Publications by authors named "Kazumi Nishino"

77 Publications

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors.

Cancer Genet 2021 Aug 28;256-257:131-135. Epub 2021 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.010DOI Listing
August 2021

Atezolizumab with bevacizumab, paclitaxel and carboplatin was effective for patients with SMARCA4-deficient thoracic sarcoma.

Immunotherapy 2021 Jul 25;13(10):799-806. Epub 2021 May 25.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

SMARCA4-deficient thoracic sarcoma (DTS) is a recently noted progressive thoracic malignancy. We recently experienced three cases of SMARCA4-DTS who were treated with atezolizumab in combination with bevacizumab, paclitaxel and carboplatin (ABCP) as the first-line therapy. Immunohistopathological analysis revealed absent expression of SMARCA4 in all cases. The tumor mutational burden was over 11/Mb and mutations in and were detected in all three cases. Partial response to ABCP treatment was observed in all three cases, with a progression-free survival of approximately 6 months or longer and a continuous response of 1 year or longer in one case. The first-line ABCP treatment demonstrated durable efficacy in SMARCA4-DTS regardless of the degree of PD-L1 expression.
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http://dx.doi.org/10.2217/imt-2020-0311DOI Listing
July 2021

The ratio of T790M to EGFR-activating mutation predicts response of osimertinib in 1st or 2nd generation EGFR-TKI-refractory NSCLC.

Sci Rep 2021 May 5;11(1):9629. Epub 2021 May 5.

Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino 3-7-1, Habikino City, Osaka, 583-8588, Japan.

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.
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http://dx.doi.org/10.1038/s41598-021-89006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099906PMC
May 2021

Late recurrence of lung adenocarcinoma harboring EGFR exon 20 insertion (A763_Y764insFQEA) mutation successfully treated with osimertinib.

Cancer Genet 2021 Aug 10;256-257:57-61. Epub 2021 Apr 10.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka 541-8567, Osaka, Japan.

The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.001DOI Listing
August 2021

A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with mutation (West Japan Oncology Group 11719L/ADJUST study).

Ther Adv Med Oncol 2021 21;13:1758835920987647. Epub 2021 Jan 21.

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

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with mutated NSCLC.

Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with mutation. Accrued patients will be pathological stage II-IIIA with completely resected NSCLC and whose tumors have mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study.

Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
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http://dx.doi.org/10.1177/1758835920987647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841658PMC
January 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

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Mar;7(3):386-394

Internal Medicine III, Wakayama Medical University, Wakayama, Japan.

Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically.

Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation.

Design, Setting, And Participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio.

Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety.

Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%).

Conclusions And Relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.
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http://dx.doi.org/10.1001/jamaoncol.2020.6758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791398PMC
March 2021

Proteasome Inhibition Overcomes ALK-TKI Resistance in -Rearranged/-Mutant NSCLC via Noxa Expression.

Clin Cancer Res 2021 Mar 11;27(5):1410-1420. Epub 2020 Dec 11.

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

Purpose: In -rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms.

Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). -rearranged NSCLC cell lines expressing wild-type or mutant were used to evaluate cellular apoptosis induced by ALK-TKIs.

Results: In 90 patients with -rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, comutated patients showed significantly worse progression-free survival (PFS) than wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. -rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from -rearranged NSCLC cells with nonfunctional p53.

Conclusions: These clinical and preclinical results indicate concomitant mutations reduce the efficacy of alectinib for -rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for -rearranged/-mutated NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2853DOI Listing
March 2021

Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy.

Anticancer Res 2020 Dec 7;40(12):6957-6970. Epub 2020 Dec 7.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients.

Patients And Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC.

Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group.

Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
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http://dx.doi.org/10.21873/anticanres.14720DOI Listing
December 2020

Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction.

Lung Cancer 2021 03 16;153:186-192. Epub 2020 Nov 16.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Introduction: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib.

Methods: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration.

Results: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022).

Conclusions: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.021DOI Listing
March 2021

Effectiveness of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients with uncommon EGFR mutations: A multicenter observational study.

Thorac Cancer 2021 01 29;12(1):90-96. Epub 2020 Oct 29.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard treatment for advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations, such as exon 19 deletion or L858 point mutation. However, the effectiveness of EGFR-TKIs for patients with uncommon EGFR mutations remains unclear.

Methods: We retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at five participating institutions. Data from NSCLC patients with uncommon mutations (including single or compound mutations), who were treated with systemic therapy between May 2016 and October 2018, were collected and analyzed.

