Publications by authors named "Koichi Azuma"

180 Publications

First-line durvalumab plus platinum-etoposide in extensive-stage small-cell lung cancer: CASPIAN Japan subgroup analysis.

Int J Clin Oncol 2021 Apr 7. Epub 2021 Apr 7.

Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background: In the phase 3 CASPIAN study (NCT03043872), first-line durvalumab plus etoposide and cisplatin or carboplatin (EP) significantly improved OS versus EP alone in patients with extensive-stage (ES)-SCLC (HR 0.73 [95% CI 0.59-0.91; p = 0.0047]). Here we report results for a preplanned subgroup analysis of patients recruited in Japan.

Methods: Treatment-naïve patients with ES-SCLC received either 4 cycles of durvalumab 1500 mg plus EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression or up to 6 cycles of EP q3w. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability.

Results: In the Japan subgroup, 18 patients were randomized to durvalumab plus EP and 16 patients to EP. At the interim analysis with a median follow-up of 12.5 months in the subgroup, OS numerically favored durvalumab plus EP versus EP (HR 0.77 [95% CI 0.26‒2.26]; median not reached vs 15.2 months). PFS was similar for durvalumab plus EP versus EP (HR 0.90 [95% CI 0.43‒1.89]). Confirmed ORR was 89% with durvalumab plus EP versus 69% with EP. Adverse events (AEs) of CTCAE grade 3 or 4 were reported in 78% versus 94% of patients in the durvalumab plus EP versus EP arms. There were no AEs leading to treatment discontinuation or death in the Japan subgroup.

Conclusion: First-line durvalumab plus EP was effective and well tolerated in Japanese patients with ES-SCLC. Despite the small size of the Japan subgroup, results were generally consistent with the global study population.
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http://dx.doi.org/10.1007/s10147-021-01899-8DOI Listing
April 2021

Clinical significance of peripheral TCR and BCR repertoire diversity in EGFR/ALK wild-type NSCLC treated with anti-PD-1 antibody.

Cancer Immunol Immunother 2021 Mar 9. Epub 2021 Mar 9.

Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

Introduction: TCR and BCR repertoire diversity plays a critical role in tumor immunity. Thus, analysis of TCR and BCR repertoires might help predict the clinical efficacy of anti-PD-1 treatment.

Methods: Blood samples from 30 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibody were collected before and six weeks after treatment initiation. The clinical significance of TCR and BCR repertoire diversity in peripheral blood was evaluated in all the enrolled patients (n = 30) or in the subset with (n = 10) or without (n = 20) EGFR/ALK mutation.

Results: TCR and BCR diversity was significantly correlated at baseline (R = 0.65; P = 1.6 × 10) and on treatment (R = 0.72; P = 1.2 × 10). Compared to non-responders (SD or PD), responders (PR) showed significantly decreased TCR and BCR diversity after treatment in the EGFR/ALK wild-type subset (P = 0.0014 and P = 0.034, respectively), but not in all the enrolled patients. The post-treatment reduction in TCR and BCR repertoire diversity was also significantly associated with the occurrence of adverse events in the EGFR/ALK wild-type subset (P = 0.022 and P = 0.014, respectively). Patients with more reduced TCR diversity showed better progression-free survival (PFS) in the EGFR/ALK wild-type subset (P = 0.011) but not in the mutant subset.

Conclusions: These findings suggest the clinical significance of changes in peripheral TCR and BCR repertoire diversity after anti-PD-1 treatment in patients with NSCLC without EGFR/ALK mutation. Monitoring of the peripheral TCR and BCR repertoires may serve as a surrogate marker for the early detection of EGFR/ALK wild-type NSCLC patients who would benefit from anti-PD-1 treatment.
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http://dx.doi.org/10.1007/s00262-021-02900-zDOI Listing
March 2021

A Phase II Study to Assess the Efficacy of Osimertinib in Patients With EGFR Mutation-positive NSCLC Who Developed Isolated CNS Progression (T790M-negative or Unknown) During First- or Second-generation EGFR-TKI or Systemic Disease Progression (T790M-negative) After Treatment With First- or Second-generation EGFR-TKI and Platinum-based Chemotherapy (WJOG12819L).

Clin Lung Cancer 2021 Jan 25. Epub 2021 Jan 25.

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

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.
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http://dx.doi.org/10.1016/j.cllc.2020.12.009DOI Listing
January 2021

Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring mutations.

