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Helena Yu
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.04 - Clinical and Molecular Characteristics of EGFR Mutant Lung Cancers with Concurrent TP53 and RB1 Mutations. (ID 12513)
13:55 - 14:00 | Author(s): Helena Yu
- Abstract
- Presentation
Background
20% of patients with metastatic lung adenocarcinoma have activating EGFR-mutations. EGFR-mutant lung cancers can undergo histologic transformation to small cell lung cancer (SCLC) as a response to the selective pressure of EGFR-TKIs in <5% of patients after earlier-generation EGFR-TKIs and have been reported after osimertinib. SCLC nearly universally harbor TP53/RB1-alterations which are rarely seen in EGFR-mutant lung adenocarcinomas. We sought to identify this subset of patients, describe their clinical course and likelihood of SCLC transformation.
a9ded1e5ce5d75814730bb4caaf49419 Method
Retrospective review of targeted next generation sequencing (NGS, MSK-IMACT) at Memorial Sloan Kettering (MSK) was performed to identify patients with concurrent EGFR-activating mutations and TP53/RB1-mutations within the same tumor sample from NGS between April 2014 to February 2018 with a data cutoff of March 2018. For comparison, consecutive patients with lung cancers harboring EGFR-mutations who were EGFR-TKI naïve and TP53/RB1-wildtype were also collected during that time-period.
4c3880bb027f159e801041b1021e88e8 Result
Of the 21% of lung cancer patients with activating EGFR-mutations (759/3662), 5% (40/759) had concurrent TP53/RB1-mutations. 43% (17/40) were female, 58% former-smokers (23/40, median pack-years: 8), and median age of 68 (range 25-86 years). 88% (35/40) were adenocarcinoma at diagnosis, of which 11% (4/35) transformed to SCLC during treatment; 10% (4/40) were de-novo SCLC at diagnosis, and 1 was large cell neuroendocrine. The transformation rate was significantly higher compared to previous work from MSK evaluating EGFR-mutant patients showing 4% (4/155) transformation (p=0.04). Concurrent PIK3CA mutations were more frequently seen in the EGFR/TP53/RB1 mutant group compared to the TP53/RB1-wildtype group (17% (n=6/35) vs 7% (n=4/60), p=0.11). 20 patients were EGFR TKI-naïve at the time of NGS; the median time on EGFR-TKI (ToT) was 7.6 months versus 14.2 months in the TP53/RB1-wildtype group (HR 4.48, p=0.0003). The overall survival (OS) of this cohort versus TP53/RB1-wildtype was not different (4.3 vs 4.1 years, HR 1.35, p=0.51). In the 4 patients with SCLC transformation, the median time to transformation was 2.4 years after a median of 1.5 EGFR-TKI therapies (range 1-5 lines). Median OS from time of transformation was 7 months. 63% (25/40) of the EGFR/TP53/RB1-mutant cohort had brain metastases during their disease course as compared to 50% (n=30) in the TP53/RB1-wildtype group (p=0.30).
8eea62084ca7e541d918e823422bd82e Conclusion
SCLC transformation is enriched in EGFR/TP53/RB1-mutant lung cancers, occurring in 11% of patients. Once SCLC transformation occurs, overall survival is short. Patients with EGFR/TP53/RB1 have a shorter time on EGFR-TKI. Further investigation into optimal treatment for this subset of EGFR/TP53/RB1 mutant lung cancers is critical.
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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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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MA26.10 - CNS Activity of Ramucirumab in Combination with Osimertinib in Patients with Advanced T790M-Positive EGFR-Mutant NSCLC (ID 12295)
14:35 - 14:40 | Author(s): Helena Yu
- Abstract
- Presentation
Background
Many patients with NSCLC develop central nervous system (CNS) metastasis. Osimertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), has previously demonstrated CNS and systemic efficacy in patients with EGFR-mutant NSCLC. Combination of an EGFR TKI with a VEGF/VEGFR2-directed monoclonal antibodies (mAb) have shown promising results in EGFR-mutant NSCLC. Ramucirumab, human IgG1 VEGFR2 mAb, was used in combination with osimertinib. Planned exploratory and CNS response analyses aim to examine the safety/efficacy of ramucirumab+osimertinib in patients with CNS metastasis.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this ongoing, open-label, multicenter Phase 1 study (NCT02789345), patients with T790M-positive EGFR-mutant (Ex19del or L858R) NSCLC who had relapsed after first-line EGFR TKI therapy were enrolled. Patients with asymptomatic and stable CNS metastasis (with/without prior radiotherapy) were eligible. Primary objective of the study was to assess safety and tolerability of ramucirumab+osimertinib. Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Exploratory endpoints relevant to CNS include CNS ORR and CNS DCR.
