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Poster Discussion – Developmental therapeutics

4556 - Genomic Profiling of Three Pathways through Molecular Profiling-based Assignment of Cancer Therapy (NCI- MPACT)

Date

28 Sep 2019

Session

Poster Discussion – Developmental therapeutics

Presenters

Alice Chen

Citation

Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244

Authors

A. Chen1, S. Kummar2, S.S. Khan3, N. Moore3, L. Rubinstein3, G. O'Sullivan Coyne4, Y. Zhao3, A. Palmisano3, P. Williams5, V. Datta5, D. Sims5, C. Karlovich5, C. Lih5, K.P.S. Raghav6, F. Meric-Bernstam7, S. Leong8, S. Waqar9, N. Takebe3, E. Sharon1, J. Doroshow3

Author affiliations

  • 1 Early Clinical Trials Development Program, National Cancer Institute, 20892 - Bethesda/US
  • 2 Oncology, Stanford University, 94305 - Stanford/US
  • 3 Division Of Cancer Treatment And Diagnosis, National Cancer Institute, 20892 - Bethesda/US
  • 4 Division Of Cancer Treatment And Diagnosis, Developmental Therapeutics Clinic, National Cancer Institute, 20892 - Bethesda/US
  • 5 Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, 21702 - Frederick/US
  • 6 Department Of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 7 Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 8 Division Of Medical Oncology, University of Colorado Denver School of Medicine, 80045 - Aurora/US
  • 9 Division Of Oncology, Washington University School of Medicine, 63110 - St Louis/US

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Abstract 4556

Background

Emerging clinical data show prediction of response to therapies targeting specific genetic aberrations have unexpectedly variable outcomes. This multicenter, double-blind, randomized trial opened in 2013 to compare response rates (RR) between 2 groups of patients (pts) identified to have an actionable mutation of interest (aMOI) in one of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF/MEK): group A) Pts treated with agent(s) targeting one selected pathway (experimental arm-A) and B) Pts treated with agent(s) not targeting that pathway (control arm-B). Based on the data available at the time, the aMOI selection criteria encompassed alterations throughout the entire selected pathway instead of specific genetic changes.

Methods

Primary objective is to compare the RR (CR and PR) and 4 months PFS between treatments arms A and B. A CLIA-certified genetic analysis of a fresh tumor biopsy was performed at entry. Pts with an aMOI were randomized 2:1 to arm A vs. B. Study drugs were: 1) DNA repair-a) veliparib & temozolomide (VT); b) AZD1775 & carboplatin (AC); pts with p53 mutations were preferentially selected for AC; 2) PI3K- everolimus (E); 3) RAS- trametinib(T). At disease progression, Arm B pts could cross over to their target arm (A).

Results

193 pts underwent biopsies; >90% of samples completed DNA sequencing. 96 pts (50%) had an aMOI and were randomized to treatment. Cohort VT had insufficient accrual on the experimental arm to be evaluable. AC, E and T cohorts were closed due to futility. Enrollment rate after treatment assignment was 77% for Arm A and 53%, for arm B. Attrition analysis between arms A and B are ongoing.

Conclusions

The increasing availability of genetic sequencing and bias toward expected benefit of highly specific treatment agents may account for the large number pt withdrawal from Arm A. This imbalance made comparison of arms A and B uninterpretable. The trial has been amended to employ a non-randomized design to complete the assessment of VT’s activity. Analysis of the aMOIs are ongoing to develop a more stringent selection criteria for future precision medicine trials.

Clinical trial identification

NCT01827384.

Editorial acknowledgement

Christina Rosenberger, PhD.

Legal entity responsible for the study

NCI.

Funding

NCI.

Disclosure

S. Kummar: Advisory / Consultancy: Corvus Pharmaceuticals; Advisory / Consultancy: MedTree; Advisory / Consultancy: Nodus Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: ShangPharma Innovation; Advisory / Consultancy: Seattle Genetics; Travel / Accommodation / Expenses: Bayer; Shareholder / Stockholder / Stock options: Dhrishti Inc.; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Taiho Pharmaceutical. N. Moore: Licensing / Royalties: Nestle Nutrition. P. Williams: Licensing / Royalties, I was a co-inventor of the DLBCL cell of origin patent recently filed by the NIH: NIH; Research grant / Funding (institution): Illumina. K.P.S. Raghav: Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: TRACON Pharma; Honoraria (self): Bayer; Honoraria (self): Eisai. F. Meric-Bernstam: Advisory / Consultancy: Genentech; Advisory / Consultancy: Inflection Biosciences; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Clearlight Diagnostics; Advisory / Consultancy: Darwin Health; Advisory / Consultancy: Samsung Bioepis; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy: Origimed; Advisory / Consultancy: Xencor; Advisory / Consultancy: Debiopharm Group; Advisory / Consultancy: Mersana; Honoraria (self): Sumitomo Group; Honoraria (self): Dialectica; Research grant / Funding (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Genentech; Research grant / Funding (self): Calithera Biosciences; Research grant / Funding (self): Debiopharm Group. S. Leong: Shareholder / Stockholder / Stock options: Antares Pharmaceuticals; Shareholder / Stockholder / Stock options: Spectrum Pharmaceuticals; Honoraria (self): Lilly; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lilly. S. Waqar: Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Newlink Genetics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Synermore biologics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Vertex; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Stem CentRx; Research grant / Funding (institution): Hengrui Therapeutics; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): ARIAD. All other authors have declared no conflicts of interest.

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