Results: A total of 23 of the 524 patients whose data were collected had uncommon EGFR mutations. Of these, 22 received EGFR-TKIs (gefitinib = 6, erlotinib = 4, and afatinib = 12). Patients who received first EGFR-TKIs had overall response and disease control rates of 59.1% and 81.8%, respectively. The median progression-free survival (PFS) of patients with G719X mutation (n = 13, median PFS = 32.9 months) was favorable, compared with those of patients with L861Q mutation (n = 4, median PFS = 6.4 months) and compound mutations (n = 4, median PFS = 7.3 months). The PFS of patients who received first- and second-generation EGFR-TKIs was 14.0 months (n = 10) and 7.3 months (n = 12), respectively. The median cumulative duration of treatment (DOT) with EGFR-TKIs was 30.4 months, which was longer than those of cytotoxic chemotherapy (median DOT = 10.7 months) or immune checkpoint inhibitors (median DOT = 6.6 months).

Conclusions: EGFR-TKIs elicit favorable responses and contribute to long-term disease control in NSCLC patients with uncommon EGFR mutations.

Key Points: Significant findings of the study: Our results demonstrate that both first- and second-generation EGFR-TKIs elicit favorable responses in NSCLC patients with uncommon EGFR mutations. What this study adds This study revealed all clinical courses for NSCLC patients with uncommon EGFR mutations. In addition to EGFR-TKIs, CCT and ICIs were found to contribute to long-term disease control in this cohort.
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http://dx.doi.org/10.1111/1759-7714.13718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779206PMC
January 2021

Dermatopathic Lymphadenopathy Mimicking Disease Progression During Osimertinib Treatment.

J Thorac Oncol 2020 10;15(10):e178-e180

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

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http://dx.doi.org/10.1016/j.jtho.2020.07.015DOI Listing
October 2020

Multiplex gene-panel testing for lung cancer patients.

Pathol Int 2020 Dec 21;70(12):921-931. Epub 2020 Sep 21.

Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.
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http://dx.doi.org/10.1111/pin.13023DOI Listing
December 2020

Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512).

Support Care Cancer 2021 May 11;29(5):2327-2334. Epub 2020 Sep 11.

Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan.

Purpose: This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial.

Methods: Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks.

Results: Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks.

Conclusion: In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence.

Trial Registration: UMIN000024113.
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http://dx.doi.org/10.1007/s00520-020-05765-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981297PMC
May 2021

Multiregional sequence revealed SMARCA4 R1192C mutant clones acquired EGFR C797S mutation in the metastatic site of an EGFR-mutated NSCLC patient.

Lung Cancer 2020 10 3;148:28-32. Epub 2020 Aug 3.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Objectives: Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR-mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment.

Materials And Methods: We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site.

Results: MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation.

Conclusion: MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.035DOI Listing
October 2020

A Multivariable Regression Model-based Nomogram for Estimating the Overall Survival of Patients Previously Treated With Nivolumab for Advanced Non-small-cell Lung Cancer.

Anticancer Res 2020 Aug;40(8):4229-4236

Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Aim: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms.

Patients And Methods: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS.

Results: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab.

Conclusion: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.
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http://dx.doi.org/10.21873/anticanres.14424DOI Listing
August 2020

The impact of EGFR mutation status and single brain metastasis on the survival of non-small-cell lung cancer patients with brain metastases.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa064. Epub 2020 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC.

Methods: This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured.

Results: Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients.

Conclusions: Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.
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http://dx.doi.org/10.1093/noajnl/vdaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284117PMC
May 2020

Successful treatment of an osimertinib-resistant lung adenocarcinoma with an exon 18 EGFR mutation (G719S) with afatinib plus bevacizumab.

Invest New Drugs 2021 Feb 18;39(1):232-236. Epub 2020 Jun 18.

Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Otemae 3-1-69, Chuo-ku, Osaka City, Osaka, 541-8567, Japan.

Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.
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http://dx.doi.org/10.1007/s10637-020-00966-7DOI Listing
February 2021

Improvement strategies for successful next-generation sequencing analysis of lung cancer.

Future Oncol 2020 Aug 3;16(22):1597-1606. Epub 2020 Jun 3.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, 541-8567, Japan.

We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.
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http://dx.doi.org/10.2217/fon-2020-0332DOI Listing
August 2020

Genome analysis of peeling archival cytology samples detects driver mutations in lung cancer.

Cancer Med 2020 07 29;9(13):4501-4511. Epub 2020 Apr 29.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

Introductions: When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin-fixed paraffin-embedded (FFPE) tumor samples.

Patients And Methods: Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole-exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR-TKI.

Results: A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy-seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR-TKI-resistant mutation (EGFR p.T790M) during the course of treatment.