4c3880bb027f159e801041b1021e88e8 Result
Patients (N=25) were 45-80 years (median 64) with ECOG-PS 0 (n=3) or 1 (n=22) and 10 patients had CNS metastasis at enrollment while 15 never had CNS metastasis. Patients with CNS metastasis could have had prior radiotherapy (n=7) or no radiotherapy (n=3) to the CNS. Median follow-up time was 7.23 months. Fifteen patients remained on study treatment (five with CNS metastasis, ten without). TEAEs of interest (CNS metastasis, no CNS metastasis), such as headache (4/10, 5/15), vomiting (3/10, 4/15), and nausea (2/10, 4/15), were observed with comparable rates in patients with or without CNS metastasis. One patient developed TEAE of cerebral hemorrhage (Grade 1), related to CNS metastasis, but unrelated to study treatment, according to the investigator. Another patient with CNS metastasis developed Grade 5 TRAE of subdural hemorrhage, unrelated to CNS metastasis, ~7 weeks after the last dose of ramucirumab. Only one patient with CNS metastasis had measurable CNS lesions (tumor shrinkage of 24% [SD] as best response). The other nine patients with CNS metastasis had non-measurable CNS lesions, one of whom had a CNS complete response; his systemic best response was SD. The rest of patients had CNS non-CR/non-PD. To date, one patient (1/25) developed CNS progression (due to new CNS lesion); her CNS best response was SD.
8eea62084ca7e541d918e823422bd82e Conclusion
Ramucirumab+osimertinib showed potential antitumor activity in the CNS. Patients with CNS metastasis, with/without prior radiotherapy, appeared to tolerate this combination similarly to patients without CNS metastasis.
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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MS23 - What's New in Targeted Therapy? (ID 801)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 106
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MS23.04 - Targeting Driver Oncogenes in Stage 1-3 NSCLC (ID 11499)
11:15 - 11:30 | Presenting Author(s): Helena Yu
- 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.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-74 - MET Exon 14-Altered Lung Cancers: Central Nervous System (CNS) Metastases and Patterns of CNS Progression on MET Inhibition. (ID 14263)
16:45 - 18:00 | Author(s): Helena Yu
- Abstract
Background
MET exon 14 (METex14) alterations are targetable drivers found in 3-4% of lung cancers. The frequency of intracranial disease and patterns of central nervous system (CNS) progression on MET tyrosine kinase inhibitors (TKI) are not well characterized.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced METex14-altered lung cancers identified by next-generation sequencing (MSK-IMPACT) between January 2014 and March 2018 were eligible for analysis. A retrospective review of clinical features, patterns of metastases, and CNS progression on MET-TKI was performed. The frequency of intracranial disease was compared to cohorts single-center of EGFR-mutant (n=200), ERBB2-mutant (n=98) and KRAS-mutant (n=200) lung cancers.
4c3880bb027f159e801041b1021e88e8 Result
82 patients with metastatic METex14-altered lung cancers were identified. The median age was 73; 56% (n=46) were female and 54% (n=44) were former smokers. The frequency of brain metastases at baseline was 11% (n=9/82). The lifetime frequency of intracranial metastases from diagnosis of metastatic disease was 34% (n=28/82). By comparison, the frequency of brain metastases was 47% (94/200, p=0.05) with EGFR-, 47% (46/98), p=0.09) with ERBB2-, and 32% (64/200, p=0.78) with KRAS-driven tumors. 6% (n=5/82) of patients developed leptomeningeal disease. The overall survival (OS) of patients who developed intracranial disease on therapy compared to those who did not develop intracranial disease was not significantly different (HR 0.66, 95% CI 0.30-1.43, p=0.29). 51 patients received crizotinib, 26 of whom developed progressive disease. The frequency of intracranial (alone), intracranial and extracranial, and extracranial (alone) progression was 8% (2/26), 19% (5/26), and 73% (19/26), respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
A third of patients with METex14-altered lung cancers develop intracranial disease. This proportion is lower than that seen in EGFR- and ERBB2-mutant lung cancers and comparable to KRAS-mutant lung cancers. The frequency of CNS failure on crizotinib was lower than expected compared to historical rates in ALK-rearranged lung cancers.
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P1.01-75 - Utility of cfDNA Testing for Acquired Resistance: The Memorial Sloan Kettering Experience with Plasma EGFR T790M Clinical Testing. (ID 12514)
16:45 - 18:00 | Author(s): Helena Yu
- Abstract
Background
Liquid biopsy for circulating tumor DNA (ctDNA) has been increasingly adopted for the detection of oncogenic drivers and drug resistance mechanisms. Practice guidelines for liquid biopsy are lacking and biologic factors influencing ctDNA detection and shedding are poorly understood. We evaluated factors influencing ctDNA detection, using EGFR-T790M as a case-study, in patients with acquired resistance to first/second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI).
a9ded1e5ce5d75814730bb4caaf49419 Method
This single-center study included metastatic sensitizing EGFR-mutant lung cancer patients (exon 19 deletions, L858R, G719) who underwent plasma EGFR-T790M testing after acquired resistance to erlotinib, gefitinib, or afatinib between January 2016 and August 2017. Plasma T790M was performed by digital PCR. Variant allele fraction (VAF) was calculated as mutant/(wildtype+mutant) allele. Concordance between plasma and tissue testing was examined if tissue analysis (MSK-IMPACT and/or targeted PCR) occurred within 90 days of blood draw. Turnaround time (TAT) was measured from date of blood draw and/or biopsy to result. ctDNA results were correlated with metastatic site and the number of organs involved.
4c3880bb027f159e801041b1021e88e8 Result
177 patients underwent plasma T790M testing; 65% female, 47% current/former smokers. Plasma T790M was positive in 32% (56/177) of patients, tissue testing was T790M-positive in 46% (45/97), and overall T790M-positivity by either platform was 49% (86/177). The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs 15 days, p<0.0001), and led to osimertinib use in 84% (47/56) of positive patients. Concordance between plasma and tissue T790M was 80% (32/40). 15 patients with positive plasma had matched tissue, 87% (13/15) were concordant on tissue. 76% (19/25) of the patients that were T790M-negative on plasma also tested negative on tissue. Median plasma T790M-VAF was 0.98% (range 0.1–49.5%), lower than tissue T790M-VAF (12.8%, range 2.58–27.8, p<0.0001). Plasma T790M-VAF did not correlate with time on osimertinib (p=0.72). Plasma T790M status correlated with a higher number of metastatic sites (4 vs 3, p<0.0001). Plasma T790M detection by organ sites were: pleura (58% with metastases vs 34% without metastases, p=0.14), bone (80% vs 21%, p=0.0002), hepatic (61% vs 41%, p=0.28), nodal (61% vs 33%, p=0.07), adrenal (64% vs 44%, p=0.60), brain (71% vs 38%, p=0.08), and bone/hepatic concurrently (94% vs 98%, p=0.04).
8eea62084ca7e541d918e823422bd82e Conclusion
Using plasma T790M as an archetypal example, cfDNA testing showed concordance and a shorter turnaround compared to tissue testing. cfDNA was more likely to result positive in patients with more metastatic sites, or osseous and hepatic metastases possibly driven by increased ctDNA shedding.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-43 - Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC (ID 13484)
16:45 - 18:00 | Author(s): Helena Yu
- Abstract
Background
While outcomes for patients with EGFR-mutant NSCLC have significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients once they develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poor outcomes. U3-1402 is a novel HER3-targeting antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio (DAR) of ~8:1. In vivo xenograft mouse model studies with human tumor cell lines indicate that U3-1402 exhibits HER3 expression-dependent tumor growth inhibition activity.
a9ded1e5ce5d75814730bb4caaf49419 Method
This is a multicenter Phase 1, Dose Escalation and Dose Expansion study of U3-1402 in metastatic or unresectable adenocarcinoma NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with an EGFR TKI, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45%, do not have QTc prolongation, and do not have spinal cord compression or clinically active brain metastases. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. Additionally, intra-subject dose escalation may be considered in subjects who have completed at least 4 cycles of treatment without ≥ Grade 2 treatment-emergent adverse events. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion (RDE) determined in Dose Escalation. Primary objectives are to determine the safety, tolerability, and RDE of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402 and its components, and to assess antitumor activity of U3-1402 (RECIST v1.1). Enrollment to Dose Escalation cohort 1 was completed in April 2018. Clinicaltrials.gov identifier: NCT03260491
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable - CTIP
8eea62084ca7e541d918e823422bd82e Conclusion
Section no applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
