Abstract 1002P
Background
Pharmacodynamic biomarkers (PD) are considered fundamental for go/no-go decisions in phase I (Ph1) trials. Despite increased availability of blood-based assays, the requirement of tumor biopsies remains common. In the immune-oncology (IO) era, the impact of PD for confirmation of biologic activity and recommended phase II dose (RP2D) has not been investigated.
Methods
Ph1 studies from 2014 to 2020 were reviewed. Among 12053 abstracts screened, 386 Ph1-IO studies were identified. Characteristics of studies that included on-treatment PD biomarkers [tissue-derived (tPD), blood-based (bPD) and imaging-based (iPD)] were analyzed. PD outcomes in terms of proof of mechanism/biologic activity and significant correlation with efficacy endpoints were collected. Authors’ statements on the influence of PD results on RP2D were also noted.
Results
Of 386 trials, 276 (72%) were monotherapy. The most frequent IO agents evaluated were vaccines (32%) and PD(L)1 inhibitors (25%). Of the combinations, 54 (49%) included a second IO drug while the others included molecular-targeted agents. No PD data was reported in 100 studies (26%). Of the remaining 286 studies, tPD alone, bPD alone, iPD alone, and >1 PD types were tested in 14 (5%), 189 (66%), 1 (0.3%), and 82 (29%), respectively.
Among 35 tPD studies with negative results, 16 reported concurrent positive bPD results. Table: 1002P
| Biomarker type | Proof of mechanism/biological activity (without clinical correlation) | Correlation with clinical efficacy endpoints | Biomarker results influenced RP2D and/or further development as per authors |
| tPD | 52/94 (55%) | 7/94 (7%) | 36/94 (38%) |
| bPD | 169/270 (63%) | 23/270 (9%) | 144/270 (53%) |
| iPD | 8/12 (67%) | 1/12 (8%) | 5/12 (42%) |
Conclusions
In the IO era, most studies perform PD analyses. There were similar proportions of tPD and bPD studies showing proof of mechanism/biologic activity, but 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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A. Hernando Calvo: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merk Serono; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Kyowa Kirin International. D.V. Araujo: Financial Interests, Personal, Other, honoraria: GlaxoSmithKline. M. Oliva: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation expenses: MSD Oncology; Financial Interests, Personal and Institutional, Research Grant: Mirati Therapeutics; Other, Personal, Other: Bristol Myers Squibb; Other, Personal, Other: Merck. 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. All other authors have declared no conflicts of interest.