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Tatsuya Yoshida
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.04 - Predictive Efficacy of Morphological Biomarkers Based on Digital Pathology for ICI Therapy of Non-Small Cell Lung Cancer (ID 3436)
00:00 - 00:00 | Author(s): Tatsuya Yoshida
- Abstract
Introduction
PD-L1 IHC is a widely used biomarker for immune checkpoint inhibitor therapy (ICI), but it does not have high specificity. It is essential to establish more accurate biomarkers for modern medicine. Our previous preliminary study (presented at 2019 WCLC) indicated the morphological feature's substantial value as a biomarker for ICI therapy. The morphological biomarkers (MBM) using digital whole-slide images can be tested from archived FFPE specimens. Here, we report our study on the prediction potency of morphological biomarkers for lung cancer patients treated by anti-PD1 inhibitors.
Methods
255 NSCLC who received ICI therapy were recruited. Digital images of H&E and PD-L1 (22C3) IHC stained slides of pre-treatment biopsied or resected materials were examined by previously reported image analysis techniques (NEC, Japan). The morphological characteristics of cancer cells were also evaluated by the pathologist's eyeball (PPI, pathological prediction index score 1-3). PD-L1 IHC (22C3) and tumor mutation burden (TMB) by the NGS-based target sequence (NCC oncopanel ®) were examined. Using morphological characteristics of HE images, we build a prediction model using the decision tree method (MBM-DT) first, then applied a deep learning framework (MBM-DNN) to response prediction. We compared the prediction potency for the ICI-therapeutic response of each score. The relative area proportion of the seven-index spider plot using test quality indicators was measured. The logistic regression test was calculated (SPSS). A p-value of less than 0.05 was defined as statistically significant.
Results
Pathological prediction index (PPI) scores showed superior prediction ability to that of the PD-L1 test. The accuracy of PPI-score 3, PPI-score 2+3, PD-L1 with 1% cutoff (PD-L1-1%), PD-L1 with 50% cutoff (PD-L1-50%), TMB-high, and driver gene mutation-negative was 0.71, 0.64, 0.60, 0.66, 0.57 and 0.57, respectively. MBM_DNN had the highest accuracy, specificity, positive prediction value (PPV), and the lowest false-negative rate (FNR) among the tested biomarkers. PPI-(2+3) had the highest sensitivity and negative prediction value (NPV), and false-negative rate (FNR). The seven-index spider plot showed the superiority of PPI-score 3, PPI-score 2+3 to PD-L1. Both PPI and MBM showed superior accuracy to PD-L1, TMB, and gene mutation status. The area proportion of seven test-index spider plots was 50, 56, 45 for PPI-score 3, MBM_DNN, and PD-L1-50%. Accuracy of training, validation, and a test set of MBM-DNN resulted in 0.85, 0.61, and 0.64, respectively. The logistic regression analysis revealed that males, smokers, the absence of driver gene mutation, positive/high expression of PD-L1, high PPI-score, the positive MBM-DNN, and MBM-DT are likely to be non-responder by univariate analysis. PPI-score 2+3(0.31, <0.001), MBM-DNN (0.23, <0.001), and MBM-DT (0.32, <0.001) are the significant factors for prediction of ICI response, but others are not by multivariate analysis. Conclusion
Our results showed the superior value of the morphological biomarker for ICI response prediction, compared to PD-L1 IHC and TMB. The morphological biomarker can be a useful biomarker for clinical therapeutic decisions.
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P75 - Immunotherapy (Phase II/III Trials) - Misc. Topics (ID 248)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P75.01 - Activity of Brigatinib in Alectinib-Resistant ALK-Positive NSCLC According to ALK Plasma Mutation Status From J-ALTA Trial (ID 3615)
00:00 - 00:00 | Author(s): Tatsuya Yoshida
- Abstract
Introduction
Brigatinib is a selective and potent ALK tyrosine kinase inhibitor (TKI) with preclinical activity against wild-type ALK and a broad spectrum of ALK secondary mutants, known to confer clinical resistance to crizotinib, ceritinib, and alectinib. Brigatinib has shown promising efficacy in Japanese patients with ALK+ NSCLC previously treated with alectinib in a phase 2 trial (J-ALTA). As an exploratory correlative analysis, we examined the relationship of ALK mutation status with brigatinib treatment outcome by NGS analysis of cell free DNA (cfDNA) using plasma specimens at baseline prior to brigatinib treatment (baseline [BL]) in ALK+ NSCLC patients who progressed on alectinib or other ALK TKIs and enrolled in this study.
Methods
Plasma samples were analyzed using the PGDx elioTM plasma resolve (Personal Genome Diagnostics, Baltimore, MD, USA) to determine ALK kinase domain mutations and EML4-ALK fusion status. Brigatinib activity was defined by the confirmed objective response rate (ORR) (RECIST v1.1). Data are reported as of January 22, 2019 for J-ALTA trial.
Results
Of the 72 ALK+ NSCLC patients enrolled, evaluable plasma samples were obtained from 70 patients at BL; alectinib was the most recent ALK TKI (with or without prior crizotinib) in 51 patients. Of these, 30.0% (21/70) of patients had confirmed response to brigatinib, and 35.3% (18/51) of post-alectinib patients responded to brigatinib. Secondary ALK mutations were detected in plasma in 15.7% (11/70) of patients (10 post-alectinib and 1 post-ceritinib). ORR was confirmed in 45.5% (5/11) of these patients. Best responses in patients with secondary ALK mutations were: 5 confirmed partial responses (PRs); 4 stable disease (SD); 2 progressive disease (PD), including 1 confirmed PR and 2 SD in patients with ALK G1202R mutation at BL. No secondary ALK mutations were detected in 84.2% (59/70), ORR was confirmed in 27.1% (16/59) of these. Gene amplification was detected in only 1 patient (MYC gene amplification).
Conclusion
BL EML4-ALK fusion was detected in 51.4% (36/70) of the post-ALK TKIs patients; 25.0% (9/36) of these had secondary ALK mutations. Post-BL samples were also collected from 49 patients at the end of brigatinib treatment. Secondary ALK mutations were detected in 7 patients: 1 with F1174L (also had G1202R at BL); 1 with E1210K (also had I1171S at BL); 5 with G1202R (2 not present at BL; 2 present at BL; 1 present at BL and S1206F also detected). MYC gene amplification was detected in 2 patients.
ALK fusions were detected in the plasma of over 50% of ALK+ NSCLC patients resistant to alectinib and/or other TKIs. Brigatinib demonstrated meaningful activity in ALK TKI-resistant patients regardless of the presence of secondary ALK mutations and EML4-ALK fusion status in plasma. Clinical trial information: NCT03410108.