Conclusion: Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations.
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http://dx.doi.org/10.1002/cam4.3089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333826PMC
July 2020

Infectious pericarditis caused by induced by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA): A case report.

Respir Med Case Rep 2020 13;30:101057. Epub 2020 Apr 13.

Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.

A 69-year-old man had experienced right chest pain for several months. Chest computed tomography (CT) showed a right upper lobe lung tumor and swelling of multiple mediastinal and right hilar lymph node. Three punctures to 4R lymph nodes and two punctures to 11i lymph nodes were performed, using endobronchial ultrasonography. Thirty days after punctures, he was admitted with appetite loss and general fatigue. Chest CT supposed the evidence of mediastinitis and pericarditis. Despite the antibiotics, cardiac tamponade developed on the third hospital day. Pericardial fenestration and pericardial drainage were performed. Gram-positive cocci were identified and was eventually identified as the microbial identification system. Like the former reports, the necessity of surgical procedure for late onset of mediastinitis and pericarditis. caused by EBUS-TBNA was suggested.
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http://dx.doi.org/10.1016/j.rmcr.2020.101057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183228PMC
April 2020

Switching from first or second generation EGFR-TKI to osimertinib in mutation-positive NSCLC.

Lung Cancer Manag 2020 Mar 19;9(2):LMT29. Epub 2020 Mar 19.

Department of Thoracic Oncology, Osaka International Cancer Institute 3-1-69 Otemae, Chio-ku, Osaka 541-8567, Japan.

Aim: We evaluated the efficacy of a novel switch protocol for EGFR-TKIs for mutation-positive NSCLC.

Materials & Methods: Clinical records were collected from the patients who had received one of two sequential combination strategies of EGFR-TKIs: Salvage use of osimertinib for -mediated acquired resistance to an prior EGFR-TKI or switch use of osimertinib where an EGFR-TKI was switched to osimertinib before disease progression.

Results: Progression-free survival of osimertinib and time from the start of treatment until progression to osimertinib was comparable between the salvage use and switch use of osimertinib.

Conclusion: Switch use of osimertinib seemed to produce improved efficacy for patients with activating mutations, because of the lack of patient selection via .
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http://dx.doi.org/10.2217/lmt-2020-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186852PMC
March 2020

Favorable response to pembrolizumab after durvalumab failure in a stage III sarcomatoid carcinoma of the lung: a case report.

BMC Pharmacol Toxicol 2020 04 3;21(1):26. Epub 2020 Apr 3.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuo-ku, Osaka, 541-8567, Japan.

Background: Pulmonary sarcomatoid carcinoma is a rare non-small-cell lung cancer (NSCLC) subtype with a poor prognosis. In the phase III PACIFIC study, durvalumab significantly improved progression-free survival and overall survival versus placebo, in patients with stage III NSCLC who do not have disease progression after concurrent chemoradiotherapy. However, treatments for patients who discontinue durvalumab due to disease progression, are unknown.

Case Presentation: We report a case of favorable response to pembrolizumab in a patient with disease progression during durvalumab consolidation therapy after chemoradiotherapy for stage III pulmonary sarcomatoid carcinoma with high programmed cell death ligand 1 (PD-L1) and PD-L2 expression.

Conclusion: Here, we present what, to the best of our knowledge, is the first reported case in which durvarumab resistance after definitive chemoradiotherapy in a patient with stage III pulmonary sarcomatoid carcinoma was overcome by pembrolizumab.
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http://dx.doi.org/10.1186/s40360-020-00404-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118808PMC
April 2020

Biomarker testing for personalized, first-line therapy in advanced nonsquamous non-small cell lung cancer patients in the real world setting in Japan: a retrospective, multicenter, observational study (the BRAVE study).

Ther Adv Med Oncol 2020 22;12:1758835920904522. Epub 2020 Feb 22.

Department of Medical Oncology, Faculty of Medicine & Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Molecular diagnostic testing is necessary to guide optimal first-line treatment. The number of patients who receive first-line treatment based on biomarker analysis in Japan is unknown. We aimed to determine the proportion of nonsquamous non-small cell lung cancer (NSCLC) patients for whom first-line treatment was selected based on biomarker testing.

Methods: This retrospective, multicenter, observational study registered patients aged ⩾20 years with locally advanced or metastatic nonsquamous NSCLC who started first-line treatment between August and December 2017 in Japan. Data were collected from medical records between January and May 2018. The primary endpoint was the proportion of patients with confirmed biomarker status for first-line treatment decision.

