Managing Expectations in the Transition to Proof of Concept Studies.
As we move away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents.



Literature searches indicate that molecular oncology mechanistic-based agents are being linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and clinical trial design are reviewed.



The design and conduct of clinical trials have not been fully adjusted to the new era of personalized oncology, and so we are in transition. A part of this transition is the management of expectations and trial designs that need to be considered relative to preclinical experience in the development of therapeutics. For example, pathological complete response is now considered a surrogate marker for favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate marker is tied to novel agents' mechanistic characteristics with no preclinical counterpart.



The old paradigm considers patients equal with similar chances to respond to treatments, but the new paradigm considers patient's heterogeneity, a major fact that informs the design of clinical trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker, new trials are going to have more subjects who are likely to respond to the treatment.
Department of Pathology, University of Arkansas for Medical Sciences, BioMed 2 Suite 309, 4301 West Markham St, Little Rock, Arkansas 72205, United States.
Thomas
T
Kieber-Emmons
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Issam
I
Makhoul
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Angela
A
Pennisi
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Eric R
ER
Siegel
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Peter D
PD
Emanuel
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Bejotaloh
B
Monzavi-Karbassi
Agathera Therapeutics, Malvern PA, United States.
Zenon
Z
Steplewski
Highlands Oncology Group, Rodgers AR, United States.
J Thaddeus
JT
Beck
Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, United States.
Laura F
LF
Hutchins
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D005544:Forecasting; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D057285:Precision Medicine / Q000639:trends*; D000075082:Proof of Concept Study
D000970:Antineoplastic Agents
Breast cancer; clinical benefit; clinical trials; immunotherapy; pathological complete response; patient advocacy; process management; proof of concept; tumor response