Investigational targeted therapies for the treatment of testicular germ cell tumors

ABSTRACT

Introduction: Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting.

Areas covered: To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed.

Expert opinion: The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated.

KEYWORDS:

• Germ cell tumor
• platinum-refractory disease
• targeted therapy
• testicular cancer

Article highlights

• The treatment of cisplatin-refractory germ cell tumors remains challenging and there is still a need for personalized targeted treatment approaches.

• Cabazitaxel is currently tested in two trials in refractory patients particularly after prior paclitaxel exposure.

• Preclinical studies have revealed different aspects of cisplatin resistance and detected several ‘druggable’ targets in testicular cancer, but these are not uniformly detectable and are rather limited to subgroups of refractory tumors.

• Despite promising preclinical activity, none of the tested targeting agents has shown reasonable efficacy in non-biomarker selected patient groups.

• Given the high curability by standard treatment and the overall low incidence of GCTs, trial design will be hindered by small patient numbers available and an unfavorable cost-benefit ratio, which will make the raise of funding difficult.

• To date, molecularly targeted treatment does not play a role in the treatment of testicular cancer.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.