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Hidenobu Ishii
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-30 - Phase I Study of Afatinib Plus Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations (ID 1580)
09:45 - 18:00 | Author(s): Hidenobu Ishii
- Abstract
Background
Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is one of the standard therapies for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. The first-generation EGFR-TKIs in combination with bevacizumab have been reported to improve progression-free survival (PFS). However, data on afatinib plus bevacizumab are limited.
Method
In this phase I study, we examined the safety and the efficacy of afatinib plus bevacizumab in patients with advanced non-squamous NSCLC harboring EGFR mutations. This study comprised two cohorts. In the dose-finding cohort, eligible patients received afatinib 20, 30, or 40 mg/day (days 1–21) plus bevacizumab 15 mg/kg (day 1) in 21-day cycles. This cohort was designed and conducted in a 3 + 3 manner. In the expansion cohort, the patients were treated with the recommended dose (RD) based on the findings in the dose-finding cohort, and we evaluated the preliminary efficacy of this combination therapy. The serum trough concentration of afatinib was assessed at the steady state.
Result
Sixteen patients were enrolled in this study (5 patients in the dose-finding cohort and 11 patients in the expansion cohort). No dose-limiting toxicities (DLTs) occurred with afatinib 30 mg/day. With afatinib 40 mg/day, 2 out of 2 patients had DLTs (grade 3 diarrhea) in cycle 1. From these results, afatinib 30 mg/day plus bevacizumab 15 mg/kg was decided as the RD. Additionally, 11 patients in the expansion cohort were treated with RD. Common treatment-emergent 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 and interstitial lung disease. The response rates and median PFS were 56% and 16.8 months in EGFR-TKI naïve patients, and 0% and 4.9 months in patients pretreated with EGFR-TKIs. The median serum concentration at the steady state was 13.7 ng/mL (range: 8.1–38.1 ng/mL) in the patients treated with the RD. Rebiopsy was conducted in eight patients after disease progression with afatinib plus bevacizumab, and three patients acquired an exon 20 T790M mutation.
Conclusion
Afatinib 30 mg/day plus bevacizumab 15 mg/kg was well tolerated. Large-scale studies are warranted to evaluate the efficacy of this combination therapy.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- 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): Hidenobu Ishii
- 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.
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P2.04-85 - Clinical Significance of the PD-L2 Expression in Patients with NSCLC Receiving Anti-PD-1 Inhibitors (ID 1611)
10:15 - 18:15 | Presenting Author(s): Hidenobu Ishii
- Abstract
Background
The programmed cell death 1 (PD-1) receptor–ligand interaction is a major pathway often hijacked by tumors to suppress immune control. Programmed cell death-ligand 1 (PD-L1), a ligand of PD-1, can potentially predict the response to anti-PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC); however, the role of PD-L2, another ligand of PD-1, remains unclear in patients receiving anti-PD-1 inhibitors. This retrospective study aims to determine the significance of the PD-L2 expression in anti-PD-1 inhibitors–treated patients with NSCLC.
Method
We enrolled 82 patients with advanced or recurrent NSCLC who received anti-PD-1 inhibitors. The PD-L2 expression was assessed by immunohistochemical analysis staining with an antibody of PD-L2 (1:200, clone 176611), and cases with >1% tumor staining of PD-L2 were considered positive. Furthermore, we analyzed correlations between PD-L2 expression and patients’ characteristics, efficacy, and immune-related adverse events (irAEs) of anti-PD-1 inhibitors.
Result
In this study, 59 (72.0%) and 56 (68.3) patients with NSCLC exhibited positive tumor PD-L2 and PD-L1 staining, respectively. Overall, 39 irAEs developed in 36 patients. The PD-L2 expression markedly correlated with the development of irAEs; however, we observed no correlation between PD-L2 expression and the efficacy of anti-PD-1 inhibitors. Other factors, including the PD-L1 expression, age, sex, smoking status, histology, did not correlate with the development of irAEs.
Conclusion
This study suggests that the PD-L2 expression could be accountable for the development of irAEs in anti-PD-1 inhibitors–treated patients with NSCLC.
