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Poster Display session 3

4727 - Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single agent pembrolizumab (P)

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Translational Research

Tumour Site

Presenters

Cindy Yang

Citation

Annals of Oncology (2019) 30 (suppl_5): v25-v54. 10.1093/annonc/mdz239

Authors

C. Yang1, M.A. Iafolla2, S. Dashner3, W. Xu4, A.R. Hansen2, P. Bedard2, S. Lheureux5, A. Spreafico2, A.A. Razak2, H. Wu3, S. Shchegrova3, Z.A. Liu6, P.S. Ohashi7, D. Torti8, M. Louie9, H. Sethi10, A. Aleshin9, L.L. Siu11, S. Bratman4, T.J. Pugh8

Author affiliations

  • 1 Medical Biophysics, University of Toronto, M5S3M2 - Toronto/CA
  • 2 Medical Oncology, Princess Margaret Cancer Center, M5G 2M9 - Toronto/CA
  • 3 Research, Natera, Inc., 94070 - San Carlos/US
  • 4 Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto/CA
  • 5 Division Of Medical Oncology & Hematology, UHN-Princess Margaret Hospital, Toronto/CA
  • 6 Research, Princess Margaret Cancer Center, M5G2M9 - Toronto/CA
  • 7 Immunology, University of Toronto, Toronto/CA
  • 8 Ontario Institute For Cancer Research, Ontario Institute for Cancer Research, M5G0A3 - Toronto/CA
  • 9 Oncology, Natera, Inc., 94070 - San Carlos/US
  • 10 R&d, Natera, Inc., 94070 - San Carlos/US
  • 11 Medical Oncology And Hematology Department, Princess Margaret Cancer Centre, M5G 1Z5 - Toronto/CA

Resources

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Abstract 4727

Background

Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade.

Methods

Pts with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if ≥ 2 of 16 pt-specific targets met the qualifying confidence score threshold.

Results

Of 94 pts are presented. Demographics: male 38%; median age=55 yrs (range 21–81); triple negative breast (19%), ovarian (19%) and head and neck (17%) cancers comprised the major malignancies. Median no. of P cycles=3 (range 1–35); follow up was 14m (range 0.6-35.4); RECIST responses: CR 3.2% (n = 3), PR 14% (n = 13), CBR (CR+PR+SD>6 cycles) 28% (n = 26), RECIST/clinical PD (n = 61/18; 65%/19%). Median PFS=2.5m and median OS = 14m. In all 94 pts, ctDNAB correlated with PFS (adjusted HR 0.53, 95% CI 0.34-0.84, p = 0.01) and OS (adjusted HR 0.47, 95% CI 0.28-0.8, p = 0.01). Among 74 pts with both ctDNAB and ctDNAC3, the change (ΔctDNA) correlated with clinical efficacy parameters (Table).Table: 113P

EndpointORR N = 72*CBR N = 72*EndpointPFS N = 73*OS N = 73*
SubgroupCR/PR N = 15SD/PD N = 57CR/PR/SD≥6 cycles N = 22CR/PR/SD<6 cycles N = 50Subgroup↑ from baseline N = 33↓ from baseline N = 40↑ from baseline N = 33↓ from baseline N = 40
ΔctDNA (% change)Median = -91.5% Range = -100% to 60%Median = 40% Range = -98.4% to 2458%Median = -75% Range = -100% to 96%Median = 52% Range = -94.6% to 2458%Results based on ΔctDNAMedian = 7.9m 6m = 51.5%Median = 2.8m 6m = 10.0%Median = not reached 6m = 91% 12m = 82%Median = 9.1m 6m = 73% 12m = 45%
P-valueP < 0.001P < 0.001Adjusted HR (95% CI)^0.43 (0.25-0.75) P = 0.0030.35 (0.18–0.67) P = 0.002
^

Adjustment on cohorts;

*

2 pts were excluded from ORR/CBR analyses as baseline ctDNA = 0; 1 of these 2 pts (with PR) excluded from PFS/OS analyses as C3 ctDNA = 0

Conclusions

Strong correlations exist between both ctDNAB and ΔctDNA with clinical outcome, suggesting both prognostic and predictive values in pts with mixed solid tumors.

Clinical trial identification

NCT02644369, December 31, 2015.

Editorial acknowledgement

Legal entity responsible for the study

University Health Network, Toronto.

Funding

Merck, Netera, Terry Fox Research Institute, Princess Margaret Cancer Foundation.

Disclosure

S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A.R. Hansen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. P. Bedard: Honoraria (institution), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Oncothyreon. S. Lheureux: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Tesaro. A. Spreafico: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Oncology/Johnson & Johnson; Research grant / Funding (institution): Array Biopharma. A.A. Razak: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Adaptimmune. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. P.S. Ohashi: Honoraria (self), Advisory / Consultancy: Symphogen Inc; Honoraria (self), Advisory / Consultancy: Providence Therapeutics. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. L.L. Siu: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfiser; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Honoraria (self), Advisory / Consultancy: Morphosys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy: GeneSeeq; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: Oncorus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boerhinger-Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Shattucks; Spouse / Financial dependant: Agios. S. Bratman: Research grant / Funding (self): Nektar Therapeutics; Licensing / Royalties, Co-inventor of a patent relating to circulating tumor DNA detection technology: Roche Molecular Diagnostics. T.J. Pugh: Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Medical Advisors; Advisory / Consultancy: DynaCare; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

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