Publications by authors named "Takashi Seto"

205 Publications

Anti-PD-1 Monotherapy for Advanced NSCLC Patients with Older Age or Those with Poor Performance Status.

Onco Targets Ther 2021 17;14:1961-1968. Epub 2021 Mar 17.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Purpose: Anti-programmed death 1 (PD-1) antibodies have emerged as frontline treatments for patients with advanced non-small cell lung cancer (NSCLC) on the basis of global Phase III trials. However, current data regarding responses to anti-PD-1 therapy in older patients with NSCLC or those with poor performance status (PS) are limited. Therefore, we examined the therapeutic effect of anti PD-1 antibody in these patients.

Patients: We retrospectively examined consecutive patients treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) from January 2016 to September 2018.

Results: We enrolled 125 patients (median age, 60 years), 80.8% of whom were men. Patients aged ≥75 years were considered older patients (n = 15), and those with PS 2-3 were regarded as having poor PS (n = 11). The objective response and disease control rates were 15.4% and 46.2%, respectively, in older patients and 9.1% and 27.3%, respectively, in those with poor PS. Progression-free survival (PFS) and overall survival (OS) did not significantly differ between older and younger patients. However, poor PS was significantly associated with poor survival. High programmed death ligand 1 (PD-L1) expression in tumor specimens (≥50%) was associated with favorable survival in the entire cohort as well as patients with poor PS. Safety analyses demonstrated no significant difference in the occurrence of any adverse event, including grade ≥3 adverse events, between patients with poor PS or older age and the remaining patients.

Conclusion: Anti-PD-1 therapy had similar efficacy in older and younger patients with NSCLC, whereas survival was significantly worse in patients with poor PS. However, immune checkpoint inhibitors may be considered for patients with poor PS harboring positive PD-L1 expression.
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http://dx.doi.org/10.2147/OTT.S301500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982715PMC
March 2021

Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer.

Lung Cancer 2021 May 10;155:40-45. Epub 2021 Mar 10.

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

Objectives: The LURET phase II study evaluated the efficacy and safety of the multikinase inhibitor vandetanib in patients with previously treatedRET-rearranged advanced non-small cell lung cancer (NSCLC). Among the eligible patients included in the primary analysis, the objective response rate met the primary endpoint (53 %, 90 % confidence interval [CI]: 31-74). Here, we report final survival outcomes of the LURET study.

Materials And Methods: Nineteen patients with previously treated RET-rearranged advanced NSCLC continuously received 300 mg of oral vandetanib daily. This final analysis provides updated data on progression-free survival (PFS), overall survival (OS) and safety. This study was registered with UMIN-CTR (number UMIN 000010095).

Results: Among the 19 patients in the intention-to-treat population, 42 % had been heavily treated with 3 or more prior chemotherapy regimens. The median PFS was 6.5 months (95 % CI, 3.9-9.3) as determined by an independent radiology review committee. The median OS was 13.5 months (95 % CI, 9.8-28.1) and the overall survival rate at 12 months was 52.6 % (95 % CI 28.7-71.9). The most common adverse events were hypertension (84.2 %), diarrhea (78.9 %), and rash acneiform (63.2 %). Overall, 11 patients (57.9 %) had adverse events leading to a dose reduction, although the safety profile was consistent with that reported in previous studies.

Conclusion: Our results indicated that vandetanib enabled a prolonged and clinically meaningful PFS and OS in patients with previously treatedRET-rearranged advanced NSCLC at the updated final analysis. The safety profile was consistent with that reported in previous studies, although most of the patients experienced off-target adverse events besides RET.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.002DOI Listing
May 2021

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).

Transl Lung Cancer Res 2021 Jan;10(1):314-325

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: Rearranged during transfection () rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for.

Alk: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with.

Ret: rearranged NSCLC.

Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with -rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib.

Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2.

Conclusions: Alectinib exerts limited activity against -rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.
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http://dx.doi.org/10.21037/tlcr-20-549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867784PMC
January 2021

Dramatic intracranial response to tepotinib in a patient with lung adenocarcinoma harboring MET exon 14 skipping mutation.

