Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology

Abstract

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient's/physician's choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.

Conflict of interest statement

A.-M.T. Clinical Trial Research Funding (received through the institution): OBI Pharma, IMMATICS, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, Karus Therapeutics; Consulting or Advisory Role: Vincerx, Diaccurate, BrYet. V.S. reports grants from Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics, Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, V. Subbiah reports a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Relay therapeutics, Roche, Medimmune; travel funds from Pharmamar, Incyte, ASCO, ESMO; other support from Medscape; all outside the submitted work. A.N. Consulting or Advisory Role: Novartis, CytomX Therapeutics, OncoSec, STCube Pharmaceuticals Inc, Kymab, Takeda (I), CSL Behring (I), Horizon Pharma (I), Genome & Company, Immune-Onc, Deka Bioscience, Nouscom. Research Funding (to the institution): NCI, EMD Serono, MedImmune, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance BioSciences Inc, Healios, Lilly, Kymab, PsiOxus Therapeutics, Immune Deficiency Foundation (I), Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Baxalta (I), Jeffrey Modell Foundation (I), Chao Physician-Scientist Awards (I). Travel, Accommodations, Expenses: ARMO BioSciences. D.D.K. Clinical Trials. Paid to Institution: Phosplatin Therapeutics, Pfizer, Arcus, Arqule, Bristol-Myers Squibb, Eli Lilly, Five Prime Therapeutics, Glaxo Smith Kline, Genmab, Holy Stone Healthcare Co., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response, Red Hill Biopharma Ltd., Rgenix, Sanofi-Aventis, Xencor, Astellas, Janssen, Affigen, Black Beret Life Sciences, NIH Clinical Translational Science Award Grant. D.S.H. Research/Grant Funding through the institution from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai,Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda,TCR2, Teckro, Turning Point Therapeutics, Verstatem, VM Oncology. Consulting fees from Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, Ziopharm. Travel/Accommodations/Expenses: from Bayer, Genmab, AACR, ASCO, SITC, Telperian; Other ownership interests include Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder,Advisor). D.J.V. is the CEO and majority owner of VisionSR and an inventor of Bracco Diagnos-tics. D.A.B. Other ownership interests: co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutical and medical device companies, National Institutes of Health cooperative groups, international consortia, and patient advocacy groups. F.J. Research/Grant Funding (received through the institution): support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Astex, Agios, Bicara, Bioxcel Therapeutics, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Merck, Ideaya Biosciences, JS Innophram, Synthorx, Sanofi, SpringBank Pharmaceuticals, SQZ Biotechnologies, Synlogic, FujiFilm Pharmaceuticals, Sotio, Novellus and Proximagen; is or has been on the Scientific Advisory Boards for Bicara, Guardant Health, Illumina, Ideaya Biosciences, IFM Therapeutics, Synlogic, Sotio, Puretech Health, Petra Pharma, Novellus and Deciphera; is a paid consultant for Cardiff Oncology and Immunomet; and has ownership interests in Cardiff Oncology. Current position: Chief Medical Officer—Monte Rosa Therapeutics. F.M.-B. Consulting: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks. Advisory Committee: Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis. Sponsored Research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals. Other (Travel Related): None. J.R. Research Funding—Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d’Hebron Institute of Oncology/Cancer Core Europe. Clinical Research—Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics. Support for attending meetings and/or travel: European Society for Medical Oncology. Monitoring Board or Advisory Board: Advisory Board—Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA. Other financial or non-financial interests: Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC. S.P.-P. receives Research/Grant Funding through the institution from the following sources: AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol-Myers Squib; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Cyclacel Pharmaceuticals; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; F-Star Beta Limited; F-Star Therapeutics; Gene Quantum; Genmab A/S; Gilead Sciences, Inc.; GlaxoSmithKline; Helix BioPharma Corp.; HiberCell, Inc.; Immunomedics, Inc.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Lytix Biopharma AS; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Purinomia Biotech, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Silverback Therapeutics; Synlogic Therapeutics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; ZielBio, Inc.; NCI/NIH; P30CA016672—Core Grant (CCSG Shared Resources). She has additionally worked as a consultant for CRC Oncology. S.F. Clinical Trial Research Support/Grant Funding through the institution from the following sources: NIH/NCI P30CA016672—Core Grant (CCSG Shared Resources); Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; Nykode Therapeutics AS. T.A.Y. Employment: University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios). Grant/Research support (to Institution): Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith. Consultancies: AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol-Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio. Stockholder in: Seagen. V.M. Patent Royalties: Memorial Sloan Kettering Cancer Center, USPO 850141. Stock Holder: Foundation Medicine/ROCHE; EQRX; Mirati Therapeutics. Other Compensation: Board of Directors, Revolution Medicines; EQRX Employee. C.C. holds a senior leadership position (Sr Vice President, Medical Affairs, Tempus Labs, Inc), received compensation, and holds stock in Tempus Labs, Inc. Chicago, IL. The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. IMPACT2 enrollment and randomization over time.

A Number of patients enrolled. B Number of patients randomized in Part A and Part B.

Fig. 2

IMPACT2, Part A: Consort diagram.

Fig. 3. IMPACT2, Part B: consort diagram.

Notably, patients who are randomized to matched targeted therapy and patients who select matched targeted therapy are to be analyzed together. Similarly, patients who are randomized to non-matched targeted therapy and patients who select non-matched targeted therapy are to be analyzed together.

Fig. 4. IMPACT2 study algorithm.

IMPACT2. Study design Part A, May 2014-March 2017A Patients with metastatic cancer undergo a tumor biopsy and genomic profiling. B If patients have targetable molecular aberrations and FDA-approved drugs within labeled indication are available, the patients will receive FDA-approved targeted therapy. C If patients have targetable molecular aberrations and there are no FDA-approved drugs within labeled indication, the patients are considered for commercially available targeted therapy or clinical trial. Patients are presented at tumor board. D Patients are offered randomization to one of two arms: MTT or non-MTT E Criteria (biomarker present, available clinical trial, eligibility criteria met) are met. F Analysis. IMPACT2. Study design Part B, March 2019-present.A Patients with metastatic cancer undergo a tumor biopsy and genomic profiling. B If patients have targetable molecular aberrations and FDA-approved drugs within labeled indication are available, the patients will receive FDA-approved targeted therapy. C If patients have targetable molecular aberrations and there are no FDA-approved drugs within labeled indication, the patients are considered for commercially available targeted therapy or clinical trial. Patients are presented at tumor board. D Patients are offered randomization between two arms: MTT or non-MTT E Criteria (biomarker present, available clinical trial, eligibility criteria met) are met. F In March 2019, we amended the trial to include a “patient-preference” cohort for each arm. Patients who decline randomization are offered their choice of arm. G The primary analysis will use both randomized and patient-preference cohorts based on a Bayesian hierarchical model that “borrows” from the patient-preference cohorts to the extent to which its PFS agrees with that in the randomization cohort.