1509MO - Adherence to the Food and Drug Administration (FDA) guidance for the co-development of two or more investigational new drugs in phase 1/2 cancer trials

Background

Combinations of cancer therapeutics (combo) have potential to improve antitumor efficacy over monotherapies, but their development remains challenging. To improve likelihood for success, the FDA issued guidance for the co-development of ≥2 INDs in 2013.

Methods

We reviewed all combo protocols in the MD Anderson Phase I Program between 2015-2020 for adherence to 4 key criteria: (1) intention to treat serious illness, (2) biological rationale, (3) full non-clinical characterization of combo, (4) compelling reason to not develop each drug independently. Parameters studied also included drug pharmacology, preclinical data, trial design, sponsor and biomarker use. Categorical variables are shown as percentages and compared by Chi-Square method.

Results

Of 470 protocols, 188 included combos [phase 1 (n=113), phase 1/2 (n=62), and phase 2 (n=13)], and 30 included multiple treatment arms. 166 combos included ≥1 approved drug, while 72 comprised only investigational agents. 54% of combos (n=128/238) met all 4 criteria. Industry-sponsored trials (51%, n=101/204) adhered to FDA guidance less often than non-Industry sponsored (74%, n= 25/34 Investigator and NCI sponsored) trials (p=0.01). Of 72 investigational agent-only combos, All treated a serious illness, 96% (n=69) had biological rationale, 79% (n=57) had full non-clinical characterization, 64% (n=46) had compelling reasons to not develop each drug independently; and 57% of these studies (n=41) met all 4 guidance criteria. Between immunotherapy only combos (IO) and targeted therapy only combos (TT): 98% (n=83/85) IO had biological rationale vs 89% (n=73/82) TT (p=0.03). 84% (n=69/82) TT had full non-clinical characterization vs 69% (n=59/85) IO combos (p=0.02). TT and IO combos had similar rates to not develop each drug independently (68% vs 60%; p=0.26) and to meet all 4 FDA criteria (60% vs 52%; p=0.30). Interestingly, IO combos incorporated patient selection biomarkers less often (15% vs 60%; p<0.001).

Conclusions

The FDA guidance for co-development provides a useful framework to evaluate combos, but only 57% of combos met all criteria. There are differences in adherence to the FDA guidance and use of biomarkers between IO and TT combos.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Authors.

Funding

Has not received any funding.

Disclosure

D.S. Hong: Financial Interests, Personal, Advisory Role: Adaptimmune; Financial Interests, Personal, Advisory Role: Alphasights; Financial Interests, Personal, Advisory Role: Axiom Biotechnologies; Financial Interests, Personal, Advisory Role: Baxter; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Esai; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: GroupH; Financial Interests, Personal, Advisory Role: Guidepoint Global; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Medscape; Financial Interests, Personal, Advisory Role: Merrimack; Financial Interests, Personal, Advisory Role: Numab; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Tries Therapeutics; Financial Interests, Personal, Funding: Abbvie; Financial Interests, Personal, Funding: Adaptimmune; Financial Interests, Personal, Funding: Amgen; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Bayer; Financial Interests, Personal, Funding: Bristol-Myers Squibb; Financial Interests, Personal, Funding: Daiichi Sankyo; Financial Interests, Personal, Funding: Eisai; Financial Interests, Personal, Funding: Fate Therapeutics; Financial Interests, Personal, Funding: Genentech; Financial Interests, Personal, Funding: Genmab; Financial Interests, Personal, Funding: Ignyta; Financial Interests, Personal, Funding: Infinity Pharmaceuticals; Financial Interests, Personal, Funding: Kite; Financial Interests, Personal, Funding: Kyowa Hakko Kirin; Financial Interests, Personal, Funding: Lilly; Financial Interests, Personal, Funding: Loxo; Financial Interests, Personal, Funding: MedImmune; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Mirati; Financial Interests, Personal, Funding: miRNA Therapeutics; Financial Interests, Personal, Funding: Molecular Templates; Financial Interests, Personal, Funding: MOLOGEN; Financial Interests, Personal, Funding: National Cancer Institute; Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Funding: Pfizer; Financial Interests, Personal, Funding: Seattle Genetics; Financial Interests, Personal, Funding: Takeda. S. Fu: Financial Interests, Personal, Funding: Soricimed Biopharma Inc.. D. Karp: Non-Financial Interests, Personal, Invited Speaker: Phosplatin Therapeutics. A. Naing: Financial Interests, Personal, Funding: EMD Serono; Financial Interests, Personal, Funding: MedImmune; Financial Interests, Personal, Funding: Helios Onc. Nutrition; Financial Interests, Personal, Funding: Atterocor/Millendo; Financial Interests, Personal, Funding: Amplimmune; Financial Interests, Personal, Funding: ARMO BioSciences; Financial Interests, Personal, Funding: KaryoPHarm Therapeutics; Financial Interests, Personal, Funding: Incyte; Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Funding: Regeneron; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Bristol-Myers Squibb; Financial Interests, Personal, Funding: Pfizer; Financial Interests, Personal, Funding: CytomX Therapeutics; Financial Interests, Personal, Funding: Neon Therapeutics; Financial Interests, Personal, Funding: Calithera Biosciences; Financial Interests, Personal, Funding: Top Alliance; Financial Interests, Personal, Funding: Eli Lilly; Financial Interests, Personal, Funding: Kymab; Financial Interests, Personal, Funding: PsiOxus; Financial Interests, Personal, Funding: Arcus Biosciences; Financial Interests, Personal, Funding: NeoImmune Tech; Financial Interests, Personal, Funding: ImmuneOncia; Financial Interests, Personal, Funding: Surface Oncology; Financial Interests, Personal, Advisory Board: CytomX Therapeutics; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Genome and Company; Financial Interests, Personal, Advisory Board: OncoSec; Financial Interests, Personal, Advisory Board: Kymab; Financial Interests, Personal, Advisory Board: STCube Pharmaceuticals. S. Pant: Financial Interests, Personal, Other, Honoraria: Tyme; Financial Interests, Personal, Other, Honoraria: Zymeworks; Financial Interests, Personal, Other, Honoraria: Xencor; Financial Interests, Personal, Other, Honoraria: 4-D Pharma. F. Janku: Financial Interests, Personal, Advisory Role: Asana; Financial Interests, Personal, Advisory Role: Bursh Health; Financial Interests, Personal, Advisory Role: Cardiff oncology; Financial Interests, Personal, Advisory Role: Deciphera; Financial Interests, Personal, Advisory Role: Gaurdant Health; Financial Interests, Personal, Advisory Role: Ideaya; Financial Interests, Personal, Advisory Role: IFM Therapeutics; Financial Interests, Personal, Advisory Role: Immunomet; Financial Interests, Personal, Advisory Role: Jazz Pharmaceutuicals; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: PureTech; Financial Interests, Personal, Advisory Role: Sotio; Financial Interests, Personal, Advisory Role: Synlogic; Financial Interests, Personal, Ownership Interest: Cardiff Oncology. S.A. Piha-Paul: Financial Interests, Personal, Advisory Role: Merck. J. Rodon: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Certara; Financial Interests, Personal, Advisory Role: Ellipses Pharma; Financial Interests, Personal, Advisory Role: iOncologi; Financial Interests, Personal, Advisory Role: Kelun; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Sharpe & Dohme; Financial Interests, Personal, Advisory Role: Peptomyc; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Spectrum Pharmaceuticals; Financial Interests, Personal, Funding: Bayer; Financial Interests, Personal, Funding: Novartis. V. Subbiah: Financial Interests, Personal, Advisory Role: Helsinn Therapeutics; Financial Interests, Personal, Advisory Role: Loxo; Financial Interests, Personal, Advisory Role: MedImmune; Financial Interests, Personal, Advisory Role: QED Therapeutics; Financial Interests, Personal, Advisory Role: R-Pharm; Financial Interests, Personal, Other, Bayer; Helsinn Therapeutics; Novartis; PharmaMar: Bayer; Financial Interests, Personal, Other, Bayer; Helsinn Therapeutics; Novartis; PharmaMar: Helsinn Therapeutics; Financial Interests, Personal, Other, Bayer; Helsinn Therapeutics; Novartis; PharmaMar: Novartis; Financial Interests, Personal, Other, Bayer; Helsinn Therapeutics; Novartis; PharmaMar: PharmaMar. A.M. Tsimberidou: Financial Interests, Personal, Advisory Role: Tempus; Financial Interests, Personal, Other, Honoraria: Covance; Financial Interests, Personal, Other, Honoraria: Genentech. F. Meric-Bernstam: Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Funding: Genentech; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Darwin Health; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Inflection; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Research Grant: Pieris; Financial Interests, Personal, Research Grant: Clearlight; Financial Interests, Personal, Research Grant: Samsung Bioepsis; Financial Interests, Personal, Research Grant: Spectrum Pharmaceuticals; Financial Interests, Personal, Research Grant: Aduro Biotech; Financial Interests, Personal, Research Grant: Originimed; Financial Interests, Personal, Research Grant: Xencor; Financial Interests, Personal, Advisory Board: IBM/Watson; Financial Interests, Personal, Research Grant: SeaGen; Financial Interests, Personal, Research Grant: Silverback; Financial Interests, Personal, Research Grant: PACT; Financial Interests, Personal, Research Grant: eFFECTOR; Financial Interests, Personal, Research Grant: TAIHO; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Aileron; Financial Interests, Personal, Research Grant: Puma Technology; Financial Interests, Personal, Research Grant: Jounce Therapeutics; Financial Interests, Personal, Research Grant: Zymework; Financial Interests, Personal, Research Grant: Curis; Financial Interests, Personal, Research Grant: AbbVie; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Gaurdant; Financial Interests, Personal, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Research Grant: Daiichi Sanko. T.A. Yap: Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Almac Diagnostics; Financial Interests, Personal, Advisory Role: Astra Zeneca; Financial Interests, Personal, Advisory Role: Atrin Pharmaceuticals; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Calithera Biosciences; Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: Cybrexa Therapeutics; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: SeaGen; Financial Interests, Personal, Advisory Role: Tesaro; Financial Interests, Personal, Advisory Role: Vertex; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Bayer; Financial Interests, Personal, Funding: Constellation Pharmaceuticals; Financial Interests, Personal, Funding: Jounce Therapeutics; Financial Interests, Personal, Funding: Kyowa Hakko Kirin; Financial Interests, Personal, Funding: Lilly; Financial Interests, Personal, Funding: Pfizer; Financial Interests, Personal, Funding: Seattle Genetics; Financial Interests, Personal, Funding: Tesaro; Financial Interests, Personal, Funding: Vertex; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: EMD Sorono; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Tesaro. All other authors have declared no conflicts of interest.