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Toru Kumagai
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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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EP1.01-13 - A Phase 2 Trial Assessing Osimertinib Activity Against Leptomeningeal Carcinomatosis in EGFR-Mutant Lung Cancer (Now Available) (ID 470)
08:00 - 18:00 | Author(s): Toru Kumagai
- Abstract
Background
Leptomeningeal carcinomatosis (LMC) occurs in 10 % of EGFR-mutant lung adenocarcinoma (LA). Retrospective studies have suggeted a clinical benefit of osimertinib in treating LMC in patients with EGFR-mutant LA. We conducted a phase 2 prospective trial to demonstrate the clinical efficacy, activity, and LMC-specific mechanisms of resitance to osimertinib in EGFR-mutant LA patients.
Method
We performed gadalidium-enhanced brain MRIs at the time of enrollment, followed by scheduled brain imaging once every six weeks. Clinical neurological exams were performed every four weeks. Adverse Events (AEs) were assessed by NCI-CTCAE Ver. 4. Cerebral spinal fluid (CSF) and plasma was obtained on day 1 and 21 for all patients. The CSF osimertinib penetration rate was measured by liquid-chromatography mass spectrometry (LC-MSMS) and compared to plasma osimertinib levels. Targeted droplet digital PCR (ddPCR) was used to detect copy number changes of Met and the EGFR C797S mutation in patients CSF-DNA and plasma cell free (cf) DNA.
Result
We enrolled six pre EGFR-TKI treated EGFR mutant LA with LMC. We observed a LMC-specific progression free survival of 3.7 months and overall survival of 6.2 months or longer with osimertinib. Four and three of six patients showed neurological and radiological responses, respectively. No patients had any AEs greater than grade 3 and all patients continued osimertinib beyond PD. The osimertinib CSF penetration rate was 1.2±0.5%. Met copy number was normal in plasma, but increased in the CSF of 2/6 patients prior to progression. Met copy number was confirmed in 1/6 patients at the time of progression. An aquired EGFR C797S mutation was observed in 1/6 patients prior to progression.
Conclusion
Osimertinib 80 mg is efficacious in the treatment of LMC in EGFR mutated LA. CSF-specific MET copy number gain and EGFR C797S mutations arise prior to progression in EGFR-mutant LA patients treated with osimeritinib.
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-08 - Irreversible Severe Cardiotoxicities Except for QTc Interval Prolongation Associated with Osimertinib (Now Available) (ID 2255)
08:00 - 18:00 | Author(s): Toru Kumagai
- Abstract
Background
QTc interval prolongation is a known and warning cardiotoxicity associated with Osimertinib. The final summary on the safety profile of Osimertinib (AstraZeneca plc) reports that severe cardiotoxicities except for QTc interval prolongation are 0.8 % (29/3578 patients) and alerts us to such adverse events. Here, we report irreversible severe cardiotoxicities associated with Osimertinib except for QTc interval prolongation.
Method
We reviewed the medical records of EGFR-mutated Non-Small Cell Lung cancer patients who were treated with Osimertinib at Osaka International Cancer Institute between March 2016 and January 2019. We checked cardiotoxicities associated with Osimertinib based on the medical records.
Result
We enrolled 123 patients treated with Osimertinib into this study. The median age was 69 (range: 33-86) years. Of 123 patients, 40 (32.5%) were male, all cases except one were adenocarcinoma, EGFR mutation profile was Ex. 19 del/ L858R/ de novo T790M/ others(G719S, L861Q); 62 (50.4%)/ 56 (45.5%)/ 3/ 2. Osimertinib treatment line was 1st line; 23 (18.7%), 2nd line; 30 (24.4%), 3rd line; 18 (14.6%), ≧4th line; 41 (33.3%), 11 pts; switching from other EGFR-TKI during 1st line. Severe cardiotoxicities (CTC-AE Gr.3≧) were observed in 5 pts (4.1%); acute myocardinal infarction (1), irreversible congestive heart failure due to systolic dysfunction (1), exacerbation of tricupid regurgitation (1), decreasing ejection fraction (EF) (2). QTc interval prolongation was observed only in one patient (Gr.1). Histopathological analysis of a myocardial biopsy from one patient with decreased EF (Gr.3) revealed inflammatory cells infiltration into cardiomyocytes. Intriguingly, afatinib switched from osimertinib overcame osimertinib induced cardiomyopathy in the patient.