Transl Lung Cancer Res 2021 Jan;10(1):183-192

Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Afatinib is a second-generation epidermal growth factor receptor () tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab.

Methods: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state.

Results: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation.

Conclusions: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.
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http://dx.doi.org/10.21037/tlcr-20-824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867760PMC
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.

Internal Medicine III, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8509, Japan. Electronic address:

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

Comparative incidence of immune-related adverse events and hyperprogressive disease in patients with non-small cell lung cancer receiving immune checkpoint inhibitors with and without chemotherapy.

Invest New Drugs 2021 Jan 22. Epub 2021 Jan 22.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Immune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and March 2020. We recruited 210 patients, of whom 172 (81.9%) had received PD-1/PD-L1 inhibitor MT and 38 (18.1%) had received CT. The incidence of irAE during the 3 months after treatment initiation was significantly higher in the MT group (57 of 172, 33.1%) than in the CT group (6 of 38, 15.8%) (p = 0.049). During the same period, the incidence of pneumonitis was also higher in the MT group (18 of 172, 10.9%) than in the CT group (0 of 38) (p = 0.049). A similar trend was observed in patients who had received these treatments on a first line basis. The HPD rate was significantly lower in the CT group (1 of 34, 2.9%) than in the MT group (25 of 142, 17.6%) (p = 0.031). The incidences of HPD and irAE, especially pneumonitis, during 3 months after treatment initiation were relatively lower in the CT group than in the MT group. The mechanisms underlying these differences warrant further study.
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http://dx.doi.org/10.1007/s10637-021-01069-7DOI Listing
January 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

Predicting osimertinib-treatment outcomes through EGFR mutant-fraction monitoring in the circulating tumor DNA of EGFR T790M-positive patients with non-small cell lung cancer (WJOG8815L).

Mol Oncol 2021 01 17;15(1):126-137. Epub 2020 Nov 17.

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

The WJOG8815L phase II clinical study involves patients with non-small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third-generation EGFR-TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR-TKI-sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing-and T790M-EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation-positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression-free survival were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
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http://dx.doi.org/10.1002/1878-0261.12841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782093PMC
January 2021

Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C.

Cancers (Basel) 2020 Sep 11;12(9). Epub 2020 Sep 11.

Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka 8138588, Japan.

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75-2.12, = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98-4.25, = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC.
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http://dx.doi.org/10.3390/cancers12092602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563479PMC
September 2020

Predictive value of CD8/FOXP3 ratio combined with PD-L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy.

Head Neck 2020 12 18;42(12):3518-3530. Epub 2020 Aug 18.

Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, Kurume, Japan.

Background: Little is known about immune-related radiosensitivity in patients with squamous cell carcinoma of the larynx (SCC-L) treated with radiation therapy (RT).

Methods: We retrospectively reviewed 91 patients with SCC-L treated with RT or chemoradiation therapy and performed immunohistochemical examination to analyze PD-L1 level on tumor cells, CD4 tumor-infiltrating lymphocytes (TILs), CD8 TIL, and FOXP3 TIL using pretreated biopsy specimens. The association between these immune-related parameters and radiosensitivity was evaluated.

Results: Multivariate analyses showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression was an independent and significant favorable predictive factor for local control, compared with the other groups.

Conclusions: We showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression might be a useful biomarker of radiosensitivity in patients with SCC-L receiving definitive RT. We propose that coassessment of CD8/FOXP3 ratio and PD-L1 expression level in tumor cells can help predict potential radiosensitivity in patients with SCC-L.
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http://dx.doi.org/10.1002/hed.26416DOI Listing
December 2020

Atezolizumab plus carboplatin and etoposide in small cell lung cancer patients previously treated with platinum-based chemotherapy.

Invest New Drugs 2021 Feb 11;39(1):269-271. Epub 2020 Aug 11.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Although immune checkpoint inhibitors have improved the survival of small cell lung cancer (SCLC) patients, their efficacy in SCLC patients who relapsed after systemic chemotherapy is unclear. This retrospective study aimed to investigate the utility of treatment with atezolizumab plus carboplatin and etoposide in SCLC patients previously treated with platinum-based chemotherapy. We retrospectively screened consecutive eight SCLC patients who received atezolizumab plus carboplatin and etoposide after platinum-based chemotherapy. We evaluated the efficacy of this treatment and its association with programmed cell death-ligand 1 (PD-L1) expression. Three and five patients had sensitive relapse and refractory relapse for first-line platinum-based chemotherapy, respectively. The overall response rate and disease control rate was 37.5% and 75.0%, respectively. Median progression-free survival was 4.0 months. Out of three patients who achieved clinical response, two patients had refractory relapse for first-line platinum-based chemotherapy. No patient exhibited PD-L1 expression. Atezolizumab plus carboplatin and etoposide therapy was effective in SCLC patients with sensitive and refractory relapse and might be a second-line treatment option for SCLC patients previously treated with platinum-based chemotherapy.
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http://dx.doi.org/10.1007/s10637-020-00983-6DOI Listing
February 2021

