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Yoshiro Nakahara
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-72 - Treatment Outcome of 2nd Generation EGFR-TKI for Non-Small Cell Lung Cancer (Now Available) (ID 1988)
08:00 - 18:00 | Author(s): Yoshiro Nakahara
- Abstract
Background
Efficacy of EGFR-TKI has been demonstrated in 1st line treatment for EGFR mutation positive NSCLC. Afatinib, 2nd generation EGFR-TKI inhibits HER2 (ErbB2) or ErbB4 in addition to the EGFR (ErbB1), is expected more effective compared to the 1st generation EGFR-TKI. In this study, we investigated retrospectively on the treatment outcome of the cases that received 2nd generation EGFR-TKI treatment at our institution.
Method
The subjects were 70 patients treated with a 2nd generation EGFR-TKI afatinib for the period from May 2014 to April 2018. Age, gender, smoking history, performance status (ECOG), EGFR mutation type, starting dose, dose reduction during treatment period, objective response, presence of brain metastasis, EGFR-TKI treatment line and T790M mutation result were retrospectively analyzed the association with the time to treatment failure and survival.
Result
Among the 70 patients, male 28 cases and female 42 cases, and 42 never smoker included. Median age was 65 years old (43-88 years old). EGFR mutation type included exon 19 deletion 42 cases, exon 21 L858R 13 cases, uncommon mutation 13 cases and compound mutation 2 cases. 18 cases were administered with 40mg initial dose, 28 cases were 30mg and 24 cases were 20mg. 68 cases were good performance status (0 or 1), and 33 (47%) cases had brain metastasis. Dose reduction were performed in 43 (61%) cases, and partial response were observed in 34 (49%) cases. 36 (51%) cases were no pretreatment with EGFR-TKI (afatinib as first EGFR-TKI). Of the 70 cases, 33 (47%) cases were performed re-biopsy, and 15 cases of those were proved T790M acquired resistant mutation.
Conclusion
Good performance status, dose reduction, good objective response, no brain metastasis, early EGFR-TKI treatment line and T790M mutation positivity were significantly associated with prolongation of the time to treatment failure, but no significant characteristics were associated with prolongation of the survival.
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)
14:30 - 16:00 | Author(s): Yoshiro Nakahara
- Abstract
- Presentation
Background
We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).
Method
Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.
Result
From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.
Conclusion
This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-15 - Multicenter, Single-Arm Phase II Study of Nab-Paclitaxel/Carboplatin in Untreated PS2 Patients with Advanced NSCLC: TORG1426 (Now Available) (ID 519)
09:45 - 18:00 | Author(s): Yoshiro Nakahara
- Abstract
Background
Performance Status (PS) has been shown to predict survival in patients with advanced non-small cell lung cancer (NSCLC). To date, PS2 patients have been underrepresented in clinical trials due to concerns about tolerability. Consequently, no standard of care exists for these patients. In CA031 trial, nab-paclitaxel/carboplatin (nab-PTX/CBDCA) demonstrated significantly higher response rate (RR) compared with PTX/CBDCA in PS0-1 patients with advanced NSCLC. Furthermore, in elderly subgroup, nab-PTX/CBDCA tended to show superior progression-free survival (PFS) and overall survival (OS) based on better tolerability compared with PTX/CBDCA. Therefore, this phase II trial was designed to characterize the efficacy, safety, and tolerability of nab-PTX/CBDCA in untreated PS2 patients with advanced NSCLC.
Method
Chemotherapy-naive PS2 patients with stage IIIB/IV NSCLC were treated with nab-PTX (70 mg/m2 on day1, 8, and15, q4w) and CBDCA (AUC 5 on day1, q4w) up to 6 cycles if they did not have uncontrolled brain metastasis or pleural effusion. The primary endpoint was PFS rate at 6 months. Its achievement of more than 50% was considered worthy of further development of this regimen, whereas that of less than 30% was considered insufficient for further investigation. The estimated power was 80% with type I error of 0.05, resulting in 35 patients needed. Concurrently, Symptom Score and Charlson Comorbidity Index (CCI) were evaluated.
Result
This trial was terminated due to slow accrual. Between September 2015 and August 2018, 17 patients (median age, 68 years [range, 50-73]) were enrolled and received a median of 3 cycles. The reasons for PS2 were tumor progression (71%), comorbidities (12%), or both (17%). The PFS rate at 6 months was 20.8% (95% confidence interval, 0%-41.6%). The median PFS, OS, RR, and disease control rate (DCR) were 3.0 months, 9.5 months, 17.4%, and 70.6%, respectively. Grade 3-5 adverse events (AE) included fatigue (24%), lung infection (24%, including 6% of grade 5), neutropenia (18%), and anemia (18%), resulting in trial withdrawal rate of 24%. The median PFSs of 11 patients with and 6 patients without 2nd line chemotherapy were 5 months and 1.7 months, respectively (p = 0.009). Symptom Score was improved by chemotherapy (p = 0.004), whereas comparison between lower and higher CCI values demonstrated no difference regarding chemotherapy cycles administered (p = 0.5) and regarding chemotherapy efficacy (p = 0.268).
