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Poster session 06

1669P - Monitoring immune checkpoint inhibition in advanced solid tumors using genome-wide cfDNA fragmentomes

Date

10 Sep 2022

Session

Poster session 06

Topics

Cancer Biology;  Immunotherapy

Tumour Site

Presenters

Jamie Medina

Citation

Annals of Oncology (2022) 33 (suppl_7): S758-S771. 10.1016/annonc/annonc1078

Authors

J.E. Medina1, E.T. Roussos Torres2, A. Leal1, V. Adleff1, K. Lumbard3, L. Keefer3, J. Carey3, A. Brufsky4, P. Lorusso5, J.P. Eder6, V. Chung7, M. Downs1, A. O'Connor1, R. Piekarz8, H. Streicher9, E.M. Jaffee1, R.B. Scharpf1, V. Stearns1, R.M. Connolly10, V.E. Velculescu1

Author affiliations

  • 1 Oncology, Johns Hopkins Medicine - The Sidney Kimmel Comprehensive Cancer Center, 21231 - Baltimore/US
  • 2 Medical Oncology, USC - University of Southern California - Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 3 Data Science, Delfi Diagnostics, Inc., 21224 - Baltimore/US
  • 4 Division Of Hematology/oncology, Comprehensive Breast Cancer Center, University of Pittsburgh Medical Center, 15213 - Pittsburgh/US
  • 5 Medical Oncology, Yale School of Medicine - Radiology and Biomedical Imaging, 06520 - New Haven/US
  • 6 Early Drug Development Program, Yale University School of Medicine - Yale Cancer Center, 06520 - New Haven/US
  • 7 Medical Oncology Department, City of Hope Comprehensive Cancer Center, 91010 - Duarte/US
  • 8 Investigational Drug Branch, National Cancer Institute (NCI)/National Institute of Health (NIH), 20892 - Bethesda/US
  • 9 Investigational Drug Branch, National Cancer Institute (NCI)/National Institute of Health (NIH), 20892-9739 - Bethesda/US
  • 10 Cancer Research Ucc, University College Cork, Cork/IE
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Abstract 1669P

Background

The rapid identification of disease progression in patients receiving immune checkpoint inhibitors (ICIs) is challenging using methods that rely on imaging assessments. Here, we investigated genome-wide cell-free DNA (cfDNA) fragmentation profiles to molecularly detect disease progression in the phase I study of entinostat and nivolumab +/- ipilimumab in advanced solid tumors (ETCTN-9844, NCT02453620).

Methods

Patients with metastatic or unresectable solid tumors received an entinostat run-in 2 weeks prior to the addition of anti-PD-1 and anti-CTLA-4 ICIs. Blood was collected at baseline (50/50 patients) and at 10 weeks after treatment initiation (27/50 patients). Low-coverage (1-2x) whole genome sequencing was performed on cfDNA from plasma samples. Genome-wide cfDNA fragmentation features were included in a Bayesian model to approximate a tumor fraction as compared to best response by RECIST v1.1. Molecular response was defined as reduction (≥ 30%) of the fragmentation based tumor fraction between the baseline and 10-week time point.

Results

50 patients with breast (n = 28), salivary gland (n = 7), gastrointestinal (n = 6), gynecological (n = 4), sarcoma (n = 3), and lung cancer (n = 2) received a median of 4 prior lines of therapy (0-14). Response assessment using molecular analyses and best overall response by RECIST were reported at a mean of 9.3 (5-10.7) and 14.3 weeks (5-73). Molecular responders and non-responders at week 10 experienced a median PFS that was not reached (NR) and 4.5 months (HR = 5.4; 95% CI 1.7-17; p = 0.004) while patients with RECIST response and non-response at week 10 had similar PFS (median 6.4 vs. 6.7 months; HR = 1.7; 95% CI 0.54-5.3; p = 0.36). Among the subgroup of radiographic non-responders with stable disease, PFS for molecular responders was NR while for molecular non-responders it was 5.2 months (p = 0.021).

Conclusions

There is a clinical need for non-invasive tests to identify primary or acquired resistance to ICIs, sparing patients from ineffective treatments associated with immune-related adverse events. Here, we demonstrate a cfDNA fragmentation based approach for molecular detection of disease progression that could guide future trials with ICIs.

Clinical trial identification

NIH/NCI 9844.

Editorial acknowledgement

Legal entity responsible for the study

NCI CTEP.

Funding

Dutch Cancer Society grant 10438, Stand Up to Cancer–Dutch Cancer Society International Translational Cancer Research Dream Team Grant SU2C-AACR-DT1415, The Mark Foundation for Cancer Research, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, The Gray Foundation, The Commonwealth Foundation, ColeFoundation, US National Institutes of Health grants CA121113, CA006973, and CA233259.

Disclosure

A. Leal: Financial Interests, Personal, Ownership Interest: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics. V. Adleff: Financial Interests, Personal, Other, Consultant: Delfi Diagnostics. K. Lumbard: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics. L. Keefer: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics. J. Carey: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics. A. Brufsky: Financial Interests, Personal, Other, Consultant: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma; Financial Interests, Institutional, Other, Research support: Agendia, AstraZeneca. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: Sotio, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Serono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board - Member: University of Arizona; Other, External Scientific Advisory Board - Member: University of New Mexico; Other, Scientific External Advisory Board - Member: University of California at San Diego. V. Chung: Financial Interests, Personal, Invited Speaker: Ipsen, Coherus Biosciences, AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, Consultant: Perthera; Financial Interests, Institutional, Research Grant, Funding for investigator sponsored trial: Merck. E.M. Jaffee: Financial Interests, Other, Support: Abmeta, Parker Institute; Financial Interests, Personal, Other: Genocea, Achilles, DragonFly, Candel Therapeutics, Carta, NextCure; Financial Interests, Other, Grants and other support: Lustgarten, Genentech, AstraZeneca, Break Through Cancer. R.B. Scharpf: Financial Interests, Personal, Ownership Interest, Founder: Delfi Diagnostics; Financial Interests, Personal, Other, Consultant: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics. V. Stearns: Financial Interests, Institutional, Research Grant: AbbVie, Biocept, Pfizer, Novartis, Puma Biotechnology; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, Chair, Data Safety Monitoring Board: AstraZeneca; Non-Financial Interests, Personal, Other: Foundation Medicine Study Assays. R.M. Connolly: Financial Interests, Institutional, Funding, Research: MSD Ireland, Pfizer, Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Other, Unrestricted Education grant: Pfizer. V.E. Velculescu: Financial Interests, Personal, Ownership Interest, Founder: Delfi Diagnostics; Financial Interests, Personal, Member of the Board of Directors: Delfi Diagnostics; Financial Interests, Personal, Other, Consultant: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Advisory Role: Danaher, Takeda Pharmaceuticals, Viron Therapeutics; Financial Interests, Personal, Other, Divested equity to LabCorp February 2022: Personal Genome Diagnostics (PGDx). All other authors have declared no conflicts of interest.

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