Clinical Challenges

Participants in the Markers in Cancer Tutorial will be assigned to small Challenge Groups to work through the process of biomarker development in breakout sessions. With faculty facilitation and guidance, these groups will practice applying what they learn throughout the Tutorial to real-world scenarios designed by the Planning Committee. At the conclusion of the Tutorial, each Challenge Group will make a brief presentation to a mock institutional board consisting of committee members and faculty.

Clinical Challenge 1: Use of biomarkers and therapy to overcome resistance to initial treatment for patients with advanced solid tumors

Increased molecular marker testing and target-driven drug development have resulted in more therapies being approved with companion diagnostics. Drug targetable (“druggable”) molecular alterations in tumors have included EGFR mutation in lung cancer, BRAF in melanoma, HER-2 amplification and overexpression in breast cancer, ALK rearrangement in lung cancer, and others. Mutations in tumors can be identified in up to approximately 50% of solid tumors and some of these are potentially druggable with approved or investigational agents. Clinical trials have established overall benefit for some of these therapies for patients with advanced cancers, but inevitably, the therapies become less effective and the disease progresses due to the emergence of resistance. This may occur due to the emergence of new molecular alterations in the tumor or due to a shift of existing rare clonal subpopulations to more dominant status. Further tailoring of therapy then becomes essential – whether by initial use of therapeutic agents in concert to target multiple druggable mutations simultaneously, or by the intermittent or sequential use of agents that directly overcome the emergent mechanism of resistance. The potential to treat cancer with combination or sequential treatment strategies continually increases. Given the multitude of possible treatment combinations and sequences, development and evaluation of therapeutic strategies to overcome resistance to initial treatment will present challenges for diagnostic test development and application in clinical settings where there is continual evolution of a patient’s disease. 

 

Clinical Challenge 2: Use of biomarker panels and innovative clinical trial designs to optimize therapy selection and accelerate the drug development process for promising targeted and immunotherapeutic anticancer therapies

Traditional approaches for drug development and evaluation are rapidly being replaced by approaches in which molecularly targeted or immune therapies and companion diagnostic assays for guiding their use are developed, validated and approved in tandem. This new paradigm brings both complexities as well as potential efficiencies to the therapeutics development process. Most targeted drugs are likely to benefit only a subgroup of patients; for some drugs the benefiting subgroup could be small or poorly defined, but the benefits of the targeted drug are anticipated to be large for the appropriately defined subgroup of patients. The need for biomarker testing to identify patients who might benefit from each drug brings logistical challenges of assay development and potentially limited availability of tumor specimen from any single patient. However, efficiencies can be realized by use of biomarker panels that allow for evaluation of large numbers of markers with small specimen amounts, and screening trial platforms (e.g., “basket” or “umbrella” trials) can offer efficient means to direct patients to different trials or trial arms depending on their tumor profiles.

Collaborating Organizations