Conclusion
We experienced severe cardiotoxicities associated with Osimertinib at a higher frequency (4.1%) than reported before. Considering some patients were forced to quit their chemotherapy due to severe cardiotoxicities. We should pay attention to not only QTc interval prolongation but also other cardiotoxicities in administrating Osimertinib in the clinical setting. Afatinib could be an alternative to Osimertinib for overcoming Osimertinib-induced cardiotoxicities.
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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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P1.01-57 - Association of Initial PD-L1 Expression with T790M-Acquired Resistance in Advanced EGFR-Mutant Lung Adenocarcinoma Patients (Now Available) (ID 716)
09:45 - 18:00 | Author(s): Toru Kumagai
- Abstract
Background
The primary objective was to investigate the association between initial programmed cell death-ligand 1 (PD-L1) expression levels and the frequency of T790M-acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase Inhibitor (TKI) in patients with advanced EGFR-mutant lung adenocarcinoma.
Method
We examined patients with advanced EGFR-mutant lung adenocarcinoma whose initial PD-L1 expression levels and T790M-acquired mutation status after EGFR-TKI failure (gefitinib, erlotinib or afatinib) could be evaluated. We retrospectively investigated the patients’ characteristics and survival, as well as the association between initial PD-L1 expression levels and frequency of T790M-acquired resistance
Result
Overall, 100 patients were enrolled. Nine (9%) patients had an initial PD-L1 tumor proportion score (TPS) of ≥50%, 19(19%) had PD-L1 TPS of 1%-49%, and 72 (72%) had PD-L1 TPS of <1%. T790M-acquired mutation (T790M+) was identified in 57 (57%) patients. Initial PD-L1 expression levels were not associated with the frequency of T790M-acquired mutations in patients (p=0.822). Positive PD-L1 expression (PD-L1+) was associated with lower OS compared with negative PD-L1 expression (PD-L1-) (median overall survival [OS], 40.3 vs 74.3 months, p=0.0053). Furthermore, T790M+ was associated with longer OS compared with T790M- in total and PD-L1- population (total: median OS, 74.3 vs 41.3 months, p=0.0154, PD-L1-: median OS, 82.0 vs 41.2 months, p=0.00412), but not in PD-L1+ population (median OS, 36.2 vs 46.2 months, p=0.792). Among 57 patients with T790M-aquired mutation, 49 received osimertinib treatment. The estimated median progression-free survival rate of osimertinib was 13.2 months in PD-L1- patients (n=37) and 6.9 months in PD-L1+ patients (n=12) (p=0.224).
Conclusion
There was no association between initial PD-L1 expression levels and the frequency of T790M-aquired mutations in patients. However, PD-L1+ expression levels in patients with treatment-naïve advanced EGFR-mutant lung adenocarcinoma predicted poorer outcomes. Intriguingly, T790M-aquired mutations were related to longer OS in PD-L1- patients, but not in PD-L1+. Thus, for patients with T790M-acquired mutant and initial PD-L1 positive lung adenocarcinoma in whom the use of osimertinib is indicated, other treatment options should be considered without hesitation if the treatment effects are not as expected.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-62 - Nomogram Based on Multivariable Regression Model Estimates the Overall Survival of Nivolumab for Previously Treated Advanced NSCLC (ID 2231)
09:45 - 18:00 | Author(s): Toru Kumagai
- Abstract
Background
Nivolumab (Nivo) has demonstrated with its efficacy against metastatic non-small cell lung cancer (NSCLC). However, it has been also reported that Nivo does not show beneficial effects in approximately 80% of patients. The predictive ability of biomarkers still is yet unclear; thus identifying biomarkers which better predict overall survival (OS) of such patients treated with Nivo is crucial. In this study, we conducted multivariable cox regression analysis including biomarkers and clinical factors measured at the time of initiating treatment with Nivo to assess predictive ability of OS of patients. Results of the multivariable analysis were elucidated with a nomogram which estimates the OS of Nivo in previously treated patients with advanced NSCLC.
Method
In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement, and we evaluated two programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems (22C3 and 28-8).
