Name:
Xevinapant + chemoradiotherapy in LA SCCHN: extended follow-up of a phase II clinical trial
Description:
Xevinapant + chemoradiotherapy in LA SCCHN: extended follow-up of a phase II clinical trial
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T00H14M52S
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Upload Date:
2024-01-12T00:00:00.0000000
Transcript:
Language: EN.
Segment:1 Introduction.
[MUSIC PLAYING]
PROF. JEAN BOURHIS: My name is Professor Jean Bourhis. I am chief of radiation oncology department at the Center Hospitalier Universitaire Vaudois in Lausanne, Switzerland. I specialize in radiation oncology and specifically in the treatment of head and neck cancers. Today, on behalf of my co-authors, I would like to discuss our article titled "Extended follow up of a phase II trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck, a randomized clinical trial. " This article was published online in the European Journal of Cancer in January 2023.
PROF. JEAN BOURHIS: It reports long-term follow-up analysis from the phase II trial. The primary data were published earlier in 2020.
Segment:2 Background - What is head and neck cancer?.
PROF. JEAN BOURHIS: Head and neck cancer is one of the most common diagnosed cancer types globally. In 2020, head and neck cancer accounted for over 850,000 new cases and 400,000 deaths worldwide.
PROF. JEAN BOURHIS: Over 90% of head and neck cancers are classified as squamous cell carcinoma of the head and neck, and around 60% of patients are initially diagnosed with locally advanced disease. Squamous cell carcinoma of the head and neck includes cancers of the lip, of the mouth, the tongue or the throat, and the larynx. Approximately 50% of patients with locally advanced squamous cell carcinoma of the head and neck are unresected.
PROF. JEAN BOURHIS: That is they do not undergo surgery. The current standard of care for these unresected patients is cisplatin-based chemoradiotherapy. Despite curative intent treatment, half of the patients will have local relapse or develop distant metastasis generally within two years of completing the chemoRT. And median overall survival for these patients with disease recurrence is approximately 12 months.
PROF. JEAN BOURHIS: Standard of care for unresectable locally advanced squamous cell carcinoma of the head and neck has remained relatively unchanged for more than two decades. And novel treatment options are urgently needed to improve the outcome of these patients.
Segment:3 Background - What is the mechanism of action of xevinapant?.
PROF. JEAN BOURHIS: Xevinapant is a first-in-class, potent, oral, small-molecule inhibitor of apoptosis protein, so-called IAP inhibitor.
PROF. JEAN BOURHIS: Currently, it is under investigation for the treatment of locally advanced squamous cell carcinoma of the head and neck that is thought to restore cancer cells sensitivity to apoptosis and thereby enhance the efficacy of chemotherapy and radiotherapy. Tumor cells can avoid cell death by suppressing apoptotic signaling, for example, by overexpressing IAPs, which regulate apoptosis via the inhibition of caspase activity.
PROF. JEAN BOURHIS: Overexpression of IAPs is associated with a poor prognosis in locally advanced squamous cell carcinoma of the head and neck. And in preclinical models, it has been shown to diminish the effect of both chemo and radiotherapy. Xevinapant inhibits x-linked IAP, XIAP, and cellular IAP1/2, so-called cIAP1/2, releasing the blockade on downstream caspase activity which is crucial for apoptosis and anticancer activity of both chemotherapy and radiotherapy.
PROF. JEAN BOURHIS: Inhibition of cIAP1/2 may also facilitate the immune cell activation by activating the non-canonical NFkB signaling which induce the production of inflammatory cytokines in response to tumor necrosis factor receptor signaling.
Segment:4 What was the design of the phase II portion of the phase I/II study evaluating xevinapant with CRT in LA SCCHN.
PROF. JEAN BOURHIS: A two-part phase I/II clinical trial evaluating the safety and efficacy of xevinapant in combination with chemoRT was performed.
PROF. JEAN BOURHIS: The trial began with an initial phase I period of dose escalation, which identified 200 milligram per day as the recommended dose for the phase II. Subsequently, in the double-blind multicenter randomized phase II portion of the study, 96 patients with previously untreated unresected locally advanced squamous cell carcinoma of the head and neck were randomized to receive either xevinapant plus chemoRT or placebo plus chemoRT.
PROF. JEAN BOURHIS: Most patients were at stage IV disease. All patients were heavy smokers with a median smoking history of 40 pack years. Only a small number of patients were HPV positive, with three patients in the xevinapant arm versus five in the placebo arm.
Segment:5 What were the primary endpoint results from the phase II study?.
PROF. JEAN BOURHIS: In the double-blind randomized phase II portion of the study, xevinapant plus chemoRT was compared with placebo plus chemoRT in these patients with unresected locally advanced squamous cell carcinoma of the head and neck.
