Next‐generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity

Abstract

The promise of ‘personalized cancer care’ with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized heterogeneity within any given tumor-type from patient to patient (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) as demonstrated by molecular evolution through space (primary tumor to metastasis) and time (after therapy). These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents. Classic trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic ‘oncogenic driver’ aberrations with adequate power. Usual accrual difficulties to clinical trials are exacerbated by low frequencies of any given molecular driver. To address these challenges, there is need for innovative clinical trial designs and strategies implementing novel diagnostic biomarker technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for pre-defined treatment priority algorithms given numerous aberrations commonly observed within any one individual sample. Access to multiple available therapeutic agents simultaneously is crucial. Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression. This report discusses various ‘next-generation’ biomarker-driven trial designs and their potentials and limitations to tackle these recognized molecular heterogeneity challenges. Regulatory hurdles, with respect to drug and companion diagnostic development and approval, are considered. Focus is on the ‘Expansion Platform Design Types I and II’, the latter demonstrated with a first example, ‘PANGEA: Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma’. Applying integral medium-throughput genomic and proteomic assays along with a practical biomarker assessment and treatment algorithm, ‘PANGEA’ attempts to address the problem of heterogeneity towards successful implementation of molecularly targeted therapies.

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

“…When mutations can be found in nearly all possible coding regions within a tumor, resistance to most drugs seems highly likely. Read et al (37) pointed out that aggressive strategies against cancerous cells are effective only in the absence of resistance at treatment and various strategies for administering drugs in the face of resistant clones have been proposed (38)(39)(40)(41)(42). Finally, a key feature of the non-Darwinian model is the rapidity with which mutations accrue.…”

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

“…As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3,4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor.…”

Management of metastatic esophagogastric junction adenocarcinoma

“…PANGEA is a phase II trial that gastroesophageal tumors are classified into the following six categories (HER2+, MET+, FGFR2+, VEGFR2+, MSI-H, and EGFR+), and then paired specific targeted therapies (trastuzumab, TBD, anti-EGFR antibody ABT-806, TBD2, ramucirumab, and nivolmab) are assigned according to the biomarkers, along with standard chemotherapy [32] . VIKTORY is a screening trial without drug intervention for metastatic GC patients who failed or progressed on first-line chemotherapy, using cancer panel/nanostring CNV and immunohistochemistry [33] .…”