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Mari Mino-Kenudson
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (ID 14731)
13:40 - 13:45 | Author(s): Mari Mino-Kenudson
- Abstract
- Presentation
Background
The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
4c3880bb027f159e801041b1021e88e8 Result
41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
8eea62084ca7e541d918e823422bd82e Conclusion
RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA03 - Advances in Lung Cancer Pathology (ID 897)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)
10:50 - 11:00 | Author(s): Mari Mino-Kenudson
- Abstract
- Presentation
Background
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.04-21 - The Utility of PD-L1/CD8 Dual Immunohistochemistry for Prediction of Response to Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 13815)
16:45 - 18:00 | Presenting Author(s): Mari Mino-Kenudson
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is an important predictive biomarker for PD-(L)1 blockade in advanced non-small cell lung cancer (NSCLC); however, this assay is imperfect. The presence of CD8+ tumor infiltrating lymphocytes (TILs) may be a complimentary biomarker for response to immunotherapy. Thus, we examined the performance of PD-L1/CD8 dual IHC (dIHC) in two cohorts of NSCLC patients receiving immunotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients were identified through retrospective review of medical oncology and pathology databases. The first cohort predominantly received nivolumab as a 2nd or later line treatment; tissue samples were mainly obtained at initial diagnosis. The second cohort received pembrolizumab as a first line therapy, and tissue samples were procured immediately before the initiation of immunotherapy. PD-L1/CD8 dIHC was performed on those tissue samples. Percentage of tumor cells with membranous PD-L1 expression and CD8+ stromal cells were measured, and CD8+ TILs were semi-quantitatively evaluated. The quantities of CD8+ T cells were dichotomized with appropriate cut-offs.
4c3880bb027f159e801041b1021e88e8 Result
Eighty-four patients were identified, including 60 in the Nivolumab cohort (NC) and 24 in the Pembrolizumab cohort (PC). In the NC, PD-L1 expression ≥1% was marginally associated with improved progression-free survival (PFS, p=0.09), and an increased rate of response (p=0.08). CD8+ TILs and stromal cells did not correlate with outcome. However, a subset of PD-L1-positive patients who showed abundant CD8+ TILs and stromal cells had significantly reduced PFS (p=0.04). In the PC cohort, all cases chosen exhibited PD-L1 expression in ≥50% of tumor cells. Increased CD8+ TILs were correlated with improved PFS, (p=0.0194), and an increase in both CD8+ TILs and stromal cells was also associated with improved PFS (p= 0.0238).
8eea62084ca7e541d918e823422bd82e Conclusion
Although limited by small sample size, this study suggests that PD-L1/CD8 dIHC improves the prediction of response to the PD-1/PD-L1 blockade in advanced NSCLC patients when it is performed on tissue samples obtained immediately before the initiation of the blockade as first-line therapy . However, for the 2nd or later line of treatment, dIHC on archival tissue samples obtained before initial therapy provides a useful but less clear picture of the tumor immune microenvironment. Reduced PFS seen in patients with PD-L1 expression and abundant CD8+ TILs and stromal cells may be due to T-cell exhaustion after the chemotherapy before the PD-1/PD-L1 blockade. These findings suggest that PD-L1/CD8 dIHC may be useful for treatment response stratification in advanced lung cancer patients.
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P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.12-17 - Overall Survival and Recurrence After Surgical Resection of Pure and Mixed Large Cell Neuroendocrine Tumors. (ID 13051)
16:45 - 18:00 | Author(s): Mari Mino-Kenudson
- Abstract
Background
Large-cell neuroendocrine carcinoma (LCNC) is an aggressive tumor with poor prognosis and undefined treatment. We performed a retrospective analysis on the outcomes of surgical resection and adjuvant therapy to assess the effectiveness of treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
Retrospective review of patients with LCNC who underwent surgical resection at a single-center tertiary care facility from 2002-2017. Survival times were assessed from day of surgery until death. A Kaplan-Meier method for overall survival (OS) and for recurrence was used and compared across prognostic factors using log-rank analysis and a Cox proportional hazard model.
