Opportunities and challenges in the era of molecularly targeted agents and radiation therapy

Abstract

The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

Figure 1.

Hypothetical examples of Kaplan–Meier overall survival curves comparing drug developments in a selected patient population based on biomarkers vs unselected patient population. A) Like many drug trials directed at specific populations of patients based on biomarker selection, the initial part of the curve separates early in the targeted agent group (Drug X) compared with the standard of care (SOC) arm, but eventually resistance develops in the majority of these patients. B) For a trial testing the efficacy of Drug X in an unselected group of patients, practically no real separation is seen in the curves between the experimental (Drug X + SOC) and SOC arms early on; the curves eventually split, and a statistically significant separation occurs later in the trial, with some patients having durable responses.

Figure 2.

Schematic to accelerate progress in molecular-targeted radiation therapy. To bring upfront patient selection into radiation treatment selection, we need more predictive biomarker discovery and validation, which will increase the number of established biomarkers associated with novel therapeutics and subsequent improvement in patient outcome. CSA = clonogenic survival assays; GEMM = genetically engineered mouse models; G-1 = group 1 drugs (drugs with biomarkers); G-2 = group 2 drugs (drugs without biomarkers); RT = radiation therapy; SOC = standard of care.