T. Feys MBA, MSc

New oncology reimbursementsin Belgium

OVERVIEW OF BELGIAN REIMBURSEMENT NEWS

(BELG J MED ONCOL 2021;15(5):264-5)

Immunotherapy as first-line treatment for metastatic NSCLC

The added value of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibition as first-line treatment in non-oncogene addicted metastatic non-small cell lung cancer (NSCLC) is supported by substantive scientific evidence and clinical experience. In the absence of a true contra-indication, the use of immune checkpoint inhibitors (ICIs) is recommended as first-line therapy in phase IV NSCLC patients without targetable oncogenic driver. However, a growing challenge in clinical practice consists of the choice for one of the available first-line anti-PD-(L)1-based treatment options. The main decision in this respect consists of the choice whether to use single agent anti-PD-(L)1 therapy, or go for one of the available combination strategies.

Targeted therapies for non-metastatic NSCLC

Approximately a quarter of patients with non-small-cell lung cancer (NSCLC) is being diagnosed in an early stage of the disease and are amenable for a radical surgery. Despite radical surgery, the five-year survival rates for fully resected early stage NSCLC remains rather disappointing. To address this, several studies have assessed the use of adjuvant chemotherapy in an attempt to reduce the recurrence rate after surgery. Unfortunately, how-ever, the survival benefit obtained from adjuvant chemotherapy is somewhat modest, with approximately half of patients suffering a disease relapse. The identification of reliable predictive biomarkers for a response to targeted agents in the metastatic setting, the design of molecularly oriented studies, and the availability of novel potent and less toxic agents paves the way for the evaluation of these targeted agents in the (neo)adjuvant treatment of patients with earlier-stage NSCLC harboring an oncogenic driver mutation. The results obtained with this therapeutic strategy will be summarized in this article.

New therapeutic targets in patients with advanced NSCLC

A better understanding of critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC) has led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Since the introduction of tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, we have witnessed a continued shift towards a biomarker-driven treatment algorithm for patients with advanced-stage NSCLC. The identification of less common oncogene drivers led to a marked reshaping of the diagnostic and therapeutic approach towards NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC. In this article we will briefly discuss the recent advances for the targeted treatment of advanced NSCLC patients with RET fusions, MET exon14 skipping, HER2 overexpression and KRAS mutations.

The changing first-line treatment landscape for patients with ALK-positive NSCLC

The discovery of the EML4-ALK fusion gene in a limited subset of non-small-cell lung cancer (NSCLC) patients and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistance to crizotinib regularly develops ultimately leading to disease progression. Since then, several novel ALK targeting tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, lorlatinib and ensartinib have been developed. While initially showing their worth in the second line treatment of ALK-positive advanced NSCLC, more recent studies have also demonstrated superior efficacy of second-generation ALK inhibitors over crizotinib in the first-line treatment of these patients. As a result, second-generation ALK inhibitors have largely replaced crizotinib as the preferred first-line treatment for patients with advanced ALK-positive NSCLC. In this article we want to provide an overview of the current evidence on the best sequence in the treatment of ALK-positive NSCLC patients.

Overcoming crizotinib resistance in ROS1-positive NSCLC

Rearrangements involving the ROS1 gene are found in approximately 2% of patients with non-small-cell lung cancer (NSCLC). Based on the results of the pivotal PROFILE 1001 trial, the multikinase tyrosine kinase inhibitor (TKI) crizotinib became the first targeted treatment option for patients with advanced ROS1-positive NSCLC in 2016. Unfortunately, responses to crizotinib tend not to be durable and almost all patients eventually develop disease progression after a certain amount of time, often involving brain metastases. To overcome this crizotinib resistance, several next generation ROS1 inhibitors have been developed and tested in the treatment of crizotinib-pretreated and treatment naïve ROS1-positive advanced NSCLC.

Dual EGFR-VEGF strategy in EGFR-mutant NSCLC

The VEGF pathway is well-recognized mediator of angiogenesis and tumorigenesis in many cancer types. As a result, multiple therapeutic agents targeting this pathway have been developed and were subsequently registered in multiple tumor types. Interestingly, preclinical studies have demonstrated a close relationship between VEGF and EGFR pathways. Based on this observation, several studies have investigated whether the addition of a VEGF-targeting agent to an EGFR-directed tyrosine kinase would provide clinical benefit in patients with EGFR-mutant non-small cell lung cancer. In recent years, several large, randomized studies demonstrated that the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improves the progression-free survival (PFS) in this setting. The topline results of these studies will be briefly discussed in this article.