The heterogenous nature of cancer molecular profiles and the widespread variability of anticancer responses underscore the need to tailor therapies to individual genomic profiles. Several molecularly targeted cancer therapies have become the standard-of-care in the treatment of different tumor types, but the efficacy of single-agent activity is hampered by the development of cancer drug resistance and disease progression on these treatments.
“Novel combination strategies are required to more effectively overcome intrinsic and acquired mechanisms of resistance and prolong the duration of clinical benefit achieved for these agents when used as monotherapies,” says Elena Garralda, Executive Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – Caixa Research, Principal Investigator of VHIO’s Early Clinical Drug Development Group.
Preliminary results of a phase I combination and patient-centric study led by Alexander Drilon of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College of Medicine in New York, which were presented at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO), 2-6 June, Chicago, and published in parallel in Cancer Discovery (1), demonstrate proof-of-concept of the novel allosteric SHP2 inhibitor PF-07284892 in potentially overcoming resistance mechanisms to targeted therapies in the clinic.
This novel and adaptive phase I dose-escalation clinical trial encompassed two parts. The first tested the efficacy of the novel allosteric SHP2 inhibitor PF-07284892 as monotherapy in patients with advanced solid tumors and disease progression on prior targeted treatment. Those patients with progressive disease after treatment with PF-07284892 were then allowed to continue on trial in the combination dose-escalation part. Patients then received a combination of PF-07284892 with a specific molecularly guided therapy (lorlatinib, encorafenib + cetuximab or binimetinib), based on their individual genomic profiles.
“This study represents a significant step forward in optimizing dose-escalation clinical trial design by including a first-in-human dose-defining part for a single-agent targeted therapy, followed by treatment with a personalized combination matched to individual genomic profiles. Its novel design also defines an optimized framework for the accelerated testing of novel treatment combinations in phase I dose-escalation clinical trials,” observes Elena Garralda, corresponding author of an accompanying viewpoint article published in the same issue of Cancer Discovery (2).
“This unique study model will no doubt contribute to the general implementation of patient-centric personalized treatment approaches in the setting of phase I clinical trial designs and methodology,” says Alberto Hernando-Calvo, a Clinical Investigator of VHIO’s Early Clinical Drug Development and Cancer Genomics Groups, and first author of the viewpoint article.
Patient centricity in phase I oncology trials
The progressive implementation of precision medicine in oncology makes it increasingly complex to test new drug combinations in populations defined by their molecular profiles, given the low prevalence of some genomic alterations.
Novel study designs focused on patient centric approaches for phase I combination trials include N-of-1 studies, in which personalized therapies are offered for each specific patient based on the molecular profile of each tumor and each individual patient’s characteristics. These types of studies pose specific l challenges in terms of implementation and raise some regulatory concerns.
“The novel design of this present adaptive two-part trial enables the evaluation of personalized drug combinations based on genomic profiles of individual patients and at the same time allows for the identification of optimal dose and the potential adverse events specific to each drug combination,” adds Hernando-Calvo.
“Reflective of the theme of this year’s ASCO meeting—Partnering With Patients: The Cornerstone of Cancer Care and Research—our patients are at the very center of shared treatment decision-making. Their crucial engagement in these must-have conversations must also include the balanced consideration of potential therapeutic benefits versus side-effects in the selection of optimal, personalized treatment strategies matched to the unique molecular make-up of disease,” concludes Garralda.
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