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Review
. 2022 Sep:173:167-177.
doi: 10.1016/j.ejca.2022.06.045. Epub 2022 Jul 21.

Impact of pharmacodynamic biomarkers in immuno-oncology phase 1 clinical trials

Abdulazeez Salawu  1 , Alberto Hernando-Calvo  1 , Rachel Y Chen  2 , Daniel V Araujo  3 , Marc Oliva  4 , Zhihui A Liu  1 , Lillian L Siu  5
Affiliations
Free article
Review

Impact of pharmacodynamic biomarkers in immuno-oncology phase 1 clinical trials

Abdulazeez Salawu et al. Eur J Cancer. 2022 Sep.
Free article

Abstract

Background: Phase 1 immuno-oncology (IO) trials frequently involve pharmacodynamic (PD) biomarker assessments involving tumour biopsies and/or blood collection, with increasing use of molecular imaging. PD biomarkers are set to play a fundamental role in early drug development of immuno-oncology (IO) agents. In the IO era, the impact of PD biomarkers for confirmation of biologic activity and their role in subsequent drug development have not been investigated.

Methods: Phase 1 studies published between January 2014 and December 2020 were reviewed. Studies that reported on-treatment PD biomarkers [tissue-derived (tissue-PD), blood-based (blood-PD) and imaging-based (imaging-PD)] were analysed. PD biomarker results and their correlation with clinical activity endpoints were evaluated. Authors' statements on the influence of PD biomarkers on further drug development decisions, and subsequent citations of PD biomarker study results were recorded.

Results: Among 386 trials, the most frequent IO agent classes evaluated were vaccines (32%) and PD-(L)1 inhibitors (25%). No PD biomarker assessments were reported in 100 trials (26%). Of the remaining 286, blood-PD, tissue-PD, and imaging-PD data were reported in 270 (94%), 94 (33%), and 12 (4%) trials, respectively. Assessments of more than one PD biomarker type were reported in 82 studies (29%). Similar proportions of blood-PD (9%), tissue-PD (7%), and imaging-PD studies (8%) had positive results that correlated with clinical activity. Results of 22 PD biomarker studies (8%) were referenced in subsequent clinical trials.

Conclusions: Most phase 1 IO studies performed PD biomarker assessments. Overall, positive PD biomarker results were infrequently correlated with clinical activity or cited in subsequent trials, suggesting a limited impact on subsequent drug development. With emerging health regulatory emphasis on optimal dose selection based on PD activity, more informative and integrative multiplexed assays that capture the complexity of tumour-host immunity interactions are warranted to improve phase 1 IO trial methodology.

Keywords: Cancer; Drug development; Drug response biomarkers; Immune system; Pharmacodynamics; Phase 1 clinical trial.

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Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. Hernando Calvo: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merk Serono; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Kyowa Kirin Internati-onal. D.V. Araujo: Financial Interests, Personal, Other, honoraria: MSD; Financial Interests, Personal, Other, honoraria: Pfizer; Financial Interests, Institutional, Educational Grant: Astellas; Financial Interests, Institutional, Non-financial support: Novartis. M. Oliva: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation expenses: MSD Oncology; Merck. Financial Interests, Personal and Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Merck; Personal and Institutional, Research Grant: Roche. L.L. Siu: Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Astellas Pharma; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Symphogen; Financial Interests, Institutional, Research Grant: AVID Radiopharmaceuticals; Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: Intensity Therapeutics; Financial Interests, Institutional, Research Grant: Karyopharm Therapeutics; Financial Interests, Personal, Stocks/Shares, An Immediate Family Member: Agios; Financial Interests, Personal, Leadership Role, An Immediate Family Member: Treadwell Therapeutics; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune; Financial Interests, Personal, Advisory Role: MorphoSys; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Loxo; Financial Interests, Personal, Advisory Role: Voronoi; Financial Interests, Personal, Advisory Role: Oncorus; Financial Interests, Personal, Advisory Role: Symphogen; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Treadwell Therapeutics; Financial Interests, Personal, Advisory Role: Arvinas; Financial Interests, Personal, Advisory Role: Navire; Financial Interests, Personal, Advisory Role: Janpix; Financial Interests, Personal, Advisory Role: Relay Therapeutics; Financial Interests, Personal, Advisory Role: Daiichi Sankyo/UCB Japan; Financial Interests, Personal, Advisory Role: Marengo Therapeutics; Financial Interests, Personal, Advisory Role: LTZ Therapeutics. All other authors have declared no conflicts of interest.

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