ESMO Virtual Congress 2020: Complex Biomarkers in Drug Development

In this discussion, Jayesh Desai, MBBS, summarized his perspective on three mini oral presentations exploring the development and application of complex biomarkers in drug development.

529MO: Activity, safety and circulating tumour DNA (ctDNA) dynamics of paradox breaker BRAF inhibitor PLX8394 in patients with advanced cancer

Inhibition of the MAPK signaling pathway via RAF inhibition, particularly BRAF inhibition, is a high priority in cancer drug development given aberrant MAPK activation across cancers. Innate and adaptive resistance to first generation of BRAF inhibitors is a significant problem, and adaptive resistance can occur by paradoxical activation of MEK/ERK signaling through various mechanisms. PLX8394 is a next generation RAF inhibitor designed to prevent paradoxical mechanisms of adaptive resistance. In presentation 529MO, the authors presented clinical outcome data from PLX8394 treatment with or without the CYP3A4 inhibitor cobicistat (to increase systemic exposure) across multiple cancer histologies and discussed molecular data from circulating tumor DNA (ctDNA) analyses to explore the molecular heterogeneity surrounding response to PLX8394.

With regards to clinical outcome, the administration of cobicistat increased systemic exposure to PLX8394 by 2-3 fold. Severe side effects were rare (<5% of patients) and included liver chemistry abnormalities and diarrhea. Fatigue was the most common adverse effect (19% of patients). The overall response rate was 19% (10/52 evaluable patients), intriguingly including a complete response in a patient with stage IV melanoma harboring a AGK-BRAF fusion. Focused gene sequencing of circulating tumor DNA either by digital droplet PCR (ddPCR) or targeted next generation sequencing in 12 patients (all either stable or progressive disease) was performed. This revealed multiple clones present prior to treatment, higher variant allele frequency of BRAF mutations upon disease progression in a subset of progressors (including shorter PFS in patients with persistent detection of BRAF mutation throughout therapy), and changes in the variant allele frequency in other putative oncogenes with disease progression.

Dr. Desai concluded that (1) the co-administration of cobicistat is an intriguing therapeutic strategy to increasee systemic exposure to drug, and (2) ctDNA analyses may be useful for assessing efficacy and heterogeneity of response to RAF inhibitors.

530MO: Clinical Benefit in Biomarker-Positive Patients (pts) With Locally Advanced or Metastatic Solid Tumors Treated With the PARP1/2 Inhibitor Pamiparib in Combination With Low-Dose (LD) Temozolomide (TMZ) 

Quantification of deficiency in DNA repair by homologous recombination (HRD) is of interest clinically as a potential predictive biomarker for response to PARP inhibitor therapy. Multiple assays are available to do this, as shown in the figure below. These generally involve targeted sequencing of selected genes including those involved in DNA damage repair to identify patterns (mutational signatures, copy number alterations, mutations in specific genes) that are suggestive of HRD.


This presentation presented data from utilizing the Myriad myChoice CDx platform as a possible biomarker for response to combination treatment with the PARP inhibitor ramiparib in combination with temozolomide. This platform generates a numerical genomic instability score using targeted sequencing information. Across a variety of tumor types, a GIS score of 33 was utilized to identify HRD positive tumors. Tumors with GIS score of 33 tended to respond to treatment relative to tumors with GIS score less than 33. This trend held true regardless of BRCA mutation status. In contrast, individual mutations in the pre-selected list of HRD-related genes did not clearly identify responders from non-responders with the exception of BRCA1/2 mutation. Dr. Desai concluded that the myChoice CDx platform is an interesting potential predictive biomarker for response, but further work is required to understand the appropriate cutoff for HRD positivity and PARP inhibitor response, and whether the threshold will need to be different for other PARP inhibitors or specific cancer types.

531MO: VHIO immune gene-expression signature (VIGex) to enrich patient selection in immunotherapy (IT) Phase 1 clinical trials

Modulation of immune checkpoints as cancer therapy has emerged as a powerful treatment option across many cancer types, but responses are limited to a subset of patients. Given the complexity of interplay between tumor cells and the microenvironment, the identification of biomarkers predictive of response across multiple cancer contexts has been challenging. One biomarker approach has been the generation of RNA expression profiles to identify immune “hot” versus “cold” tumors. These signatures show some promise as predictors of response but require additional optimization and prospective validation. Dr. Desai summarized the results from presentation 531MO, describing the generation of a gene expression profile termed VIGex to delineate immune “hot” versus “cold” tumors, with suggestion from a small retrospective patient cohort that immune “hot” tumors by VIGex have improved progression-free survival when treated with immunotherapy. Dr. Desai concluded that the VIGex is an important tool that may help identify both patients with tumors intrinsically resistant to immunotherapy in addition to those that might respond.

Presented by: Jayesh Desai, MBBS, Medical Oncologist and Associate Director of Clinical Research at the Peter MacCallum Cancer Centre, Melbourne, Australia

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.