Thorac Cancer 2021 03 3;12(6):978-980. Epub 2021 Feb 3.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Mesenchymal-epithelial transition (MET) pathway activation is associated with the mechanisms that influence properties affecting cancer cell survival and invasiveness. The MET exon 14 skipping mutation (METex14del) is found in 2%-3% of patients with non-small cell lung cancer (NSCLC). Previous studies reported that NSCLC patients harboring a METex14del responded well to MET-tyrosine kinase inhibitors (TKIs), including tepotinib. Tepotinib is a highly selective, once-daily oral MET inhibitor that has shown promising clinical activity in patients with NSCLC with METex14del. The Food and Drug Administration accepted a new drug application for tepotinib as a treatment for patients with metastatic NSCLC harboring METex14del in February 2021 [Correction added on 5 March 2021, after first online publication: the FDA approval date for tepotinib has been corrected from 'September 2019' to 'February 2021'.]. However, in the previous clinical trials involving MET-TKIs, only patients with stable central nervous system metastases were eligible, and those with untreated symptomatic brain metastases (BMs) were excluded. Therefore, the efficacy and safety of MET-TKIs in that population remains unknown. We herein report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. In the current report, the symptoms derived from multiple BMs (headache and loss of appetite) rapidly disappeared, and brain magnetic resonance imaging (MRI) examination showed that all the lesions were too small to measure only 23 days after the commencement of tepotinib. For NSCLC patients with multiple BMs, whole-brain irradiation is a standard-of-care therapy, but its adverse effects on neurocognition are concerning. Tepotinib might therefore be a therapeutic option for NSCLC patients with symptomatic multiple BMs harboring METex14del.
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http://dx.doi.org/10.1111/1759-7714.13871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952779PMC
March 2021

Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 Mar 26;22(2):134-141. Epub 2020 Dec 26.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

Background: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer.

Patients And Methods: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m; days 1 and 8, vinorelbine 20 mg/m). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period.

Results: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%.

Conclusion: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.cllc.2020.12.012DOI Listing
March 2021

Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study.

Cancer Sci 2021 Apr 24;112(4):1556-1566. Epub 2021 Feb 24.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan.

MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non-small-cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono-1, NCT02414139) in patients with advanced METΔex14-mutated/MET-amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14-mutated or MET-amplified) and line of therapy (first- [1L] or second-/third-line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14-mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%-69.2%), median DOR was not evaluable, and progression-free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET-amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment-related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET-amplified NSCLC, consistent with the overall population.
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http://dx.doi.org/10.1111/cas.14826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019204PMC
April 2021

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

Eur J Cancer 2021 Mar 22;145:183-193. Epub 2021 Jan 22.

Respiratory Division, Department of Internal Medicine, Itami City Hospital, 1-100 Koyaike, Itami City, Hyogo, 664-8540, Japan.

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.

Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.

Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).

Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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http://dx.doi.org/10.1016/j.ejca.2020.12.026DOI Listing
March 2021

Clinical course and prognosis of patients with lung cancer who develop anticancer therapy-related pneumonitis.

J Cancer Res Clin Oncol 2021 Jun 2;147(6):1857-1864. Epub 2021 Jan 2.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka, 811-1395, Japan.

Background: Pneumonitis can be triggered by anti-cancer therapies: cytotoxic chemotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors. There are few treatment options for patients who develop such pneumonitis and their treatment including chemotherapy is generally difficult thus would limit patient's prognosis. In this study, we investigated the clinical course of patients with lung cancer who developed anti-cancer therapy-related pneumonitis.

Patients And Methods: We retrospectively examined data of patients who had developed pneumonitis triggered by anti-cancer agents and required hospitalization from January 2014 to March 2019 and analyzed their subsequent clinical course and prognosis.

Results: The median age of the 58 study patients was 68 years and 82.8% were men. The median interval between first receiving the responsible agent and drug-induced pneumonitis was 7.4 weeks. Approximately 38% of patients were subsequently able to receive some anti-cancer therapy. The median post-pneumonitis overall survival (OS) from commencement of anti-cancer treatment was 13.2 months. No significant differences were found in survival time between treatment agents. However, patients who received some anticancer therapy after pneumonitis had significantly longer survival times than those did not (HR = 4.11, p = 0.0003) and patients who took longer to develop pneumonitis had a longer survival (HR = 2.28, p = 0.0148). Multivariate analysis revealed that short interval to onset and no post-pneumonitis anticancer therapy were independent predictors of short survival.

