New kids on the block: ESMO début for novel targeted therapies

In spite of the tsunami of checkpoint inhibitors, other targeted agents continue to be developed and 2016 sees the first presentation at ESMO of promising new drugs

  • Date: 09 Oct 2016
Ahmad Awada

Ahmad Awada, Jules Bordet Institute, Université Libre de Bruxelles, Belgium

The aurora A kinase inhibitor, alisertib, was the subject of 3 presentations in sessions on Friday. Adding alisertib to paclitaxel as second-line therapy for small-cell lung cancer (SCLC) prolongs progression-free survival (PFS) compared with placebo plus paclitaxel (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.522–1.004; p=0.038), with overall survival (OS) and response rate trends also in favour of alisertib (Abstract 1423O). In a further presentation, 6 novel MYCL1 fusions were identified by hybrid-capture-based comprehensive genomic profiling of 689 SCLC cases. Investigation of their role as oncogenic drivers is warranted, as well as the value of alisertib as potential treatment (Abstract 1424O). Notably, a patient who had failed 3 previous lines of chemotherapy experienced an 18-month near-complete response to alisertib. This drug is also being investigated in neuroendocrine prostate cancer (NEPC), where N-myc and aurora A drive the NEPC phenotype. Single-agent alisertib in 56 evaluable patients with metastatic disease yielded a 6-month PFS rate of 16.3% in patients with pathologically confirmed NEPC (Abstract LBA29). Two patients achieved complete response of liver metastases and a third patient had stable disease at 39 months.

Modulation of the immune system is being used to improve the outcome of cancer patients. Survival and toxicity results from a randomised, double-blind study investigating the benefits of adding the TLR8 agonist, motolimod, to standard platinum/5 fluorouracil/cetuximab for metastatic squamous cell carcinoma of the head and neck showed that the novel combination was generally well tolerated but did not improve PFS or OS for the intent-to-treat population. However, in a subgroup of patients with immune-related motolimod injection-site reaction, addition of the TLR8 agonist significantly increased PFS (216 days versus 181 days, respectively; p=0.005) and OS compared with the standard regimen (Abstract LBA37). Final results from the randomised FAST trial will be presented today. They confirm the clinically relevant benefit of combining in the first-line setting the anti-CLDN18.2 antibody IMAB362 with epirubicin/oxaliplatin/capecitabine (EOX) in the 48% of patients with CLDN18.2-positive advanced/recurrent gastric and gastro-oesophageal junction adenocarcinomas, with significant improvements in PFS (HR 0.47; p=0.0001), OS (HR 0.51; p=0.0001) and ORR (43% versus 28%) compared with EOX alone (Abstract 614O).

Phase I data for a number of other agents are also encouraging. Yesterday, preliminary data for the antibody–drug conjugate PF-06647020 (comprising a humanised PTK7-directed monoclonal antibody, an auristatin microtubule inhibitor payload and a cleavable dipeptide linker) in advanced solid tumours were the subject of a Poster Discussion Session (Abstract LBA35). ORR was 27% in the platinum-resistant ovarian cancer cohort. Another presentation reported the safety of the pan-FGFR inhibitor, BAY 1163877, in patients with advanced solid tumours, and partial responses were recorded in 6/47 RECIST-evaluable patients with FGFR mRNA overexpressing tumours (particularly those with bladder cancer) while at least stable disease (>8 weeks) was documented in 39/47 patients (Abstract 360O_PR). These results are of particular interest due to the response profile that supports the selection of patients based on tumour FGFR mRNA levels. Today, in a Poster Discussion Session, the phase I results of single-agent treatment of advanced solid tumours with the p53/HDM2-protein–protein interaction inhibitor, NVP-CGM097, show clinical activity, with 40% of 50 patients achieving stable disease (range, 7.7–86.7 weeks), along with evidence of p53 pathway activation by induction of its downstream target, GDF-15 (Abstract 366PD).

Clinically relevant benefits can be confirmed with some novel targeted agents and it is hoped that their early promise will be realised in larger studies. Identification of targets involved in cell carcinogenesis, development of potent agents and importantly, patient and tumour enrichment, are cues for therapeutic innovation.
Targets of novel agents

Targets are upregulated/overexpressed or dysfunctional in different cancers

  • Aurora kinases are involved in cell-cycle regulation via microtubule formation and stabilisation of the spindle pole. They also interact with the MYC proto-oncogene
  • in carcinogenesis.
  • Toll-like receptors play a vital role in pathogen recognition and the activation of innate immunity.
  • Claudins are involved in the regulation of paracellular permeability, via tight junctions, and cell polarity and signal transductions.
  • PTK7 is a receptor tyrosine kinase in the Wnt signalling pathway, which is involved in determining cell function.
  • Dysregulation of the fibroblast growth factor signalling pathway is a frequent oncogenic event in multiple tumour types. 
  • TP53 is a tumour-suppressor gene frequently inactivated in multiple cancer types. Overexpression of the HDM2 protein is one of the mechanisms of loss of function.

This article appeared in the Sunday edition of the Daily Reporter