We conducted a survey (Tosi et al, J Clin Oncol 2015; Vinches et al, J Clin Oncol 2015, abstr 3040) on clinical development strategies for monoclonal antibodies (mAb) over a decade: due to mAb limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined in first-in-human trials (FIHT), and the FIHT RP2D and the maximum administered doses (MAD) were infrequently used in subsequent trials. In contrast, for cancer drugs in general, FIHT results are predictive of safety in registration trials (RT) and of approved drug dose (Jardim et al, Clin Cancer Res 2014).
In order to determine the correlations of mAb FIHT results with safety in RT and final approved dose, we identified mAb approved as single agents by FDA on March 1, 2016. For each molecule, we performed a MEDLINE search to identify FIHT and RT, then we examined the doses tested and the toxicities observed in RT with regard to the corresponding FIHT results.
We retrieved 28 mAb with a FIHT, and 60 RT. The mAb indication was cancer in 11 cases (solid tumors in 8, hematological cancers in 3), immune system diseases in 13 cases and other diseases in 4 cases. In FIHT, the RP2D was determined in 5 cancer trials (vs 2 in the other trials). For mAb with the same dose calculation in FIHT and RT, the RP2D was tested in cancer RT in only 3 cases, and the MAD in 2 cases (vs 1 and 2 cases respectively in the other trials). The median ratio between cancer RT dose and the corresponding MAD was 0.5 (n = 9; range: 0.2 to 2.5), versus 0.67 in the other trials (n = 13; range: 0.1 to 1.2). Seven out of 11 doses tested in cancer RT were of less than 75% of the MAD, with 4 RT doses of less than 50% of the MAD. Grade 3/4 toxicities were infrequent. No statistically significant concordance for grade 3/4 toxicities between RT and FIHT was observed.
These data show a major discrepancy between RP2D and MAD of mAb FIHT when compared with doses tested in RT, and toxicities detected in mAb FIHT do not correlate with RT toxicities. As FIHT data inform only partially choices of RT doses, rational strategies for mAb dose selection in the clinical setting remain an unmet need.
Clinical trial identification
Legal entity responsible for the study
C. Gongora: Research funding from Novartis, Astellas and Janssen travel funding from Lilly. L. Gianni: Activity as consultant or advisor board member: Roche, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Celgene, Tahio Pharmaceutical, Tiziana Pharma, Synthon, AstraZeneca, Genomic Health, Merck Sharp & Dohme, Synaffix. D. Tosi: research funding from Novartis, Astellas and Janssen travel funding from Bayer, Janssen, Astellas, Sanofi. All other authors have declared no conflicts of interest.