4c3880bb027f159e801041b1021e88e8 Result
Sixty-two patients were identified with a median follow up of 3.4 years. Of these, 26 (41.9%) were male and 56 (90.3%) were current or former smokers. The majority of patients underwent a lobectomy/segmentectomy (72.6%), while a smaller percentage (14.5%) underwent wedge resection, and the remainder pneumonectomy or bi-lobectomy (4.8%). Pathologically, 31 (54.4%) were stage I, 20 (35.1%) stage II, and 6 (10.5%) stage III-IV. Additionally, 35 (56.4%) represented pure LCNC while the remaining 27 (43.6%) had a mixed histology. Median OS for resected stage I disease was 11.3 years, decreased to 4.4 years in stage II disease, and was 0.8 years in stage III-IV disease (p = 0.01) (Figure 1). For those that recurred, median time to recurrence was 1.20 years for stage I and 1.15 years for stage II disease. Adjuvant therapy, type of resection, and tumor histology (pure vs. mixed) had no significant impact on OS on unadjusted or adjusted analysis.
8eea62084ca7e541d918e823422bd82e Conclusion
LCNC is associated with early recurrence after surgical resection and poor survival for patients with stage III and IV disease. In patients with mixed histology survival and recurrence remain similar to those with pure LCNC tumors.
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P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.12-02 - Dynamics of DLL3 and ASCL1 Expression in SCLC Over Disease Course (ID 12609)
12:00 - 13:30 | Author(s): Mari Mino-Kenudson
- Abstract
Background
SCLC is a high-grade neuroendocrine malignancy highly responsive to first-line therapy, etoposide plus platinum (EP), but increasingly resistant to subsequent lines of therapy. Because SCLC is rarely biopsied following the initial diagnosis, the dynamics of expression of therapeutically relevant biomarkers in relapsed disease are poorly understood. ASCL1 is an oncogenic driver of SCLC and directs transcription of delta-like protein 3 (DLL3), an atypical Notch receptor family ligand involved in neuroendocrine tumorigenesis and the target of the antibody drug conjugate rovalpituzumab tesirine (Rova-T™). We investigated ASCL1 and DLL3 expression in SCLC patient (pt) tumor biopsies and patient-derived xenografts (PDXs) collected serially from time of diagnosis (pre-treatment) and after progression following ≥1 lines of therapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Fresh cut, formalin fixed, paraffin embedded tissue from primary SCLC tumors and PDXs was sectioned and stained with mouse monoclonal antibodies against DLL3 (SC16.65) and ASCL1 (SC72.201) on the Dako platform. ASCL1 and DLL3 expression were scored as a percent of positive cells and correlated with each pt’s treatment history.
4c3880bb027f159e801041b1021e88e8 Result
Among biopsies and/or PDXs derived over serial time points, 6 cases had baseline positive DLL3 expression ranging from 15-80% of cells with a mean of 50% pre-EP. All 6 remained positive following progression after EP, with DLL3 expression ranging from 10-100% of cells with a mean of 66%. Up to 7 serial tissue or PDX samples were available over the course of multiple treatments for 2 pts, and DLL3 and ASCL1 expression remained consistent over time, being strongly positive in 1 case and negative in the other. Among biopsies and PDXs established at matched time points, ASCL1 and DLL3 expression were consistent in 7/7 and 7/8 cases, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
ASCL1 and DLL3 expression remain mostly consistent pre- and post- chemotherapy in pts with SCLC, suggesting that expression of these biomarkers in archival tissue likely accurately estimates expression even after intervening treatments. Furthermore, PDXs derived both from biopsies and circulating tumor cells maintain ASCL1 and DLL3 expression that reflects the pt tumor, supporting use of PDXs to model pt tumor biology.
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PC06 - Controversies in Immunobiomarker Testing (ID 845)
- Event: WCLC 2018
- Type: Pro-Con Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 106
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PC06.02 - Laboratory Developed Test - CON (ID 11626)
13:50 - 14:10 | Presenting Author(s): Mari Mino-Kenudson
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
