Designs and challenges for personalized medicine studies in oncology: focus on the SHIVA trial

Abstract

Personalized medicine is defined by the National Cancer Institute as "a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease." In oncology, the term "personalized medicine" arose with the emergence of molecularly targeted agents. The prescription of approved molecularly targeted agents to cancer patients currently relies on the primary tumor location and histological subtype. Predictive biomarkers of efficacy of these modern agents have been exclusively validated in specific tumor types. A major concern today is to determine whether the prescription of molecularly targeted therapies based on tumor molecular abnormalities, independently of primary tumor location and histology, would improve the outcome of cancer patients. This new paradigm requires prospective validation before being implemented in clinical practice. In this paper, we will first review different designs, including observational cohorts, as well as nonrandomized and randomized clinical trials, that have been recently proposed to evaluate the relevance of this approach, and further discuss their advantages and drawbacks. The design of the SHIVA trial, a randomized proof-of-concept phase II trial comparing therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer will be detailed. Finally, we will discuss the multiple challenges associated with the implementation of personalized medicine in oncology, as well as perspectives for the future.

Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial

“…Studies often exclude patients because of an inability to obtain a biopsy, insufficient or no tumor content in the available specimen, deteriorating performance status, or the patient's withdrawal of consent or choice of an alternate treatment (10,11,(14)(15)(16). For example, Tsimberidou and colleagues (13) report that 10.8% (139/1283) of patients had inadequate tissue for molecular analysis.…”

Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs

“…Concerning the usefulness of the global approach of selecting oncology drugs based on genetic abnormalities rather than pathological features, at least two clinical trials, the SHIVA trial in France 33,34 and the NCI-MPACT in the United States 35 are comparing a biomarker-based therapy (molecular tumor profiling and corresponding targeted therapies) with conventional therapy for patients with advanced solid cancer of any type.…”

Patient-centric trials for therapeutic development in precision oncology

“…It is likely that patient selection will also play a significant role in the development of these agents, with biomarker hypotheses actively being developed 36 . Data are beginning to emerge from early programmes such as SHIVA 37 , which broadly evaluated targeted therapies using a histology agnostic approach in end stage patients who failed standard therapy.…”