Changes in immune parameters between pre-treatment and recurrence after (chemo) radiation therapy in patients with head and neck cancer.

Sci Rep 2020 07 20;10(1):11973. Epub 2020 Jul 20.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Kurume University, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan.

Squamous cell carcinoma of the head and neck (SCCHN) has a high recurrence rate after (chemo) radiation therapy [(C)RT]. The relationship between the changing levels of immune checkpoint molecules and immune cells in pre-(C)RT tissues and locally recurrent tissues in the irradiated field, after (C)RT completion, is not known. This study aimed to assess the changes in these immune parameters between pre-(C)RT tissue and the same area after local recurrence post-(C)RT. We retrospectively reviewed 30 (C)RT-treated patients with SCCHN. We performed immunohistochemical analyses on these immune parameters using paired tissue samples obtained pre-(C)RT and at local recurrence sites post-(C)RT. No significant changes in immune parameters were found between the pre-(C)RT and locally recurrent tissues. An increased density of CD8+ tumor-infiltrating lymphocytes (TILs) showed a significantly positive correlation with PD-L expression on tumor cells (TC-PD-L1). Patients with increased TC-PD-L1 expression and CD8+TIL density showed favourable prognosis, and one of them showed a favourable response to nivolumab therapy. Our study shows a positive association between TC-PD-L1 upregulation and increased CD8+TIL density, and demonstrates that patients with these changes have a favourable survival outcome.
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http://dx.doi.org/10.1038/s41598-020-68938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371733PMC
July 2020

Evaluation of plasma EGFR mutation as an early predictor of response of erlotinib plus bevacizumab treatment in the NEJ026 study.

EBioMedicine 2020 Jul 3;57:102861. Epub 2020 Jul 3.

Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3695, Japan. Electronic address:

Background: The NEJ026 Phase 3 study demonstrated that erlotinib and bevacizumab (BE)-treated NSCLC patients with EGFR mutations had significantly better progression-free survival (PFS) than those treated with erlotinib alone (E). This study included a prospective analysis of the relationship between the mutational status of EGFR in plasma circulating tumor DNA (ctDNA) and the efficacy of TKI monotherapy or combination therapy. We describe these results herein.

Methods: Plasma samples were collected from patients enrolled in NEJ026 at the start of treatment (P0), 6 weeks after the start of treatment (P1), and upon confirmation of progressive disease (P2). Plasma ctDNA was analyzed using a modified PNA-LNA PCR clamp method. PFS and OS according to EGFR status at the time of plasma collection were evaluated.

Findings: Plasma activating EGFR mutation (aEGFR) at P0 was detected in 68% of cases; patients without plasma aEGFR had longer PFS. The frequency of T790M mutation at P2 was similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. Based on the aEGFR profiles, PFS was evaluated among three groups: type A [P0(-), P1(-)], type B [P0(+), P1(-)], and type C [P0(+), P1(+)]. This revealed that BE was more efficacious than E, and that BE was associated with improved PFS in all types.

Interpretation: Pre-treatment plasma aEGFR status have a potential of early predictor of response of TKI efficacy. Monitoring plasma aEGFR mutation will contribute to selection and continuation of treatment with BE or E.

Funding: Chugai Pharmaceutical.
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http://dx.doi.org/10.1016/j.ebiom.2020.102861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334809PMC
July 2020

Development of Hepatocellular Carcinoma by Patients Aged 75-84 with Chronic Hepatitis C Treated with Direct-acting Antivirals.

J Infect Dis 2020 Jun 25. Epub 2020 Jun 25.

Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan.

Background: Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) by patients aged 75-84 with chronic hepatitis C (CHC) following HCV elimination.

Methods: This multicenter cohort study included 2405 consecutive CHC patients without a history of HCC who achieved HCV elimination by DAAs. Patients who developed HCC within one year of DAA initiation were excluded. Propensity score matched (PSM) analysis was used to evaluate differences in the HCC risk in patients aged 75-84 and 60-74.