Result
The median age at the time of administration nivolumab was 68 years, 135 patients were male, 157 patients had a smoking history, and 152 patients had a performance status (PS) score of 0–1. 39 patients had EGFR (37) or ALK (2) mutation positive. For 22C3 and 28-8, 36.3% and 36.8% of patients were negative, 17.4% and 14.4% had PD-L1 status of 1-49%, and 11.9% and 14.9% had PD-L1 status of ≥50%, 34.3% and 33.8% had PD-L1 status of missing, respectively. Kendall’s rank correlation coefficient between 22C3 and 28-8 was 0.8414. The median OS of all patients was 333 (95% confidence interval (CI): 116-520) days. In the multivariate analysis, PS score ≥2 (hazard ratio (HR): 2.23; 95%CI: 1.36-3.66 p<0.001), high LDH level at baseline (HR: 1.13 95%CI: 1.03-1.24; p=0.008, and progression disease (PD) of pre-treatment response (HR: 3.64 95%CI: 2.29-5.79 p<0.001) were significantly associated with poor OS. There was not significant distance between PD-L1 status and OS of Nivo. Based on these analyses, we created the nomogram to estimate the OS of Nivo in previously treated patients with advanced NSCLC.
Conclusion
PS score ≥2, high LDH levels at baseline, and PD of pre-treatment response were predictive of poor OS of Nivo, moreover the nomogram might be useful to estimate the OS of Nivo in previously treated patients with advanced NSCLC. (UMIN-ID: UMIN000025908)
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P1.04-77 - Efficacy of Anti-PD-1/L1 Therapy for Advanced Non-Small Cell Lung Cancer with Preexisting Autoimmune Markers (ID 1001)
09:45 - 18:00 | Author(s): Toru Kumagai
- Abstract
Background
Targeting therapies against the programmed cell death protein-1/ligand 1 (PD-1/L1) pathway has become a standard for patients with advanced non-small cell lung cancer (NSCLC). However, most clinical trials have not evaluated its safety and efficacy in patients with autoimmune diseases or with preexisting autoantibodies. Antinuclear antibodies (ANAs) are a spectrum of autoantibodies that target various nuclear and cytoplasmic components of the cells. Rheumatoid factors (RFs) are antibodies (immunoglobulin M) that react with immunoglobulin G. They are usually used as serological markers for autoimmune diseases. Recently, the relationship between these antibodies and some types of cancers has been identified, suggesting that autoantibodies might be associated with carcinogenesis and represent a state of pre-autoimmunity. Preexisting autoantibodies have been reported to be a surrogate marker of the efficacy of immunotherapy, but the trend is different by reporting.
Method
To examine the effects of preexisting autoantibodies in anti-PD-1/L1 therapy, clinical data including ANAs and RF were reviewed retrospectively in patients with advanced NSCLC who received monotherapy with a PD-1/L1 inhibitor. Survival outcome was estimated with the Kaplan-Meier method and was compared between patient groups with the log-rank test.
Result
In this retrospective analysis, we evaluated 275 patients with advanced NSCLC who received nivolumab, pembrolizumab or atezolizumab monotherapy, at Osaka International Cancer Institute in Japan between December 2015 and December 2017. The median age was 68 (range 27 to 80 years). 199 were men. ANAs were analyzed in 176 of 275 (64%) patients, and RF were analyzed in 161(56%). 68 of 176 (38.6%) were positive for ANAs (more than 1:40 serum dilution) and 21 of 161(13%) were positive for RF (more than 15IU/ml). None of the patients had active symptoms of an autoimmune disease. The median Time to Treatment Failure (TTF) was significantly shorter in patients positive for RF, 1.9 (95%CI, 0.5-2.9) months, than in those without RF, 3.5 (95%CI, 2.0-4.3) months. No significant differences in Overall Survival (OS) (12.5 versus 19.8 months) were observed between patients with or without RF, but OS in patients positive for RF tended to be shorter. Although no significant differences in OS (21.1 versus 19.4 months) and TTF (3.6 versus 2.8 months) were observed between patients with or without preexisting ANAs, OS in patients strongly positive (more than 1:160 serum dilution) for ANAs tended to be shorter compared to mildly positive patients (1:40, 1:80 serum dilution) (22.2 versus 12.7 months).
Conclusion
The presence of preexisting RFs may be a factor for poor prognosis in NSCLC patients undergoing anti PD-1/L1 therapy. There was no significant difference between patients with and without ANAs, but high titer of ANAs may be a factor in poor OS.
