Sjoukje Oosting, MD, PhD

Invited discussant of the xevinapant study, Sjoukje Oosting, MD, PhD, of the University Medical Center Groningen, the Netherlands, commented: “There is finally hope on the horizon that we can increase the cure rate of our patients with head and neck cancer, if these data are confirmed in a phase III study.”

Dr. Oosting continued: “At ESMO Congress 2019, we heard about the significant benefit [of xevinapant] in locoregional tumor control and progression-free survival observed in this phase II trial. Now, we learned that improvement in locoregional tumor control is confirmed, and with longer follow-up, overall survival is significantly better in the xevinapant arm, with limited late toxicity.”

Mechanism of Action

To explain the possible “secret” behind the effectiveness of xevinapant, Dr. Oosting explained that it is an SMAC (second mitochondrial-derived activator of caspase) mimetic that blocks IAPs (inhibitor of apoptosis proteins), which are frequently overexpressed in head and neck squamous cell carcinoma, and blocks apoptosis, which may lead to radiotherapy resistance. “Blocking IAPs releases the brake on apoptosis, which explains the synergistic effect with chemotherapy,” she said, noting that this class of drug also has immunomodulatory properties.

Remaining Questions

Seeing the data, Dr. Oosting posed the following questions: Will this drug be effective in human papillomavirus–positive oropharyngeal cancer and in nasal carcinoma? Would it have a synergistic effect with radiotherapy alone? Will it be useful in cisplatin-ineligible patients and in those with other tumor types, which we treat with chemoradiotherapy? “Hopefully, future trials will provide some
answers,” she said. 

DISCLOSURE: Dr. Oosting has received institutional support from Novartis and Celldex.