Results: The median observational period was 3.5 years. Among the patients aged 75-84 in the high FIB-4 group (≥3.25 at baseline), there was no significant difference in the annual incidence of HCC between 12 weeks after the end of treatment FIB-4≥3.25 (2.75%/year) and <3.25 groups (2.16%/year), unlike the results of those aged 60-74 (3.61 and 1.51%/year, respectively) (adjusted hazard ratio 2.20; P=0.045). In 495 matched pairs by PSM, the cumulative HCC incidence in the age 75-84/non-cirrhosis was significantly higher compared to the age 60-74/non-cirrhosis (P=0.048).

Conclusions: Older patients aged 75-84 remained at high risk for the development of HCC, even after HCV elimination and the improvement of FIB-4 index to <3.25.
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http://dx.doi.org/10.1093/infdis/jiaa359DOI Listing
June 2020

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Expression of PD-L1, PD-L2, and IDO1 on tumor cells and density of CD8-positive tumor-infiltrating lymphocytes in early-stage lung adenocarcinoma according to histological subtype.

J Cancer Res Clin Oncol 2020 Oct 14;146(10):2639-2650. Epub 2020 May 14.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: This study examined the expression of programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2), and indoleamine 2,3-dioxygenase-1 (IDO1) in tumor cells and cluster of differentiation 8 (CD8)-positive tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma according to histological subtypes.

Methods: We evaluated PD-L1, PD-L2, and IDO1 expression in tumor cells and CD8-positive TILs in surgically resected specimens from 196 stage 0 or I lung adenocarcinoma patients by immunohistochemical staining. We also examined the relationships between the expression of PD-L1, PD-L2, and IDO1 in tumor cells and the density of CD8-positive TILs and clinical factors. Patients were divided into three groups: A, adenocarcinoma in situ and minimally invasive adenocarcinoma (N = 32); B, lepidic predominant invasive adenocarcinoma (IAD; LPA; N = 66); and C, IAD except for LPA (N = 98).

Results: PD-L1 was expressed only in Group C, but not in Groups A or B. The positive ratio of PD-L2 was significantly higher in Group C (63.3%), and that of IDO1 was also significantly higher in Group C (65.3%). The density of CD8-positive TILs was significantly higher in Group C (45 ± 2.4). There was no significant difference between the positive ratios of PD-L2 and IDO1 and the density of CD8-positive TILs in Group A (50.0%, 21.9%, and 36 ± 4.1, respectively) or Group B (60.6%, 25.8%, and 44 ± 3.0, respectively).

Conclusions: No cases in Groups A and B expressed PD-L1. The expression of immune-related factors, especially PD-L1 and IDO1, was significantly associated with Group C. This is the first report of the detailed examination of PD-L1, PD-L2, IDO1, and CD8 expression in lung adenocarcinoma subtypes with lepidic predominant components. Our results could help identify patients who would benefit from perioperative immunotherapy.
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http://dx.doi.org/10.1007/s00432-020-03250-6DOI Listing
October 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

Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B.

Liver Int 2020 07 30;40(7):1578-1589. Epub 2020 Apr 30.

Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan.

Background And Aims: Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF.

Methods: This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m . Differences in longitudinal parameters were compared by the generalized estimating equation method.

Results: In the prior ETV group (n = 191), the HBV DNA suppression rate at week 48 was significantly increased, from 75.9% to 96.9% (P < .001). Additionally, mean changes in the HBsAg level at week 48 in HBsAg ≥ 3.0 logIU/mL and < 3.0 logIU/mL groups were -0.09 and -0.13 logIU/mL respectively. In the prior NA combination group (n = 122), the mean changes in HBsAg level at week 48 in the HBsAg ≥ 3.0 logIU/mL and <3.0 logIU/mL groups were -0.08 and -0.11 logIU/mL respectively. For patients with CKD, the eGFR at week 48 was significantly improved compared to those with non-CKD (adjusted slope coefficient difference: 2.75 mL/min/1.73 m /48 weeks; P = .001).

Conclusions: Switching from ETV or an NA combination to TAF was effective for HBV suppression and continued HBsAg reduction. Moreover, the renal glomerular function of patients in the prior NA combination group with CKD was significantly improved compared to those with non-CKD.