Results: Among 202 patients enrolled from 11 centers, 161 (79.7%; 95% confidence interval, 74.2-85.2%) had confirmed biomarker status. The testing rate was highest for epidermal growth factor receptor (; 97.5%), followed by anaplastic lymphoma kinase (; 88.1%), programmed death ligand-1 (PD-L1; 87.1%), and (67.3%). For first-line treatment, 70/75 patients with -positive tumors were administered an EGFR-TKI; 14/15 patients with -positive tumors received an ALK inhibitor; 2/2 patients with -positive tumors received a ROS1 inhibitor; and 29/36 driver mutation-negative patients with a PD-L1 tumor proportion score ⩾50% were administered an anti-PD-1 monoclonal antibody. Median times from confirmed diagnosis date to first-line treatment initiation, and from first biomarker test order to last biomarker test result were 19 and 11 days, respectively.

Conclusions: The proportion of nonsquamous NSCLC patients with confirmed biomarker status for first-line treatment was considered insufficient and in need of improvement.
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http://dx.doi.org/10.1177/1758835920904522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036489PMC
February 2020

Propensity score-weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non-small cell lung cancer (WJOG10217L).

J Immunother Cancer 2020 02;8(1)

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

Background: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.

Methods: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.

Results: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, or genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.

Conclusions: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
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http://dx.doi.org/10.1136/jitc-2019-000350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057433PMC
February 2020

A phase I/II study of weekly nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer.

BMC Cancer 2020 Feb 11;20(1):115. Epub 2020 Feb 11.

Department of Thoracic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-shi, Hyogo, 673-8558, Japan.

Background: The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC).

Methods: Chemotherapy-naïve patients with advanced NSCLC were eligible. In the phase I dose-escalation cohort (3 + 3 design), patients received nab-paclitaxel (80 or 100 mg/m given intravenously on days 1, 8 and 15) plus cisplatin (60 or 75 mg/m given intravenously on day 1) every 4 weeks. The maximum tolerated dose was not reached. Nab-paclitaxel (100 mg/m given intravenously on days 1, 8 and 15) plus cisplatin (75 mg/m given intravenously on day 1) every 4 weeks was selected for the phase II cohort. The primary endpoint was the objective response rate (ORR).

Results: Twenty-three patients (phase I, n = 6; phase II, n = 17) were enrolled, and 22 patients were eligible. The median age was 67.5 years (range 37-75), 90.9% were males, 45.5% had adenocarcinoma and 81.8% had stage IV disease. The ORR was 59.1% (90% confidence interval (CI); 41.8-74.4), and the disease control rate was 86.4% (95% CI; 66.7-95.3). The median progression-free survival was 5.1 months (95% CI; 4.0-6.7), and the median overall survival was 24.2 months (95% CI; 8.4 months to not estimable). The common grade ≥ 3 adverse events were neutropenia (31.8%), leukopenia (27.3%), lung infection (18.2%) and hyponatremia (18.2%). There was one instance of grade 2 interstitial pneumonia and no treatment-related death.

Conclusions: Nab-paclitaxel plus cisplatin was well tolerated and associated with encouraging response outcomes in chemotherapy-naïve patients with advanced NSCLC. Further investigation is warranted.

Trial Registration: UMIN Clinical Trials Registry: UMIN000011776; Date of registration: 17 September 2013; Date of enrolment of the first participant to the trial: 23 January 2014.
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http://dx.doi.org/10.1186/s12885-020-6588-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014598PMC
February 2020

Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.

Cancer Genet 2020 02 25;241:51-56. Epub 2019 Dec 25.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials And Methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.
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http://dx.doi.org/10.1016/j.cancergen.2019.12.006DOI Listing
February 2020

Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L).

J Clin Oncol 2020 03 27;38(8):793-803. Epub 2019 Dec 27.

Kyushu University Hospital, Fukuoka, Japan.

Purpose: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy.

Patients And Methods: Patients with untreated advanced nonsquamous NSCLC without confirmed 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment.

Results: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank = .069). In the wild-type subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank = .020). The median progression-free survival (PFS) was 5.7 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank < .001). The safety data were consistent with previous reports of treatment regimens.

Conclusion: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.
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http://dx.doi.org/10.1200/JCO.19.01494DOI Listing
March 2020

Extrinsic Upregulation of PD-L1 Induced by Pembrolizumab Combination Therapy in Patients with NSCLC with Low Tumor PD-L1 Expression.

J Thorac Oncol 2019 10;14(10):e231-e233

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka City, Japan.

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http://dx.doi.org/10.1016/j.jtho.2019.05.026DOI Listing
October 2019

Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?

Anticancer Res 2019 Jul;39(7):3923-3929

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group).

Materials And Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions.

Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195).

Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.
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http://dx.doi.org/10.21873/anticanres.13544DOI Listing
July 2019
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