J. De Grève MD, PhD

Molecular test algorithms for digestive tumours

The Belgian Commission of Personalized Medicine has been created to advise the federal government on all matters related to personalised medicine in oncology, including the reimbursement of molecular tests. Here, we propose the Belgian strategy for molecular testing in the digestive tumours within a scientific-based framework. For each tested biomarker, a clinical test level is attached, which is key to establish the relevance of the test and to define the reimbursement. For each digestive tumour type, the different molecular tests are represented as decision trees with its test utility, test level and a brief technical test description.

(BELG J MED ONCOL 2019;13(1):4–10)

Novel therapeutic molecular targets in lung cancer: non-V600 mutant and mutant

In three sequential studies, we pre-clinically investigated several previously unexplored lung cancer-derived BRAF mutations as well as a HER3 mutation and their response to clinically available targeted therapeutics. During the FIELT I clinical study at UZ Brussel, in which 229 non-small-cell lung carcinoma patients were prospectively investigated at the genomic level, twelve patients (5.2%) were identified to harbour a BRAF mutation in their tumour and one patient found to harbour a novel HER3 mutation. As opposed to melanoma, 75% of these non-small-cell lung carcinoma-derived BRAF mutations were non-V600. RAF inhibitors have only been clinically developed against BRAF V600 mutations because of concerns of paradoxical effect in non-V600 mutant cancers. The status of non-V600 mutations with regards to BRAF inhibition effects was unknown. We functionally analysed thirteen of such tumour-derived BRAF non-V600 mutations and demonstrated that all types of BRAF mutations cause pathway activation and are sensitive to clinically relevant doses of a combination of type I RAF-inhibitor (dabrafenib) and that paradoxical pathway activation is abrogated by MEK-inhibition (trametinib). This entails that dual inhibition of non-V600 mutations is effective and safe. Further, we investigated the comparative efficacy of two modes of RAF inhibition (type I vs type II) in suppressing mutant BRAF-induced ERK signalling. Our preclinical findings in non-V600 BRAF expressing cellular models suggest that the type II RAF-inhibition (AZ628) has more potential than the type I RAF-inhibition (dabrafenib), both as single agent and combined with MEK inhibition in suppressing the ERK pathway independent of the BRAF mutation type. We also explored a novel somatic lung cancer-derived V855 HER3 mutation. Our study provided evidence for oncogenicity of V855 HER3 in a HER2 and ligand-dependent manner, in murine and human cell lines. Further, we showed that the given V855A HER3 mutation predicts sensitivity to the clinically available HER-targeting therapeutic afatinib. Our findings support the clinical investigation of non-V600 BRAF mutated lung or other cancers with dual RAF and MEK inhibition and HER3 mutant cancers with afatinib.

(BELG J MED ONCOL 2019;13(1):31–34)

P.01 A LUNG CANCER-DERIVED CRAF MUTATION IS ERK PATHWAY ACTIVATING AND PREDICTS SENSITIVITY TO COMBINED TYPE II RAF AND MEK INHIBITION

O.10 THE DEUBIQUITINASE USP13 AS A NOVEL THERAPEUTIC CO-TARGET IN EGFR MUTANT NON-SMALL CELL LUNG CANCER

‘My ambition for the BSMO is to become the Belgian ASCO’

Checkpoint inhibitors in the first-line treatment of non-small cell lung cancer

SUMMARY

Antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) have become standard-of-care in the second-line treatment for advanced non-small cell lung cancer after failure of first-line chemotherapy. The observed durable responses as well as the favourable toxicity profile have moved these agents to first-line studies for advanced non-small cell lung cancer. In tumours with high PD-L1 expression, pembrolizumab is registered as the preferred first-line treatment. Further studies are currently focusing on combination strategies. The major future challenge will be selecting the optimal treatment strategy for the patient.

(BELG J MED ONCOL 2017;11(8):380–385)

P.01 Targeting Polo-like kinase 1 and TRAIL enhances apoptosis in non-small cell lung cancer (NSCLC) cells