Improving safety and effectiveness of fluoropyrimidine-based chemotherapy

In the development of novel anticancer drugs, identifying the factors that determine treatment response is increasingly becoming an integrated part of the early stages of clinical drug development. The last three chapters of this thesis described first-in-human studies in which the focus was on safety, but also on identifying the factors that determine pharmacodynamics and treatment response. For the novel anti-HER3 monoclonal antibody lumretuzumab, investigated in the study described in Chapter 14, it was shown that pretreatment expression of the HER3 ligand heregulin in tumor tissue, might be predictive of treatment response. The only patient with high pretreatment tumor expression of heregulin was found to have a strong response of non-target lesions (determined subjectively), and a (formal) partial metabolic response on FDG-PET. This finding led us to hypothesize that tumor heregulin expression could be a predictive marker for response to treatment with lumretuzumab. This hypothesis was recently strengthened by reports from other studies. Juric et al. published data from a phase 1 study with the bispecific anti-HER3 and anti-EGFR monoclonal antibody MEHD7945A, in which the single two responding patients (with head and neck cancers) had the highest heregulin expression levels. In addition, in randomized phase 2 studies of other HER3-targeted agents in non-small cell lung cancer and breast cancer, patients with higher tumor heregulin expression levels at baseline showed longer progressionfree survival. It needs to be formally established in phase II studies of lumretuzumab, in more homogeneous patient populations, whether heregulin truly is a biomarker that is predictive of antitumor response. If confirmed, then it will be desirable to use pretreatment tumor heregulin expression to select patients for treatment with lumretuzumab. Conduction of a phase III biomarker validation study and development of a validated diagnostic test (analogous to how HercepTestR was developed for selection of patients to be treated with trastuzumab) will then be required to assure adequate patient selection in daily clinical practice. The last two chapters described studies in which the anti-TWEAK monoclonal antibody RG7212 was investigated. In the patient population evaluated, limited signs of efficacy were noted. However, the analysis described in Chapter 16 showed that inhibition of TWEAK by RG7212 resulted in early reductions of tumor TWEAK–Fn14 signaling in an exposure-dependent manner, suggesting that higher exposure might be required to achieve intratumoral pharmacodynamic effect. Also higher pretreatment tumor Fn14 expression was associated with greater reductions in Fn14 expression in response to treatment, as well as with reductions of Ki-67 expression and early changes in serum concentrations of TWEAK-inducible proteins, indicating that higher tumor Fn14 expression might be required for pharmacodynamic response. Whether the observed pharmacodynamics lead to a clinically meaningful treatment effect remains to be established. Several other critical issues need to be addressed before pursuing further development of RG7212. First, in view of the limited magnitude of the pharmacodynamic effects observed, it needs to be assured that there is sufficient target inhibition in tumor upon treatment with RG7212. Secondly, it needs to be determined which tumor types are most sensitive to TWEAK inhibition and could benefit most from treatment with RG7212. Third, it needs to be established which biomarker predicts treatment response upon treatment with RG7212. Lastly, combination treatments may be more effective than single agent anti-TWEAK, and additional preclinical investigations could be performed to address which combinations show the most pronounced antitumor activity. Whether it be old or novel anticancer drugs, an improved understanding of which patients benefit most from treatment – which can be achieved by combining clinical studies with translational investigations throughout the stages of drug development – will remain critical in order to allow safer, more effective, and more efficient treatment of cancer