IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial

Abstract Successful cancer immunotherapy requires not only tumor cell killing but also the activation of innate and adaptive immune responses. The inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2 and XIAP act as key suppressors of RIPK1-driven immunogenic cell death, thereby enabling tumor immune evasion and limiting the effectiveness of immune checkpoint blockade (ICB). ASTX660 (tolinapant) is a non-peptidomimetic antagonist with a balanced activity against all clinically relevant IAPs, designed to lower the TNF cytotoxicity threshold and sensitize tumors to T cell-mediated killing. Here, we present results from the phase I ASTEROID trial (NCT05082259), evaluating ASTX660 in combination with pembrolizumab in patients with advanced solid tumors. Primary endpoints were recommended phase 2 dose (RP2D) and safety, while secondary endpoints were anti-tumor activity and pharmacokinetics. The combination was well tolerated and demonstrated early evidence of efficacy. RP2D was ASTX660 150 mg (7-days-on/14-days-off) with pembrolizumab. Overall response rate was 33%, including responses in ER⁺ breast cancers typically resistant to ICB. Integrated translational analyses reveal that response is associated with a TNF/IFN-enriched inflammatory tumor microenvironment, increased tumor antigenicity and enhanced TCR clonal diversity, whereas resistance correlates with a CCR4/6/7/8-driven TAM/Treg-dominant niche. Together, these results provide clinical proof-of-concept that dual IAP and PD-1 blockade sensitize tumors, while identifying candidate biomarkers to guide patient stratification in future studies.

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Publication Details

Journal
Nature Communications
Published
2026-09-30
DOI
https://doi.org/10.1038/s41467-026-77552-7
Primary Topic
Cell death mechanisms and regulation
Type
article
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article

IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial

Anna Zachariou, Camila Pereira Almeida, Martin Sims, Tomoko Smyth et al.
Nature Communications
Cell death mechanisms and regulation
article

IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial

Anna Zachariou, Camila Pereira Almeida, Martin Sims, Tomoko Smyth, Aasia Hussain, Mona Parmar, Naomi Guppy, Simone Jueliger, George A. Ward, Bora Gürel, Matthew P. A. Davis, Christina Gertrude Yap, James M. Murphy, Udai Banerji, Trevor A. Graham, Ioannis Roxanis, Mateus Crespo, Ann‐Marie Baker, Pascal Meier, Ana Ferreira, Wing Yau, Tom Lund, Syed Aleem Haider, Amanda Swain, Maria Goicoechea, Toby Prout, Nina Tunariu, Tatiany Luiza Silveira, Xiaoran Lai, Nicholas C. Turner, Juanita Suzanne Lopez, Penny Flohr, Adam Sharp, Claudia Bertan, Crescens Tiu, Johann Sebastian De Bono, Anna Rachel Minchom, Giovanni Codacci-Pisanelli, Luís Zapata, Mattias Leino, André L. Samson, Andrew N.J. Tutt, Victoria Sanchez-Perez, Danna Chan, Alec Paschalis, Subham Basu, Edward Johnston, Basu Bristi, Ching Leung, Alan Dunlop, Scott Layzell, Claudio Salas, Ilya Potapov, Alistair Ring, Soham Mandal, Aram Oganesian, Bindu Baikady, Diego Carlos Dos Reis, Tencho Tenev, Daniel Lionarons
article en

Abstract

Abstract Successful cancer immunotherapy requires not only tumor cell killing but also the activation of innate and adaptive immune responses. The inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2 and XIAP act as key suppressors of RIPK1-driven immunogenic cell death, thereby enabling tumor immune evasion and limiting the effectiveness of immune checkpoint blockade (ICB). ASTX660 (tolinapant) is a non-peptidomimetic antagonist with a balanced activity against all clinically relevant IAPs, designed to lower the TNF cytotoxicity threshold and sensitize tumors to T cell-mediated killing. Here, we present results from the phase I ASTEROID trial (NCT05082259), evaluating ASTX660 in combination with pembrolizumab in patients with advanced solid tumors. Primary endpoints were recommended phase 2 dose (RP2D) and safety, while secondary endpoints were anti-tumor activity and pharmacokinetics. The combination was well tolerated and demonstrated early evidence of efficacy. RP2D was ASTX660 150 mg (7-days-on/14-days-off) with pembrolizumab. Overall response rate was 33%, including responses in ER⁺ breast cancers typically resistant to ICB. Integrated translational analyses reveal that response is associated with a TNF/IFN-enriched inflammatory tumor microenvironment, increased tumor antigenicity and enhanced TCR clonal diversity, whereas resistance correlates with a CCR4/6/7/8-driven TAM/Treg-dominant niche. Together, these results provide clinical proof-of-concept that dual IAP and PD-1 blockade sensitize tumors, while identifying candidate biomarkers to guide patient stratification in future studies.

Nature Communications
Good health and well-being
Openalex Percentile: Top 20%
Cell death mechanisms and regulation
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