Impact of pharmacodynamic biomarkers in immuno-oncology (IO) phase 1 clinical trials.
Authors: Salawu Abdulazeez , Chen Rachel , Hernando-Calvo Alberto , Araujo Daniel Vilarim , Oliva Bernal Marc , Liu Zhihui (Amy) , Siu Lillian L. 
Published: June 2021

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Background: Pharmacodynamic biomarkers (PD) are considered fundamental for go/no-go decisions in phase 1 trials. Despite an increase in the availability of blood-based biomarker assays, the requirement of invasive non-diagnostic research tumor biopsies for trial eligibility remains common. In the immuno-oncology (IO) era, the impact of PD analysis for the confirmation of biologic activity and recommended phase 2 dose (RP2D) has not been investigated. Methods: Phase 1 studies from 01/2014 to 12/2018 were reviewed. Among 12053 abstracts screened, a total of 143 phase I-IO trials were identified. Characteristics of studies that included on-treatment PD biomarkers (tissue-derived, blood-based and radiomic) were extracted and analyzed. Outcomes from the biomarker data in terms of proof of mechanism/biologic activity and statistically significant correlation with clinical benefit (objective response or survival) were collected. Authors’ statements on the influence of PD results on RP2D were also noted. Results: Out of 143 phase 1 IO trials, 107 (75%) were monotherapy. The most frequent IO evaluated were vaccines (41%), cell therapy (16%), immunomodulators (13%) and cytokines (7%). Of the 36 combination studies, 20 (61%) included a second IO drug while 16 (39%) included molecular-targeted agents. Only 18 of 143 studies (12%) did not report any PD data. Of the remaining 125 studies, tissue-derived PD (t-PD) biomarkers alone, blood-based PD (b-PD) biomarkers alone, both t-PD and b-PD biomarkers, and imaging biomarkers were tested in 3 (2%), 97 (78%), 25 (20%), and 7 (6%), respectively. Demonstration of proof of mechanism/biologic activity only were reported in 16/28 (57%), 80/122 (66%) and 4/7 (57%) of the t-PD, b-PD and imaging biomarker studies, respectively. Significant correlation with clinical benefit was reported in 2/28 (7%), 7/122 (6%) and 0/7 (0%) of the t-PD, b-PD and imaging biomarker studies, respectively; these involved 4 vaccines (1 in combination with PD1 blockade), 1 cell therapy and 1 oncolytic virus (in combination with CTLA4 blockade). Among 35 b-PD studies with negative results, 5 also performed t-PD biomarkers, all with negative results. Notably, 3 out of 10 t-PD studies with negative results reported concurrent positive b-PD results. Based on the published reports, authors stated that biomarker results helped with RP2D determination in 16/28 (57%) of t-PD and 78/122 (64%) of b-PD studies. Conclusions: Our results suggest that in the IO era, most studies perform PD analysis, with similar proportions of t-PD and b-PD showing proof of mechanism/biologic activity. IO PD biomarkers have limited correlation with clinical benefit. Many authors considered IO PD biomarkers to be relevant in RP2D decisions, but this needs confirmation by other measures of impact. With continued technological developments utilizing circulating biomarkers, b-PD may ultimately replace many t-PD tests in future IO studies.