xevinapant (Debio 1143)

Both tuvusertib and olaparib induced stronger radiosensitization than xevinapant and combining both agents resulted in especially profound radiosensitization in three out of the four cell lines tested, whereas their combination with xevinapant or the combination of xevinapant with cisplatin was less effective. Assessment of cell death induction via annexin V/DAPI staining failed to generally predict cytotoxicity or radiosensitization of these approaches. Overall, our data are in line with the recent failure of the phase 3 TrilynX trial and suggest further investigation of ATR and PARP inhibition for the curative treatment of HPV-negative HNSCC.

Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells.

Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit.

NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017.

P3, N=19, Terminated, Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Mar 2025 --> Sep 2024 | Completed --> Terminated; toxicity

P3, N=19, Completed, Groupe Oncologie Radiotherapie Tete et Cou | Suspended --> Completed | Trial completion date: Oct 2035 --> Mar 2025 | Trial primary completion date: Oct 2025 --> Dec 2024

P3, N=19, Suspended, Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Sep 2030 --> Oct 2035 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=0, Withdrawn, H. Lee Moffitt Cancer Center and Research Institute | N=12 --> 0 | Recruiting --> Withdrawn

This study demonstrates the therapeutic potential of venetoclax in combination with ATO in vitro and strongly encourages further investigation of relapsed/refractory APL with high BCL2 expression.

P3, N=730, Terminated, EMD Serono Research & Development Institute, Inc. | Trial completion date: Apr 2027 --> Sep 2024 | Active, not recruiting --> Terminated; Study has crossed the pre-defined futility boundary at the Interim Analysis.

P3, N=166, Terminated, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Terminated; No major safety concerns were identified in XRAY VISION study, but Lack of evidence of efficacy of meaningful clinical benefit.

P3, N=19, Suspended, Groupe Oncologie Radiotherapie Tete et Cou | Trial primary completion date: Jul 2024 --> Oct 2024