Conclusion: Although patients who developed pneumonitis had relatively short survival times, the interval between initial therapy and pneumonitis had survival impact. Survival can be prolonged by administering further cancer treatment after resolution of pneumonitis.
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http://dx.doi.org/10.1007/s00432-020-03478-2DOI Listing
June 2021

Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study.

Drugs R D 2021 Mar 17;21(1):65-78. Epub 2020 Dec 17.

Department of Medical Oncology, Kindai University, Faculty of Medicine, Osaka, Japan.

Background And Objective: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required.

Methods: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts.

Results: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group).

Conclusion: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.

Clinical Trial Registration: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.
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http://dx.doi.org/10.1007/s40268-020-00331-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937589PMC
March 2021

NTRK Fusion-positive Non-small-cell Lung Cancer: The Diagnosis and Targeted Therapy.

Clin Lung Cancer 2021 Jan 24;22(1):1-5. Epub 2020 Oct 24.

Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan. Electronic address:

In cases of non-small-cell lung cancer (NSCLC), molecular-targeted therapy has shown remarkable improvements in the survival and safety compared with conventional chemotherapy. Recently, the tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib were approved in the United States, Europe, and elsewhere for patients with a neurotrophic tropomyosin-related kinases (NTRK) gene fusion-positive solid tumors, including NSCLC. Furthermore, next-generation TRK inhibitors that are sensitive to certain secondary mutations mediating resistance to entrectinib or larotrectinib are also being tested in ongoing clinical trials. Although the prevalence of NTRK gene fusions among patients with NSCLC is only approximately 1%, the detection of NTRK gene fusions has become more important with the development of such TRK inhibitors. In the present review, we summarize the various diagnostic techniques for NTRK gene fusion and the effects of TRK inhibitors in NTRK fusion-positive NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.10.013DOI Listing
January 2021

Brigatinib in Japanese Patients With ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial.

J Thorac Oncol 2021 03 25;16(3):452-463. Epub 2020 Nov 25.

Internal Medicine III, Wakayama Medical University, Wakayama, Wakayama Prefecture, Japan. Electronic address:

Introduction: This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs).

Methods: This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)-assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%-49%) with median duration of response of 11.8 months (95% CI: 5.5-16.4). Disease control rate was 79% (95% CI: 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7-9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations.

Conclusions: Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).
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http://dx.doi.org/10.1016/j.jtho.2020.11.004DOI Listing
March 2021

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

Cancer Sci 2021 Jan 30;112(1):388-396. Epub 2020 Nov 30.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

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.
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http://dx.doi.org/10.1111/cas.14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780021PMC
January 2021

Identification of the Best Prognostic Marker Among Immunonutritional Parameters Using Serum C-Reactive Protein and Albumin in Non-Small Cell Lung Cancer.

Ann Surg Oncol 2021 Jun 21;28(6):3046-3054. Epub 2020 Oct 21.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Background: Three immune-nutritional parameters exist for malignant tumors using serum C-reactive protein (CRP) and albumin: the Glasgow prognostic score (GPS), the modified GPS (mGPS), and the CRP-albumin ratio (CAR). However, it remains unclear which of the three parameters is the most predictive of prognosis. Therefore, this study compared the clinical and prognostic significance of these parameters for non-small cell carcinoma (NSCLC).

Methods: The study retrospectively enrolled 596 NSCLC patients who underwent surgical resection at the authors' institution from January 2010 to December 2015 and investigated the clinicopathologic significance of GPS, mGPS, and CAR. The optimal cutoff value for CAR was determined by a receiver operating curve (ROC).

Results: The median age of the patients was 69 years. Lymph node metastases were identified in 99 patients, and 455 patients had a diagnosis of stage 1 disease. The positivity for GPS was 7.6%, and that of mGPS (score, 1 or 2) was 12.2%. Of the 596 patients, 480 patients (80.5%) were classified in the high CAR group. In univariate survival analyses, all three parameters were associated significantly with postoperative survival. The multivariate analyses showed CAR to be an independent prognostic factor. Additionally, survival analyses of the stage 1 subgroup were performed because CAR was higher for patients with an advanced stage of disease or lymph node metastases. In these subgroup analyses, CAR also was an independent prognostic factor.

