately one fifth of the lung cancer patients and was related to some baseline patient characteristics. It was also associated with a poor response to initial treatment, resulting in poor prognosis. The results of our study may be useful for early identification and intervention in patients with cachexia, which may improve their response to treatment and their prognosis.

Background The prognosis of patients with NSCLC harboring oncogenic driver gene alterations, such as EGFR gene mutations or ALK fusion, has improved dramatically with the advent of corresponding molecularly targeted drugs. As patients were followed up for about five years in most clinical trials, the long-term outcomes beyond 5 years are unclear. The objectives of this study are to explore the clinical course beyond five years of chemotherapy initiation and to investigate factors that lead to long-term survival. Methods One hundred and seventy-seven patients with advanced, EGFR -mutated or ALK -rearranged NSCLC who received their first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and according to subgroups of patients’ characteristics. Results Median OS in the total cohort was 40.6 months, the one-year survival rate was 89%, the three-year survival rate was 54%, and the five-year survival rate was 28%. Median OS was 36.9 months in EGFR -mutated patients and 55.4 months in ALK -rearranged patients. The OS curve seemed to plateau after 72 months, and most of the patients who were still alive after more than five years are on treatment. Female sex, age under 75 years, an ECOG PS of 0 to 1, ALK rearrangement, postoperative recurrence, and presence of brain metastasis were significantly associated with longer OS. Conclusions A tail plateau was found in the survival curves of patients with advanced, EGFR -mutated and ALK -rearranged NSCLC, but most were on treatment, especially with EGFR -mutated NSCLC.

Despite the poor prognosis of advanced or recurrent thymic carcinoma, the rarity of thymic carcinoma has delayed the development and introduction of novel pharmacotherapy options. Carboplatin plus paclitaxel remains a standard treatment for chemotherapy-naive advanced or recurrent thymic carcinoma. We evaluated the activity and safety of atezolizumab combined with chemotherapy. In this multicentre, single-arm, phase 2 trial in 15 hospitals in Japan, patients with metastatic or recurrent thymic carcinoma were treated with atezolizumab plus carboplatin and paclitaxel. Eligible patients were aged 20 years or older with histologically confirmed Masaoka stage III, IVA, or IVB thymic carcinoma not amenable for definitive treatment or recurrent thymic carcinoma after definitive treatment; and no previous history of systemic drug therapy for thymic carcinoma. The data of sex and race were defined via self-report. Patients received atezolizumab 1200 mg, carboplatin area under the curve 6 mg/mL per min, and paclitaxel 200 mg/m2 intravenously every 3 weeks for up to six cycles, followed by atezolizumab 1200 mg intravenously every 3 weeks for up to 2 years until progression or unacceptable toxicity. The primary endpoint was objective response rate, based on an independent central review. The primary endpoint and safety were assessed in the per-protocol set. This trial was registered at Japan Registry of Clinical Trials, jRCT2031220144, and is closed to enrolment. Between June 14, 2022, and July 6, 2023, 48 patients were enrolled and included in the efficacy and safety analyses. Median follow-up was 15·3 months (IQR 13·8–16·6). 29 (60%) patients were male and 19 (40%) of 48 patients were female. Median age of patients was 67·5 years (IQR 56·5–72·5). All patients were Asian. The objective response rate was 56% (95% CI 41–71; Fisher's exact test p<0·0001); 27 (56%) of 48 participants had a partial response. The most common adverse reactions of grade 3 or worse were neutropenia (27 [56%] of 48 patients), leukopenia (16 [33%]), febrile neutropenia (11 [23%]), and maculopapular rash (six [13%]). There were no treatment-related deaths and eight deaths overall. In previously untreated advanced thymic carcinoma, the addition of atezolizumab to carboplatin and paclitaxel conferred clinically meaningful antitumour activity with a manageable safety profile. Thus, atezolizumab plus carboplatin and paclitaxel might become a viable treatment option for previously untreated advanced or recurrent thymic carcinoma. Chugai Pharmaceutical. For the Japanese translation of the abstract see Supplementary Materials section.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown clinical activity for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the development of resistance to EGFR-TKIs is almost inevitable, posing a significant barrier to long-term survival. Local ablative therapy (LAT) may facilitate the prolonged survival of patients with oligometastatic NSCLC. Therapeutic combinations of EGFR-TKIs and LAT for residual disease have been suggested to be potentially effective in EGFR-mutated NSCLC with induced oligometastatic disease, wherein a few lesions remain following initial EGFR-TKI treatment. Various resistance pathways for third-generation EGFR-TKIs including osimertinib, current standard of care for patients with EGFR-mutated NSCLC, have also been identified. In addition to resistance mechanisms, the disease-progression pattern may be an essential element for achieving long-term response and survival. Oligo-progressive disease is a state in which only a few lesions become resistant, whereas many lesions remain controlled with effective systemic therapy. Previous studies have shown that LAT for all oligo-progressive lesions could provide survival benefits. This review discusses the current treatment options and potential future therapeutic developments for patients with EGFR-mutated NSCLC who have synchronous oligometastatic disease, oligo-residual disease during treatment with EGFR-TKIs, and oligo-progressive disease following resistance to EGFR-TKIs.

Epithelial cell adhesion molecule (EpCAM)-based enumeration of circulating tumor cells (CTC) has prognostic value in patients with solid tumors, such as advanced breast, colon, and prostate cancer. However, poor sensitivity has been reported for non-small cell lung cancer (NSCLC). To address this problem, we developed a microcavity array (MCA) system integrated with a miniaturized device for CTC isolation without relying on EpCAM expression. Here, we report the results of a clinical study on CTCs of advanced lung cancer patients in which we compared the MCA system with the CellSearch system, which employs the conventional EpCAM-based method. Paired peripheral blood samples were collected from 43 metastatic lung cancer patients to enumerate CTCs using the CellSearch system according to the manufacturer's protocol and the MCA system by immunolabeling and cytomorphological analysis. The presence of CTCs was assessed blindly and independently by both systems. CTCs were detected in 17 of 22 NSCLC patients using the MCA system versus 7 of 22 patients using the CellSearch system. On the other hand, CTCs were detected in 20 of 21 small cell lung cancer (SCLC) patients using the MCA system versus 12 of 21 patients using the CellSearch system. Significantly more CTCs in NSCLC patients were detected by the MCA system (median 13, range 0-291 cells/7.5 mL) than by the CellSearch system (median 0, range 0-37 cells/7.5 ml) demonstrating statistical superiority (p = 0.0015). Statistical significance was not reached in SCLC though the trend favoring the MCA system over the CellSearch system was observed (p = 0.2888). The MCA system also isolated CTC clusters from patients who had been identified as CTC negative using the CellSearch system. The MCA system has a potential to isolate significantly more CTCs and CTC clusters in advanced lung cancer patients compared to the CellSearch system.