Conclusion
Nab-PTX/CBDCA did not meet its primary endpoint, but could be a feasible treatment option for untreated PS2 patients with advanced NSCLC. Clinical trial information: UMIN000019458
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-40 - Serum Perforin Levels During the First Cycle of Anti-PD-1 Antibody Therapies in Non-Small Cell Lung Cancer (ID 1662)
09:45 - 18:00 | Author(s): Yoshiro Nakahara
- Abstract
Background
Blockade of PD-1 pathways by anti-PD-1 antibodies restore the function of exhausted T cells and release perforin and granzyme B which induce cytotoxic activity against tumor cells. We examined serum perforin and granzyme B as biomarkers of response to nivolumab and pembrolizumab in non-small cell lung cancer (NSCLC) patients.
Method
Advanced NSCLC patients treated with nivolumab or pembrolizumab were studied. Serum were collected on days 1, 2, 8 and 15 for nivolumab and on days 1, 2, 8, 15 and 22 for pembrolizumab. Concentration of perforin and granzyme B was determined by enzyme-linked immunosorbent assay (ELISA). Best objective response was evaluated by Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Result
Sera from 40 patients with nivolumab and 26 patients with pembrolizumab were analyzed. Optimal cutoff levels for baseline concentration of perforin (day 1) were determined by efficacy. The calculated optimal cutoff levels were 5450.46 pg/ml with nivolumab (area under the receiver-operating-characteristic curve [AUC], 0.703) and 6631.16 pg/ml with pembrolizumab (AUC, 0.806). With nivolumab, median progression-free survival (PFS) was 6.8 months (95% confidence interval [CI], 2.8 to 3.7) in high concentration group (85%) versus 0.7 months (95% CI, 0.13 to not reached) in low concentration group (15%; hazard ratio [HR] for disease progression or death, 0.24; 95% CI, 0.09 to 0.68, p=0.007). Median overall survival (OS) was 14.9 months (95% CI, 10.2 to not reached) in high concentration group versus 1.8 months (95% CI, 0.13 to not reached) in low concentration group (HR for death, 0.19, 95% CI, 0.05 to 0.78, p=0.022). With pembrolizumab, median PFS was 6.7 months (95% CI, 3.5 to not reached) in high concentration group (73%) versus 0.7 months (95% CI, 0.37 to 5.7) in low concentration group (26%; HR for disease progression or death, 0.31; 95% CI, 0.11 to 0.89; p=0.03). Median OS was not reached (95% CI, 7.9 to not reached) in high concentration group versus 2.1 months (95% CI, 0.57 to not reached) in low concentration group (HR for death, 0.2; 95% CI, 0.05 to 0.77; p=0.018). Ratios of sequential perforin levels to baseline levels were analyzed, however, their AUC were not high enough, considered as low predictive power. Serum granzyme B was difficult to measure by ELISA.
Conclusion
With anti-PD-1 antibody therapies, in patients with advanced NSCLC, higher baseline serum perforin levels before treatment were associated with significantly longer progression-free and overall survival.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-01 - Changes of BCR Repertoire Are Predictive Biomarker for the Efficacy of Immune Checkpoint Inhibitor in NSCLC (ID 1688)
10:15 - 18:15 | Author(s): Yoshiro Nakahara
- Abstract
Background
Clonal diversity of T cell receptor (TCR) and/or B cell receptor (BCR) repertoires might play a major role in antitumor immunity in cancer patients. Assessment of TCR and BCR repertoires might enable us to predict the efficacy of immune checkpoint inhibitors (ICI).
Method
The study population comprised 30 patients with non-small-cell lung cancer (NSCLC), who started treatment with nivolumab (3mg/kg, every two weeks) or pembrolizumab (200mg, every three weeks) between February 2016 and August 2017. Patient blood samples were collected before and four to six weeks after the initiation of treatment. TCR and BCR chain sequences were determined by using the unbiased gene amplification method with Adaptor-Ligation PCR. The diversity of TCR and BCR repertoires was evaluated with inverse Shannon-Weaver index (iSWI).
Result
We compared the iSWI between before and after treatment. The fold changes of iSWI in BCR repertoire after treatment in patients with PR were significantly higher than those with SD or PD. In contrast, the fold changes of iSWI in TCR repertoire after treatment were not associated with tumor responses. When the cut-off value of fold change of iSWI in BCR repertoire after treatment was determined as 0.85, 25 (83%) and 5 (17%) patients were considered as high and low fold change group, respectively. Progression free survival in the high fold change group was significantly longer compared with that in the low fold change group (182 vs 49 days; 95% confidence interval (CI);99-N.R. vs 31-168 days, respectively; P=0.01).
Conclusion
Our findings suggest that reduced repertoire diversity in BCR, but not in TCR, might be associated with better clinical outcomes in advanced NSCLC patients treated with ICI. Assessment of the changes of BCR repertoire after treatment might be useful for predicting the efficacy of ICI. The present results require confirmation in a large-scale prospective study.