Conclusion: As the most prognostic index, CAR may be useful among the immunonutritional parameters using CRP and albumin for resected NSCLC.
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http://dx.doi.org/10.1245/s10434-020-09230-xDOI Listing
June 2021

Cohesion between pulmonary artery and bronchus after immune checkpoint inhibitor therapy in a lung cancer patient.

Thorac Cancer 2020 12 16;11(12):3605-3608. Epub 2020 Oct 16.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Immunotherapy targeting programmed death-1 or programmed death-ligand 1 has become the standard of care for advanced non-small cell lung cancer (NSCLC). Several recent clinical trials have investigated the efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for early NSCLC. However, the safety and feasibility of pulmonary resection after ICIs remain unclear. We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant ICI combined with chemotherapy. After both central and peripheral sides of the left main pulmonary artery were clamped with the aim of controlling hemorrhage in case of vascular injury, the left main pulmonary artery and left upper bronchus were divided and individually cut with staplers. The thoracoscopic procedure was otherwise uneventful. The patient was discharged from our hospital with no postoperative complications. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively.
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http://dx.doi.org/10.1111/1759-7714.13697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705917PMC
December 2020

5-Hydroxytryptamine-3 receptor antagonist and dexamethasone as prophylaxis for chemotherapy-induced nausea and vomiting during moderately emetic chemotherapy for solid tumors: a multicenter, prospective, observational study.

BMC Pharmacol Toxicol 2020 10 6;21(1):72. Epub 2020 Oct 6.

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan.

Background: Of patients receiving moderate emetic risk chemotherapy (MEC), 30-90% experience chemotherapy-induced nausea and vomiting (CINV); however, the optimal antiemetic treatment remains controversial.

Methods: In this multicenter, prospective, observational study of adults treated with MEC while receiving chemotherapy for various cancer types in Japan, the enrolled patients kept diaries documenting CINV. All participants received a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone.

Results: Of the 400 patients enrolled from May 2013 to January 2015, 386 were eligible for evaluation. The median age was 64 (range, 26-84). The overall complete response (CR; no emetic events and no antiemetic measures) rate was 64%. The proportion of patients showing CR was low in the carboplatin (CBDCA)- and oxaliplatin-based chemotherapy groups, especially among women. We showed that the CR rates in men were high in the CBDCA (AUC5) + etoposide (ETP) (80%), capecitabine plus oxaliplatin (CAPOX) (78%), and CBDCA+ paclitaxel (PTX) groups for lung cancer (73%). Total control (TC; no emetic events, no antiemetic measures, and no nausea) and complete control (CC; no emetic events, no antiemetic measures, and less than mild nausea) were achieved in 51 and 61% of patients, respectively. Logistic regression analysis revealed history of motion sickness, history of pregnancy-associated vomiting and CBDCA-based chemotherapy as risk factors for CR and history of motion sickness and history of pregnancy-associated vomiting as risk factors for TC. Additional, Ages ≥65 years is an independent predictive factor for achieving TC.

Conclusions: Our data showed that two antiemetics were insufficient to control CINV in patients receiving CBDCA- or oxaliplatin-based chemotherapy. However, two antiemetics may be sufficiently effective for elderly male patients receiving CBDCA (AUC5) + ETP, CBDCA+PTX for lung cancer, or CAPOX. Additionally, we consider that three antiemetics are necessary for women with colorectal cancer receiving CAPOX. Risk factor analysis related to CR showed that CINV prophylaxis in patients treated with CBDCA-based chemotherapy was generally supportive of the guideline-recommended three antiemetics. However, the control of nausea in patients receiving non-CBDCA-based chemotherapy is a key point to note. The further individualization of antiemetic regimens for patients receiving MEC based on both types of chemotherapy regimens and sex is needed.
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http://dx.doi.org/10.1186/s40360-020-00445-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539512PMC
October 2020

Ramucirumab or placebo plus erlotinib in EGFR-mutated, metastatic non-small-cell lung cancer: East Asian subset of RELAY.

