Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT2): Challenges and Opportunities in Conducting an MD Anderson Randomized Study in Precision Oncology

Background
Precision oncology is associated with favorable outcomes in selected patients with cancer. Our first IMPACT trial (IMPACT1) demonstrated that in sequential patients with advanced cancer who had tumor molecular testing and participated in phase I clinical trials, matched targeted therapy (MTT) was associated with superior rates of response, progression-free survival (PFS) and overall survival compared with those of patients who received non-MTT. Despite the statistical significance for these outcomes, the study was non-randomized. Recognizing that it would be difficult to randomize patients we nonetheless undertook IMPACT2, a phase 2 randomized study to determine whether patients treated on the basis of tumor genomic alterations have longer PFS compared to those whose treatment is not selected on the basis of molecular alteration analysis.

Methods
Patients with metastatic cancer undergo a tumor biopsy and genomic profiling. Patients are presented at tumor board and are offered to be randomized between two arms: MTT or non-MTT, when criteria (biomarker present, available clinical trial, eligibility criteria met, insurance approval) are met. In April 2019, we amended the trial to include a “patient-preference” cohort for each arm. Patients who decline randomization are offered choice of arm (ClinicalTrials.gov: NCT02152254). The primary analysis will use both randomized and patient-preference cohorts based on a Bayesian hierarchical model that “borrows” from the patient-preference cohorts to the extent to which its PFS agrees with that in the randomization cohort.

Results
The key barriers randomizing patients with actionable molecular alterations are patient-related (advanced, metastatic setting requiring immediate intervening therapy; decline in performance status, organ function; or death); drug-related (FDA-approved drug available; or unavailable MTT against key driver biomarker) or financial (no insurance coverage of MTT; lack of patient resources to participate in trials). As the study spans over a few years, some investigational agents that were considered non-MTT at the time of treatment assignment were later proven to be MTT (e.g., immunotherapeutic agents targeting high tumor mutational burden); and/or were approved by the FDA.

Conclusions
Although randomized trials have been considered the gold standard in drug development, such studies in the advanced metastatic setting are complicated. The benefit of Precision Oncology has been exemplified in individual patients who were treated with biomarker-selected therapy. The adaptive design of IMPACT2 enables patient randomization despite the evolving tumor biomarkers and the plethora of investigational drugs. IMPACT2 provides insights for the development of cancer genome-based medicine. Outcomesfor randomized patients are awaited.

Clinical trial information
NCT02152254.