Michael Ong

Validation and utilisation of high-coverage next-generation sequencing to deliver the pharmacological audit trail.

Background:Predictive biomarker development is a key challenge for novel cancer therapeutics. We explored the feasibility of next-generation sequencing (NGS) to validate exploratory genomic biomarkers that impact phase I trial selection.Methods:We prospectively enrolled 158 patients with advanced solid tumours referred for phase I clinical trials at the Royal Marsden Hospital (October 2012 to March 2013). After fresh and/or archived tumour tissue were obtained, 93 patients remained candidates for phase I trials. Results from tumour sequencing on the Illumina MiSeq were cross-validated in 27 out of 93 patients on the Ion Torrent Personal Genome Machine (IT-PGM) blinded to results. MiSeq validation with Sequenom MassARRAY OncoCarta 1.0 (Sequenom Inc., San Diego, CA, USA) was performed in a separate cohort.Results:We found 97% concordance of mutation calls by MiSeq and IT-PGM at a variant allele frequency ⩾13% and ⩾500 × depth coverage, and 91% concordance between MiSeq and Sequenom. Common ‘actionable’ mutations involved deoxyribonucleic acid (DNA) repair (51%), RAS-RAF-MEK (35%), Wnt (26%), and PI3K-AKT-mTOR (24%) signalling. Out of 53, 29 (55%) patients participating in phase I trials were recommended based on identified actionable mutations.Conclusions:Targeted high-coverage NGS panels are a highly feasible single-centre technology well-suited to cross-platform validation, enrichment of trials with molecularly defined populations and hypothesis testing early in drug development.

Long-term benefits versus side-effects from bone-targeted therapies for cancer patients: minimizing risk while maximizing benefits.

Purpose of reviewBone-targeted therapies such as bisphosphonates and denosumab are established in the treatment of cancer patients to prevent or delay skeletal-related events and improve quality of life. Along with these benefits of bone-targeted therapies, there are also known risks and adverse effects. Recent findingsAlthough historically bone-targeted therapy use has been limited to palliation in patients with bone metastases, recent evidence suggests that these agents may also have anti-cancer effects. This will likely lead to the greater use of these agents in patients with earlier-stage disease. Increased use will lead to more adverse effects. In particular, the risk of rare but severe toxicities will become important. SummaryThis article explores strategies to maximize the clinical benefit of such therapy while minimizing associated risks.

Recent advances in second-line treatment of castration-resistant prostate cancer.

Purpose of reviewPatients with metastatic castration-resistant prostate cancer (CRPC) no longer responsive to docetaxel have a poor prognosis, worsened quality-of-life, and traditionally few options for treatment. This review addresses promising and practice-changing developments for the treatment of CRPC in the second-line setting. Recent findingsRecent data for cabazitaxel, a novel taxane chemotherapy, and abiraterone acetate, a novel inhibitor of androgen synthesis, demonstrate significant improvements in the survival of patients with docetaxel-refractory CRPC. We review the mechanisms of action of these agents and data from phase III clinical trials, contextualizing their place in therapy. We also update other areas of investigation, including oral platinum analogues, vascular-endothelial growth factor receptor targeted therapy, inhibitors of chaperone proteins, and androgen receptor antagonists. SummaryUpon disease progression after first-line docetaxel chemotherapy, cabazitaxel and abiraterone improve survival of patients with CRPC and are important novel treatment options. Potential toxicity from cabazitaxel necessitates careful patient selection and supportive care. Both abiraterone and cabazitaxel are also being evaluated in the first-line setting, and therefore the optimal sequencing of therapies remains uncertain. Many other novel agents continue to be evaluated and promising classes of agents include antisense oligonucleotides against clusterin (custirsen) and androgen receptor antagonists (MDV3100).

Abstract 1774: Progression-free survival curves suggest a dichotomous determinant of PD-L1 inhibitor efficacy

Background: PD-L1 expression varies across tumors but does not accurately predict PD-L1 inhibitor efficacy. Some negative tumors respond and some positive tumors fail. PD-L1 inhibitor progression-free survival (PFS) curve shape in non-small cell lung cancer (NSCLC) suggests that a dichotomous (present vs absent) factor might drive sensitivity rather than it being driven by a continuous variable like PD-L1 expression. PFS curves may follow first order kinetics, with a straight line if log % PFS is plotted vs time. If the population had 2 distinct subgroups with differing rates of progression then one would expect an inflection point on the log-linear curve, and the curve would fit a 2-phase decay model in nonlinear regression analysis (NLRA). A more homogeneous population would not fit a 2-phase model. Methods: We used arohatgi.info/WebPlotDigitizer/app/ to digitize published PFS curves, then GraphPad Prism5 for 2-phase NLRA, with the constraints Y0=100, plateau=0. To generate standardized 2-phase curves, we utilized 1) unselected NSCLC patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) where we expected a high proportion of curves to fit a 2-phase model as only some patients would have a sensitizing EGFR mutation; 2) NSCLC EGFR mutant and wild type (WT) patients treated with EGFR TKIs, and patients treated with platinum-based chemotherapy, taxanes or placebo/best supportive care (BSC), where we expected a lower proportion of curves to fit 2-phase models; 3) PD-L1 PFS curves in NSCLC and other tumor types. Results: With EGFR TKIs in unselected patients, 58 of 79 (73%) curves were fit by 2-phase models, vs 5 of 37 (14%) with EGFR TKIs in EGFR mutant patients (p Conclusions: Most PD-L1 inhibitor PFS curves fit a 2-phase model. This is similar to what we observed with EGFR TKIs in unselected patients and different from EGFR TKIs in EGFR mutant and WT patients, and from chemotherapy or placebo/BSC. This leads us to hypothesize the existence of a dichotomous (present vs absent) factor such as a gene mutation, deletion or silencing that sensitizes tumors to PD-1/PD-L1 inhibitors. If found, such a dichotomous factor could prove to be a highly useful biomarker that could permit accurate prediction of PD-1/PD-L1 inhibitor efficacy. Since PD-1/PD-L1 inhibitor efficacy is higher in tumors with high PD-L1 expression, any sensitizing dichotomous factor might also drive PD-L1 expression. Citation Format: David J. Stewart, Dominick Bosse, Stephanie Brule, Andrew G. Robinson, Michael Ong, John F. Hilton. Progression-free survival curves suggest a dichotomous determinant of PD-L1 inhibitor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2017-1774