Lay Summary: Nucleos(t)ide analogues, such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, inhibit hepatitis B virus (HBV) replication and are recommended as first-line oral agents for chronic HBV infection. We evaluated the virological/biochemical effects and renal safety when patients are switched from entecavir or nucleoside-nucleotide analogue combination therapy to tenofovir alafenamide. Our findings suggest that switching to tenofovir alafenamide was effective for HBV suppression and the improvement in renal function for patients with chronic kidney disease.
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http://dx.doi.org/10.1111/liv.14482DOI Listing
July 2020

Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 05 14;6(5):e196828. Epub 2020 May 14.

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

Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.

Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.

Design, Setting, And Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.

Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.

Main Outcomes And Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.

Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.

Conclusion And Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.

Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.
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http://dx.doi.org/10.1001/jamaoncol.2019.6828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068674PMC
May 2020

Predictive value of CD73 expression for the efficacy of immune checkpoint inhibitors in NSCLC.

Thorac Cancer 2020 04 15;11(4):950-955. Epub 2020 Feb 15.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background: CD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non-small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).

Methods: We screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.

Results: Analysis of progression-free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD-L1 expression in patients with EGFR mutation.

Conclusions: High CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.

Key Points: Significant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC.

What This Study Adds: High CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.
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http://dx.doi.org/10.1111/1759-7714.13346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113063PMC
April 2020

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

Cancer 2020 01 5;126(9):1940-1948. Epub 2020 Feb 5.

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

Background: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients.

Methods: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay.

Results: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months).

Conclusions: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.
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http://dx.doi.org/10.1002/cncr.32749DOI Listing
January 2020

Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib.

Sci Rep 2020 01 20;10(1):691. Epub 2020 Jan 20.

Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.
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http://dx.doi.org/10.1038/s41598-020-57624-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971280PMC
January 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

Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors.

Sci Rep 2019 12 20;9(1):19501. Epub 2019 Dec 20.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, 589-8511, Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1-generation and 29 with 2-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
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http://dx.doi.org/10.1038/s41598-019-55939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925200PMC
December 2019

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer.

Lung Cancer 2020 01 28;139:195-199. Epub 2019 Nov 28.

Thoracic Center, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan. Electronic address:

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018).

Methods: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018.

Results: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib).

Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.025DOI Listing
January 2020

Prognostic value of dual-point fluorine-18 fluorodeoxyglucose PET imaging, partial volume correction and glucose transporter-1 expression in resected nonsmall cell lung cancer patients.

Nucl Med Commun 2020 Jan;41(1):48-57

Division of Nuclear Medicine, PET Center, Department of Radiology, Fukuoka Tokushukai Medical Center, Kasuga, Fukuoka, Japan.

Objective: To investigate the relationship between the prognosis and glucose transporter-1 (Glut-1) expression or fluorine-18 fluorodeoxyglucose uptake using partial volume correction and dual-point imaging in surgically resected nonsmall cell lung cancer (NSCLC) patients.

Methods: Our patient population consisted of 108 NSCLC cases. The early maximum standardized uptake value (ESUVmax), delayed SUVmax (DSUVmax), partial volume correction SUVmax (cSUVmax) and retention index of primary lesions were calculated. Cox proportional hazard model was applied to evaluate the effects of PET parameters and Glut-1 expression. Overall survival (OS) and disease-free survival (DFS) were evaluated by Kaplan-Meier methods, and the difference in survival between subgroups was analyzed by log-rank test.

Results: On the Cox regression analysis, ESUVmax, DSUVmax, cSUVmax and Glut-1 were significantly related to DFS [ESUVmax, hazard ratio = 2.301, 95% confidential interval (CI) = 1.146-4.618, P = 0.019; DSUVmax, hazard ratio = 2.483, 95% CI = 1.257-4.905, P = 0.009; cSUVmax, hazard ratio = 2.205, 95% CI = 1.038-4.686, P = 0.04; Glut-1, hazard ratio = 2.095, 95% CI = 1.086-4.041, P = 0.001] and OS (ESUVmax, hazard ratio = 3.197, 95% CI = 1.339-7.633, P = 0.009; DSUVmax, hazard ratio = 3.599, 95% CI = 1.521-8.516, P = 0.004; cSUVmax, hazard ratio = 8.655, 95% CI = 2.048-36.658, P = 0.003; Glut-1, hazard ratio = 2.427, 95% CI = 5.140, P = 0.021). Retention index had no significant association with DFS or OS. On the Kaplan-Meier survival curves, the patients with high ESUVmax, DSUVmax, cSUVmax and Glut-1 showed significantly worse prognosis than those with low values (ESUVmax: DFS, P = 0.001, OS, P = 0.003; DSUVmax: DFS, P = 0.002, OS, P = 0.004; cSUVmax: DFS, P < 0.001, OS, P = 0.013; Glut-1: DFS, P = 0.012, OS, P = 0.002).

