Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial

Abstract

Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer.

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

“…24,25), aimed at selecting optimal innovative drug treatment strategies for patients with advanced metastatic tumors, has highlighted the utility of sampling matched normal and tumor biopsies from the same patient to identify novel therapeutic strategies based on differential gene expression in the neoplastic tissue compared with the normal sample. There are a number of clear similarities between the WINTHER study approach and the findings presented here, where the nontumor component can inform prognosis, but although there seems to be clear rationale for this approach aimed at personalized drug selection, there may be only limited benefit derived by subtracting the results of adjacent normal or stromal tissue to correctly classify the overall tumor molecular subtype.…”

Clinical Trials in the Genomic Era

“…29 Preliminary reports from such studies highlight difficulties in providing appropriate treatment to match disease complexity and probability of response, choosing the right patients, defining relevant outcomes, overcoming regulatory and logistic hurdles, and aggregating results to generate and share new knowledge about actionable mutations and biomarkers of disease resistance and evolution. [7][8][9][10][11] In fact, an interim analysis of the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial demonstrated that after screening nearly 800 patients, only 9% were found to harbor a study-targeted actionable mutation. 8 Other studies reported higher, but still limited, match rates.…”

“…1.3 has been considered clinically meaningful. 7,58,59 In one such basket trial, Von Hoff et al 58 reported that 27% of patients achieved this end point with a median PFS targeted :PFS prior line ratio of 2.9. Of note, the overall response rate was only 10%.…”

“…Initial experience from these studies highlight considerable logistic and methodological difficulties and indicate that the benefit of genetically guided therapy may be restricted to a smaller patient subpopulation than originally predicted. [7][8][9][10][11] This article briefly reviews the opportunities and challenges of clinical trials in the genomic era. It specifically focuses on the relevance to hematologic malignancies and recent insights from basket and umbrella trials as the prototype for genomic-based trials.…”

“…At international sites, the process was shorter but complicated by varying rules about testing novel therapies and the off-label use of approved drugs. 7 Another challenge in this regard would be getting pharmaceutical companies to collaborate on the same trial, particularly for the evaluation of combination therapies. 37 Long turnaround times for molecular sequencing and the requirement to perform all tests at Clinical Laboratory Improvement Amendments-certified laboratories have also emerged as prohibitive factors, especially where international collaborations are concerned.…”