ONCOGENIC SIGNALING

The IAP pathway

Inhibitor of apoptosis proteins (IAPs) negatively regulate apoptosis and modulate immune and inflammatory responses, which are frequently dysregulated in cancer. Cellular IAPs (including cIAP1 and cIAP2) and X-linked IAP (XIAP) play a crucial role in the inhibition of apoptosis by inhibiting members of the caspase family via the death receptor–mediated and mitochondria-mediated pathways. Tumor cells can resist apoptosis by increasing the expression of proteins blocking pro-apoptotic pathways, such as cellular IAPs and XIAP. IAPs are also known to have a critical role in primary and secondary resistance to anticancer agents. Therefore, the inhibition of IAPs is considered a viable therapeutic target.1,2

Xevinapant – antagonist of IAPs

Description and Mechanism of Action:

Xevinapant is an investigational oral, small-molecule antagonist of IAPs, including XIAP, cIAP1, and cIAP2. By inhibiting cellular IAPs, xevinapant is designed to restore pro-apoptotic cellular functions and increase cancer cell sensitivity to anticancer therapies.2

The IAP Pathway

Areas of Interest:

TRIALS

TrilynX (NCT04459715)

This is a phase III randomized, double-blind, placebo-controlled study of xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in patients with histologically confirmed, locally advanced SCCHN. The study will assess event-free survival, as well as progression-free survival, overall survival, locoregional control, and safety.3

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DDRiver clinical trial program

TrilynX

Are you interested in learning more about a clinical trial program investigating whether blocking inhibitor of apoptosis proteins might improve the efficacy of chemoradiotherapy? Visit our partner Debiopharma’s website to learn about our active and enrolling phase 3 trial.

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Pathways Under Investigation

EGFR/MUC1

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Abbreviations:
EGFR/MUC1, epidermal growth factor receptor/mucin 1; MET, mesenchymal epithelial transition factor.

References:

  1. Le Tourneau C, Tao Y, Gomez-Roca C, et al. Phase I trial of Debio 1143, an antagonist of inhibitor of apoptosis proteins, combined with cisplatin chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Clin Cancer Res. 2020;26:6429-6436.
  2. Sun XS, Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study. Lancet Oncol. 2020;21:1173-1187.
  3. A study of Debio 1143 (xevinapant) in combination with platinum-based chemotherapy and standard fractionation intensity-modulated radiotherapy in participants with logically advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy. ClincalTrials.gov identifier: NCT04459715. Updated October 22, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04459715

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