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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

3625 - Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Benjamin Besse

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

B. Besse1, V. Subbiah2, A. Drilon3, M. Shah4, L.J. Wirth5, T.M. Bauer6, V. Velcheti7, N. Lakhani8, V. Boni9, B.J. Solomon10, M. Johnson11, K. Park12, J. Patel13, M.E. Cabanillas14, E. Sherman3, E. Zhu15, K. Gordon15, K. Ebata15, B. Tuch15, G. Oxnard16

Author affiliations

  • 1 Dept Of Cancer Medicine, Gustave Roussy Institut de Cancérologie, 94805 - Villejuif/FR
  • 2 Investigational Cancer Therapeutics (phase 1 Program), The University of Texas, MD Anderson Cancer Center, 77030 - Houston/US
  • 3 Medical Oncology, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 4 Comprehensive Cancer Center, The Ohio State University, 43210 - Columbus/US
  • 5 Cancer Center, Massachuetts General Hospital, Boston/US
  • 6 Oncology, Sarah Cannon Research Institute, Tennessee Oncology, 37205 - Nashville/US
  • 7 Hematology And Oncology Department, Cleveland Clinic, Cleveland/US
  • 8 Developmental Therapeutics, START - Midwest, 40503 - Grand Rapids/US
  • 9 Medical Oncology, START Madrid-CIOCC HM Hospital Sanchinarro, Madrid/ES
  • 10 10molecular Therapeutics And Biomarkers Laboratory, Peter MacCallum Cancer Center, 3002 - Melbourne/AU
  • 11 Oncology, Sarah Cannon Research Institute, Tennessee Oncology, Nashville/US
  • 12 Div. Of Heamatology/oncology, Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, 135-710 - Seoul/KR
  • 13 Thoracic Oncology, University of Chicago, Chicago/US
  • 14 Department Of Endocrine Neoplasia And Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston/US
  • 15 Translational Medicine, Loxo Oncology, Inc, 94080 - South San Francisco/US
  • 16 Medical Oncology, Dana-Farber Cancer Institute, Boston/US
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Resources

Abstract 3625

Background

LOXO-292 is a novel, highly-selective, small molecule inhibitor of RET currently in clinical development (Phase 1, NCT03157128) for pts with advanced cancers harboring oncogenic RET alterations (e.g. non-small cell lung cancer [NSCLC], medullary thyroid cancer [MTC], papillary thyroid cancer [PTC], etc.). Here, we update data previously presented at ASCO 2018 on modulation of RET variant allele frequencies (AF) in plasma cfDNA with LOXO-292 therapy.

Methods

Blood was collected pretreatment, after 15 days of treatment, and at each restaging for cfDNA analysis by next-generation sequencing (NGS, Guardant).

Results

As of 4/2/18, 82 pts were enrolled (38 RET fusion NSCLC, 29 RET mutated MTC, 9 RET fusion PTC, 2 RET fusion pancreatic cancer and 4 others) to 8 dose cohorts (20mg QDà240mg BID), and 343 plasma samples were collected. Here we report on 65 pts with plasma NGS results available. Of 62 pts enrolled based on a RET variant detected in a tumor sample, concordant RET alterations were detected in 41 (66%) of the corresponding pre-treatment plasma samples, including 19/30 (63%) pts with RET-fusion NSCLC and 16/21 (76%) pts with RET-mutant MTC. Median AF was higher for MTC (7.03%) than NSCLC (0.51%). In RET alteration-negative pre-treatment samples, peak AF for other detected alterations was generally low (0.28% median), suggesting low tumor DNA shed into plasma. Of 34 pts with a detectable pre-treatment plasma RET alteration and day 15 plasma NGS, RET alteration AF decreased by a median of 96%, with complete clearance in 15 pts (44%). Day 15 plasma clearance was observed at multiple doses, and was more common in RET fusion-positive (67%) than RET-mutant (8%) pts. Data for additional pts will be updated at the time of presentation.

Conclusions

The rapid clearance of RET variants from plasma cfDNA on LOXO-292 supports its observed clinical activity across a range of doses, tumor types and RET alterations. NGS of plasma cfDNA can detect a range of targetable RET variants, though tumor genotyping remains critical if the initial plasma NGS is negative. Serial plasma genotyping warrants continued study as an early pharmacodynamic marker for novel targeted therapies.

Clinical trial identification

NCT03157128.

Legal entity responsible for the study

Loxo Oncology Inc.

Funding

Loxo Oncology Inc.

Editorial Acknowledgement

Disclosure

B. Besse: Grant funding: AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, Onxeo, OncoMed, Inivata, OSE Pharma, Loxo. A. Drilon: Honoraria: Foundation Medicine; Pfizer; Advisory board Honoraria from Roche/Genentech, Takeda/Ariad, Loxo Oncology, Ignyta. L.J. Wirth: Personal fees: Eisai Inc., Novartis. B.J. Solomon: Honoraria: Pfizer and Novartis; Consulting or advisory role: AstraZeneca, Roche, Merck, BMS, Novartis. E. Zhu: Employee: Loxo. K. Gordon: Employee and stockholder: Loxo Oncology. K. Ebata: Personal fees and other support: Loxo Oncology, Inc during the conduct of the study; Personal fees and other support: Loxo Oncology, Inc., outside the submitted work. B. Tuch: Employee and share holder: Loxo Oncology. All other authors have declared no conflicts of interest.

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