PROF. JEAN BOURHIS: The primary results of this study were published by Sun in Lancet Oncology 2020, and reported significant improvement in the rate of locoregional control at 18 months, which was the primary end point. Here, I will discuss the extended follow-up results from this study. We are reporting extended follow-up data for progression free survival, PFS, locoregional control, duration of response, overall survival, and long-term safety.
PROF. JEAN BOURHIS: Efficacy results for PFS, locoregional control, and duration of response were analyzed with three years of follow-up after the last patient was randomized, along with safety results. Overall survival was evaluated with five years of follow-up after the last patient was randomized. Long-term safety was analyzed in terms of late-onset toxicity, which were defined as adverse events that started or worsened 30 days or more after the end of the treatment.
PROF. JEAN BOURHIS:
Segment:6 What were the long-term follow-up results?.
PROF. JEAN BOURHIS: Xevinapant plus chemoRT improved progression-free survival versus placebo plus chemoRT with a 67% reduction in the relative risk of disease progression or death. And the probability of being alive and free of disease progression after three years was 72% with a xevinapant versus 36% with placebo.
PROF. JEAN BOURHIS: The relative risk of death was reduced by 53%, and the probability of survival after five years was 52% in xevinapant arm versus 28% in the placebo arm, which is nearly a doubling of overall survival rate at five years. Overall survival was also assessed in patient subgroups. The overall survival benefit of xevinapant was generally maintained across subgroups, which included HPV status, smoking status, cancer localization, which is tumor sites, nodal involvement, TNM stage, and also alcohol consumption status.
PROF. JEAN BOURHIS: Now, the relative risk of locoregional failure over the study period was reduced by 54% in xevinapant plus chemoRT arm versus the placebo plus chemoRT arm. And the probability of being in locoregional control three years after randomization was 78% in xevinapant arm versus 56% in the placebo arm. And over the study period, there was a 79% reduction in relative risk of death or disease progression after initial response for patients to receive xevinapant.
PROF. JEAN BOURHIS: The probability of maintaining a response three years after initial response was 79% in xevinapant arm versus 36% in the placebo arm. Now, if we look at subsequent anticancer therapy for progressive disease of the primary cancer, it was 33% of the patients in xevinapant arm versus 40% of the patients in the placebo arm. And the most common subsequent therapies were chemotherapy, cetuximab, and immune checkpoint inhibitor which are consistent with the current standard of care.
PROF. JEAN BOURHIS: Now, regarding late-onset of toxicities of any grade, it was reported to be 81% of patients in xevinapant arm versus 70% of patients in the placebo arm. And if we focusing on grade III or higher late-onset toxicities, it was reported to be 27.1% in xevinapant arm versus 25.5% in the placebo arm.
PROF. JEAN BOURHIS: The most common late-onset toxicity was dry mouth with 35 versus 25% in xevinapant versus placebo respectively. And we can emphasize that the majority of the late-onset toxicity was grade I or II toxicity. By the end of the study, 21 of the 48 patients died versus 29 of the 48 patients died.
PROF. JEAN BOURHIS: But none of these deaths were attributed to study treatment and especially to late toxicity.
Segment:7 What did we learn from this study?.
PROF. JEAN BOURHIS: So what did we learn from this study? The long-term analysis from this study show the continued efficacy benefits with xevinapant plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with unresected locally advanced squamous cell carcinoma of the head and neck.
PROF. JEAN BOURHIS: This is the first study in decades to demonstrate superior efficacy benefits versus standard of care chemoradiotherapy in patients with unresected locally advanced squamous cell carcinoma of the head and neck treated with curative intent. It is also the first study to demonstrate proof of concept for the clinical effectiveness of targeting IAPs in a randomized placebo-controlled phase II study.
PROF. JEAN BOURHIS: Overall benefit, survival benefits were maintained across all subgroups as we saw. PFS and duration of response were markedly improved within xevinapant, and over a period of at least five years, the risk of death was more than halved for patients in xevinapant arm compared to those within a placebo arm. Now, regarding the safety profile of xevinapant, it remained manageable, and with extended follow-up, there was a similar proportion of late-onset toxicities of grade III and more which occurred in each arm.
PROF. JEAN BOURHIS: These results are encouraging. These are encouraging data which suggest that xevinapant may be able to improve cure rates in patients with unresected locally advanced or squamous cell carcinoma of the head and neck when added to standard of care chemoradiotherapy. Now, we have the randomized phase III TrilynX study which is being conducted in the same patient demographic to confirm the efficacy of xevinapant plus chemoRT versus placebo plus chemoRT.
PROF. JEAN BOURHIS: Thank you. [MUSIC PLAYING]
Segment:8 Acknowledgments and Disclosures .
PROF. JEAN BOURHIS: