1313O - Assessment of investigational new drugs (INDs) approved in USA and Europe after early phase trials using the ESMO-magnitude of clinical benefit scale (ESMO-MCBS)

Background

Increasingly regulatory approval for novel agents is sought following early phase single-arm trials. However, many countries’ governmental agencies require value assessment of new agents to determine reimbursement. The ESMO-MCBS provides an evaluation framework based on treatment efficacy, response duration, adverse events, quality of life, and phase 4 data scored from 1-5 with scores >4 indicating substantial benefit worthy of reimbursement.

Methods

INDs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2010 and April 2022 based on single-arm early phase 1 and/or 2 trials were reviewed. INDs were assessed using form 3 of the ESMO-MCBS from published data available at time of approval.

Results

Among 94 approved IND, 34 (36%) were approved based on single arm trial data. INDs were 23 ( 68% ) targeted kinase inhibitors, 4 (12%) antibody directed cytotoxics, 5 (15%) immunotherapeutics, and 2 (6%) other. Alectinib, sonidegib, and crizotinib were the only INDs to meet the threshold for substantial benefit at the time of FDA/EMA approval (score=4). Whereas 12 (34%) had scores of 0 to 2 and the majority (n=19; 56%) had scores of 3. Results of patient reported outcomes (n=6; 17%) were uncommon at time of approval and only 1 (16%) illustrated an improved quality of life. 14/19 (74%) INDs which had published later phase trials achieved ESMO-MBCS score >4 subsequently in controlled studies. 28 of 34 FDA approved INDs (82%) were also approved by EMA. EMA approvals followed FDA approvals at a median of 10 months (range: 0 to 24). FDA and EMA approved INDs had median score of 3.0 vs 2.5 for INDs approved by FDA alone (p=0.5). 44% of INDs (n=15) provided a meaningful benefit with duration of response >12 months (n=9) and/or objective response rate >50% (n=12).

Conclusions

Only 3 early phase approvals met threshold for substantial benefit by ESMO-MBCS criteria despite clinical benefits seen in >40% of patents with INDs. Revision and recalibration of ESMO-MCBS is warranted to match the desires of patients, oncologists, and their governmental organizations to license effective drugs from early phase studies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. All other authors have declared no conflicts of interest.