Cancer Sci 2020 Dec 14;111(12):4510-4525. Epub 2020 Oct 14.

Kindai University Faculty of Medicine, Osaka, Japan.

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.
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http://dx.doi.org/10.1111/cas.14655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734014PMC
December 2020

Capmatinib in Exon 14-Mutated or -Amplified Non-Small-Cell Lung Cancer.

N Engl J Med 2020 09;383(10):944-957

From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.

Background: Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.

Methods: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.

Results: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.

Conclusions: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
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http://dx.doi.org/10.1056/NEJMoa2002787DOI Listing
September 2020

Efficacy of Selpercatinib in Fusion-Positive Non-Small-Cell Lung Cancer.

N Engl J Med 2020 08;383(9):813-824

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D., E.R.) and New York University Langone Medical Center (V.V.), New York, and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) - all in New York; Dana-Farber Cancer Institute (G.R.O.) and Massachusetts General Hospital (J.G.), Boston; National Cancer Centre Singapore, Singapore (D.S.W.T.); the Chinese University of Hong Kong, Hong Kong, China (H.H.F.L.); Sarah Cannon Research Institute, Nashville (M.J.); University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (C.E.M.), University of California, San Diego, Moores Cancer Center, La Jolla (L.B.), and City of Hope Comprehensive Cancer Center, Duarte (K.L.R.) - all in California; University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); Institut Gustave Roussy, Villejuif (B.B.), Hospital La Timone, Marseille (F.B.), and Centre Léon Bérard, Lyon (P.A.C.) - all in France; Severance Hospital, Yonsei University Health System (B.C.C.), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), Seoul, and Seoul National University Bundang Hospital, Seongnam (Y.J.K.) - all in South Korea; Soroka University Medical Center, Beer-Sheva, Israel (N.P.); University of North Carolina-Chapel Hill, Chapel Hill (J. Weiss); National Cancer Center Hospital (Y.O.) and Cancer Institute Hospital of the Japanese Foundation for Cancer Research (M. Nishio), Tokyo, National Hospital Organization Kyushu Cancer Center, Fukuoka (T. Seto), Tottori University Hospital, Tottori (T. Sakamoto), Hyogo Cancer Center, Akashi (M.S.), Okayama University Hospital, Okayama (K.O.), and National Cancer Center Hospital East, Chiba (K.G.) - all in Japan; University of Chicago, Chicago (J.P.); the Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.), and Cleveland Clinic, Cleveland (N.A.P.); Istituto Nazionale Tumori-National Cancer Institute, Università degli Studi di Milano, Milan (F.D.B.); Vall d'Hebron Institute of Oncology, Hospital Universitario Vall d'Hebron, Barcelona (E.G.); Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany (J. Wolf); Peter MacCallum Cancer Institute, Melbourne, VIC, Australia (B.S.); Sarah Cannon Research Institute at HealthONE, Denver (G.F.); Loxo Oncology, Stamford, CT (K.E., M. Nguyen, B.N., E.Y.Z., L.Y., X.H., E.O., S.M.R.); and the University of Texas M.D. Anderson Cancer Center, Houston (V.S.).

Background: fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with advanced fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 105 consecutively enrolled patients with fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.

Conclusions: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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http://dx.doi.org/10.1056/NEJMoa2005653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506467PMC
August 2020

Lorlatinib in previously treated anaplastic lymphoma kinase-rearranged non-small cell lung cancer: Japanese subgroup analysis of a global study.

Cancer Sci 2020 Oct 11;111(10):3726-3738. Epub 2020 Sep 11.

The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
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http://dx.doi.org/10.1111/cas.14576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540988PMC
October 2020

Prognostic Impact of Smoking Period in Patients with Surgically Resected Non-small Cell Lung Cancer.

Ann Surg Oncol 2021 Feb 16;28(2):685-694. Epub 2020 Jul 16.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The pack-year index, which is calculated by multiplying a smoking period by the number of cigarette packs smoked per day, is frequently used to investigate the risk of developing lung cancer. Notably, however, whether the smoking period or the number of packs per day is more predictive of postoperative prognosis remains unclear in non-small cell lung cancer (NSCLC) patients who receive curative lung resection.

Patients And Methods: Initial screening included 2055 consecutive lung cancer patients who had underwent curative lung resection between 2000 and 2016 at a single center in Japan. Data from 1134 NSCLC patients with smoking history were ultimately analyzed. Time-dependent areas under the curve (AUCs) were used to compare diagnostic accuracy.

Results: On univariate analysis, the number of packs smoked per day was not a significant predictor of disease-free survival (DFS; p = 0.2387) or overall survival (OS; p = 0.1357). On multivariable analysis, smoking period was an independent predictor of DFS and OS (both p < 0.0001). Time-dependent smoking period AUCs were superior to those of number of packs smoked per day. On subgroup analyses, patients with a smoking period ≥ 40 years had significantly shorter DFS and OS than those with a smoking period of < 40 years, independent of sex, clinical stage, and histological type.

Conclusions: Smoking period was a significant prognostic indicator in NSCLC patients who underwent curative lung resection, which should be validated in further prospective and/or multicenter studies with large sample sizes.
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http://dx.doi.org/10.1245/s10434-020-08851-6DOI Listing
February 2021

Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101).

Oncologist 2020 12 11;25(12):e1869-e1878. Epub 2020 Aug 11.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Lessons Learned: This phase II trial evaluated the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. The 17 cerebrospinal fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation. The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%-54.3%). The median time to progression was 2.2 months. The rate of cerebrospinal fluid penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis.

Background: Leptomeningeal metastases (LM) occur in approximately 5% of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting.

Methods: Patients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%).

Results: Between December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 cerebrospinal fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%-54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean cerebrospinal fluid penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and cerebrospinal fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome.

Conclusion: Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM.
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http://dx.doi.org/10.1634/theoncologist.2020-0640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108053PMC
December 2020

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 09 26;26(18):4785-4794. Epub 2020 Jun 26.

Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, California.

Purpose: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib.

Patients And Methods: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring / rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.

Results: A total of 46 patients were enrolled. Steady-state peak concentration () and exposure (AUC) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory NSCLC. One patient with differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive L2086F as an acquired taletrectinib-resistance mutation.

Conclusions: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1630DOI Listing
September 2020

Histological conversion from adenocarcinoma to small cell carcinoma of the lung after treatment with an immune checkpoint inhibitor: a case report.

Oxf Med Case Reports 2020 Apr 23;2020(4):omaa026. Epub 2020 May 23.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Japan.

The transformation of adenocarcinoma to small cell lung cancer has been reported as acquisition of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. We here report a patient who presented histologically confirmed transformation of adenocarcinoma to small cell lung cancer after treatment with immune checkpoint inhibitor. A 65-year-old man was treated with pembrolizumab as first-line therapy and achieved temporarily a stable disease with progression after six cycles of this agent. At that stage, a transbronchial biopsy showed small cell lung cancer, and he was found to have high serum concentrations of neuron-specific enolase despite concentrations of numerous tumor markers, including neuron-specific enolase, having been within normal limits at the time of presentation. The patient thereafter was treated as a small cell carcinoma patient using cisplatin plus irinotecan and amrubicin.
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http://dx.doi.org/10.1093/omcr/omaa026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243716PMC
April 2020

Brain cavernous hemangioma mimicking radiation-induced necrosis in a patient with non-small cell lung cancer.

Thorac Cancer 2020 07 29;11(7):2056-2058. Epub 2020 May 29.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

In patients with non-small cell lung cancer (NSCLC), stereotactic radiotherapy (SRT) is one of the standard therapies for those suffering with intracranial metastatic NSCLC. Radiation-induced necrosis (RIN) sometimes occurs as the result of the delayed effects of SRT. The magnetic resonance imaging (MRI) of RIN typically shows hypointense and hyperintense lesions on T1- and T2-weighted images, respectively. We herein report a patient with a growing brain cystic lesion mimicking RIN adjacent to a post-radiation brain metastasis from NSCLC harboring anaplastic lymphoma kinase rearrangement. The patient underwent surgical resection of the brain tumor because of the symptoms. The pathological diagnosis was cavernous hemangioma, and the pathological findings were an encapsulated nodular mass composed of dilated, cavernous vascular spaces with no residual tumor or recurrence. Clinicians should be aware of the possibility for the development of a brain cavernous hemangioma following SRT in NSCLC patients.
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http://dx.doi.org/10.1111/1759-7714.13494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327904PMC
July 2020

Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2020 07 14;38(19):2187-2196. Epub 2020 May 14.

Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Purpose: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC).

Patients And Methods: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m, day 1) plus cisplatin (75 mg/m, day 1) or vinorelbine (25 mg/m, days 1 and 8) plus cisplatin (80 mg/m, day 1) with stratification by sex, age, pathologic stage, mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients.

Result: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had -sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% 0.3%, respectively), neutropenia (81.1% 22.7%, respectively), and anemia (9.3% 2.8%, respectively). One treatment-related death occurred in each arm.

Conclusion: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
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http://dx.doi.org/10.1200/JCO.19.02674DOI Listing
July 2020

The impact of immune-inflammation-nutritional parameters on the prognosis of non-small cell lung cancer patients treated with atezolizumab.

J Thorac Dis 2020 Apr;12(4):1520-1528

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Background: Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has become the forefront strategy for systemic therapy in advanced non-small cell lung cancer (NSCLC) patients. PD-L1 expression on tumor cells has been reported as an eligible biomarker of response to such immunotherapies. However, useful biomarkers of response to atezolizumab, an anti PD-L1 antibody, are unestablished.

Methods: We retrospectively analyzed clinicopathological characteristics including PD-L1 expression in NSCLC patients treated with atezolizumab from January 2018 at our department. In addition, we investigated the prognostic effect of the following pretreatment immune-inflammation-nutritional parameters: prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS).

Results: Twenty-four patients were enrolled in this study. The median age was 64.5 (range, 49-82) years, and 17 (70.8%) were men. Among this cohort, two patients showed high PD-L1 expression (≥50%), seven showed low (1-49%) expression, and the other 15 patients showed 0% or unknown expression. Survival analyses showed that low PNI was an independent predictor of short time to treatment failure (TTF) [hazard ratio (HR) =6.87, P=0.0052], and high NLR (HR =3.53, P=0.0375) and high mGPS (HR =23.2, P=0.0038) were independent prognostic factors for overall survival (OS) after atezolizumab. Furthermore, the NLR high/mGPS high group had far worse prognosis than the NLR low/mGPS low group.

Conclusions: The therapeutic and prognostic effect of atezolizumab may depend on the host immune-nutritional status. This study provided novel but retrospective evidence, and thus further prospective studies are needed.
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http://dx.doi.org/10.21037/jtd.2020.02.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212122PMC
April 2020

Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 10;21(5):472-476. Epub 2020 Apr 10.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Background: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC.

Patients And Methods: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival.

Conclusion: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.03.010DOI Listing
September 2020

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

Lung Cancer 2020 06 10;144:10-19. Epub 2020 Mar 10.

University of Colorado, Aurora, CO, USA. Electronic address:

Objectives: To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily.

Materials And Methods: PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM).

Results: 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %).

Conclusions: Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.011DOI Listing
June 2020

Surgically Resected Second Primary Lung Adenocarcinoma After Pembrolizumab Administration.

Ann Thorac Surg 2020 11 24;110(5):e377-e379. Epub 2020 Apr 24.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. Electronic address:

Non-small cell lung cancer (NSCLC) patients are sometimes referred for thoracic surgical consultation to address the possibility of resecting second primary lung cancer. We report a case of pulmonary resection for second primary lung adenocarcinoma after 3 cycles of pembrolizumab under circumstances in which the primary metastatic lung adenocarcinoma was controlled. The tumor statuses, including programmed death-ligand 1, epidermal growth factor receptor, and CD8+ tumor-infiltrating lymphocytes, were different between the surgically resected specimen and the previously biopsied sample. Surgery should be considered for second primary NSCLC in cases in which the primary NSCLC are well controlled with immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.athoracsur.2020.03.059DOI Listing
November 2020

Phase II, open-label, multicenter trial of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study.

Trials 2020 Mar 30;21(1):298. Epub 2020 Mar 30.

Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.

Background: MET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations.

Methods: Co-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients.

Discussion: The results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer.

Trial Registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.
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http://dx.doi.org/10.1186/s13063-020-4221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104510PMC
March 2020