Conclusions: cSUVmax, ESUVmax, DSUVmax and Glut-1 may be more useful biomarkers than retention index for predicting outcomes in NSCLC patients.
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http://dx.doi.org/10.1097/MNM.0000000000001118DOI Listing
January 2020

Ledipasvir and sofosbuvir for 12 weeks for hepatitis C virus genotype 2 infection: A propensity score matched analysis.

Hepatol Res 2020 Feb 19;50(2):174-181. Epub 2019 Nov 19.

Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan.

Aim: Hepatitis C virus genotype 2 is common in East Asia, sub-Saharan Africa, and Latin America. However, many countries in these areas lag behind other areas of the world in government approval for new direct-acting antivirals. The aim of this study was to evaluate the treatment outcome of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C virus genotype 2 infection.

Methods: This is a two-part multicenter, real-world cohort study. Study 1 consisted of 58 consecutive patients who were treated with LDV/SOF for 12 weeks. Study 2 used propensity score matching for LDV/SOF (n = 58) and glecaprevir/pibrentasvir (n = 207) treatment groups (1:1) with a set of clinically important variables. Sustained viral response 12 weeks after the end of treatment (SVR12) and adverse events were evaluated in both studies.

Results: In study 1, the overall SVR12 rates of the intention-to-treat and modified intention-to-treat populations were 94.8% (55/58) and 96.5% (55/57), respectively. High SVR12 rates were observed in almost all subgroups, including older age, compensated cirrhosis, and treatment experience. In study 2, propensity score matching of the entire study population yielded 52 matched pairs with similar baseline characteristics. There were no statistically significant differences between the LDV/SOF (96.1%) and glecaprevir/pibrentasvir (98.0%) groups in the overall SVR12 rates of the modified intention-to-treat populations, and their rates of treatment discontinuation and adverse events were similar.

Conclusions: Treatment with LDV/SOF for hepatitis C virus genotype 2 resulted in a high rate of SVR12 and excellent tolerability. The outcomes of LDV/SOF were very similar to those of glecaprevir/pibrentasvir.
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http://dx.doi.org/10.1111/hepr.13437DOI Listing
February 2020

Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors.

Cancer 2020 01 10;126(1):219-227. Epub 2019 Sep 10.

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

Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment.

Methods: Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing.

Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P < .001) for EGFR-TKI-naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04).

Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.
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http://dx.doi.org/10.1002/cncr.32481DOI Listing
January 2020

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR-mutated non-small cell lung cancer.

Thorac Cancer 2019 10 16;10(10):1928-1935. Epub 2019 Aug 16.

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

Background: Non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one-fifth of NSCLC patients with acquired resistance to EGFR-TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown.

Methods: Tumor tissue and plasma specimens were collected from 25 EGFR-mutated NSCLC patients before EGFR-TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme-linked immunosorbent assays.

Results: AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR-TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue.

Conclusion: Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR-mutated NSCLC.
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http://dx.doi.org/10.1111/1759-7714.13166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775020PMC
October 2019

Different responses to nivolumab therapy between primary and metastatic tumors in a patient with recurrent hypopharyngeal squamous cell carcinoma.

Oral Oncol 2020 02 9;101:104366. Epub 2019 Jul 9.

Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

We report the case of a 70-year-old man with primary and metastatic tumors, showing clinically progressive disease and complete response to nivolumab therapy, respectively. He underwent total pharyngo-laryngectomy, bilateral neck dissection, and reconstruction with free-jejunum after nivolumab therapy failure, and had no recurrent or newly arising lesions 8 months after the surgery. Immunohistochemistry analysis revealed that metastatic neck tumor with the clinical complete response to nivolumab showed higher PD-L1 expression with higher CD8+ TIL density, while primary lesion with progressive disease showed lower PD-L1 expression with lower CD8+ TIL density. This represents the first case reported on head and neck squamous cell carcinoma treated with salvage surgery after nivolumab therapy failure.
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http://dx.doi.org/10.1016/j.oraloncology.2019.07.009DOI Listing
February 2020