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Editorial
. 2023 Aug 4;13(8):1762-1764.
doi: 10.1158/2159-8290.CD-23-0534.

Patient-Centric Approaches for Phase I Combination Trials Come on Stage

Alberto Hernando-Calvo  1   2 , Elena Garralda  1   2
Affiliations
Editorial

Patient-Centric Approaches for Phase I Combination Trials Come on Stage

Alberto Hernando-Calvo et al. Cancer Discov. .

Abstract

A disruptive clinical trial design allowed Drilon and colleagues to demonstrate proof of concept of the potential of PF-07284892 to overcome resistance mechanisms to targeted therapies in the clinic. See related article by Drilon et al., p. 1789 (7).

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Figures

Figure 1. Challenges and potential solutions for the implementation of the next generation of phase I clinical trials for precision oncology adapted from Drilon and colleagues’ proposed design (7). Universal screening of tumor genomic alterations for patients with advanced solid tumors will be required to maximize the chances of detecting targetable alterations across the population. The implementation of biomarker enrichment strategies will be required to improve efficacy outcomes across early-phase clinical trials. For this purpose, early molecular profiling at recurrence and novel next-generation sequencing (NGS) platforms with shorter turnaround times will be required to avoid patient deterioration. For biomarker-selected populations, clinical trial designs customized to minimize exposure to inactive drugs or subtherapeutic treatment doses could rely on real-time integration of circulating tumor DNA-variant allele frequency (ctDNA-VAF), patient-reported outcomes (PRO), and pharmacokinetic/pharmacodynamic (PK/PD) data in addition to RECIST evaluation. Finally, clinical trials including sequential dose-escalation parts for monotherapies and combinations or N-of-1 trials with the implementation of digital twins and data sharing initiatives could help to optimize rational combination testing (8, 10). DLT, dose-limiting toxicity; TA, targeted agent. Created with BioRender.com.
Figure 1.
Challenges and potential solutions for the implementation of the next generation of phase I clinical trials for precision oncology adapted from Drilon and colleagues’ proposed design (7). Universal screening of tumor genomic alterations for patients with advanced solid tumors will be required to maximize the chances of detecting targetable alterations across the population. The implementation of biomarker enrichment strategies will be required to improve efficacy outcomes across early-phase clinical trials. For this purpose, early molecular profiling at recurrence and novel next-generation sequencing (NGS) platforms with shorter turnaround times will be required to avoid patient deterioration. For biomarker-selected populations, clinical trial designs customized to minimize exposure to inactive drugs or subtherapeutic treatment doses could rely on real-time integration of circulating tumor DNA-variant allele frequency (ctDNA-VAF), patient-reported outcomes (PRO), and pharmacokinetic/pharmacodynamic (PK/PD) data in addition to RECIST evaluation. Finally, clinical trials including sequential dose-escalation parts for monotherapies and combinations or N-of-1 trials with the implementation of digital twins and data sharing initiatives could help to optimize rational combination testing (8, 10). DLT, dose-limiting toxicity; TA, targeted agent. Created with BioRender.com.
See this image and copyright information in PMC

Comment on

References

    1. Jin H, Wang L, Bernards R. Rational combinations of targeted cancer therapies: background, advances and challenges. Nat Rev Drug Discov 2023;22:213–34. - PubMed
    1. Araujo D, Greystoke A, Bates S, Bayle A, Calvo E, Castelo-Branco L, et al. . Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022. Ann Oncol 2023;34:48–60. - PubMed
    1. Spreafico A, Hansen AR, Abdul Razak AR, Bedard PL, Siu LL. The future of clinical trial design in oncology. Cancer Discov 2021;11:822–37. - PMC - PubMed
    1. Bunda S, Burrell K, Heir P, Zeng L, Alamsahebpour A, Kano Y, et al. . Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nat Commun 2015;6:8859. - PMC - PubMed
    1. Sai-Hong I, Koczywas M, Ulahannan SV, Janne P, Pacheco J, Burris HA, et al. . The SHP2 inhibitor RMC-4630 in patients with KRAS-mutant non-small cell lung cancer: preliminary evaluation of a first-in-man phase 1 clinical trial. Sixth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; 2020 Jan 11–14; San Diego, CA. Poster A12. Available from: https://www.revmed.com/media/shp2-inhibitor-rmc-4630-patients-kras-mutan....