The biological logic behind the combination rests on a family of proteins called inhibitors of apoptosis, or IAPs. Three members of this family, cIAP1, cIAP2 and XIAP, act inside cells as gatekeepers of cell death and inflammatory signaling. Rather than simply preventing suicide, these proteins actively suppress a form of cell death driven by RIPK1, a signaling kinase that can trigger what scientists call immunogenic cell death. When tumor cells die immunogenically, they release signals that recruit and activate both innate and adaptive immune responses, effectively turning a dying tumor cell into a vaccine. By keeping this pathway in check, IAPs help tumors evade immune surveillance and blunt the effectiveness of drugs that release the brakes on T cells.

Tolinapant was designed to remove that shield. It is a non-peptidomimetic antagonist, meaning it binds the IAP proteins without mimicking the natural peptides that normally regulate them, and it does so with balanced activity against all clinically relevant IAP family members. The intended effect is to lower the threshold at which tumor necrosis factor, or TNF, becomes lethal to the tumor cell. In practical terms, the drug makes cancer cells far more vulnerable to being killed by T cells, the very cells that pembrolizumab unleashes by blocking the PD-1 checkpoint. The trial therefore tested whether priming tumors with tolinapant could convert immunologically cold or resistant cancers into ones that respond to PD-1 blockade.

The ASTEROID trial enrolled patients with advanced solid tumors and followed a classic phase I design. The primary endpoints were safety and the identification of a recommended phase 2 dose, while secondary endpoints captured anti-tumor activity and the pharmacokinetics of the combination. Dosing of tolinapant followed an intermittent schedule of seven days on treatment followed by fourteen days off, an approach intended to balance target engagement against toxicity. Pembrolizumab was administered on its standard intravenous schedule. The combination proved well tolerated overall, an important finding because IAP antagonists can, in principle, sensitize normal cells to TNF-driven inflammation as well as tumor cells.

The recommended phase 2 dose was established at 150 milligrams of tolinapant given on the intermittent schedule alongside pembrolizumab. Within that framework, the investigators observed early but meaningful evidence of efficacy. The overall response rate across the treated population reached 33 percent, a striking figure for a phase I study in a heavily pretreated cohort of mixed tumor types. Particularly notable were responses in estrogen receptor-positive breast cancer, a disease subtype that has historically resisted immune checkpoint blockade and is generally considered immunologically quiet. Seeing durable responses in this setting suggests that lowering the TNF cytotoxicity threshold can genuinely reprogram how tumors interact with the immune system.

Beyond the headline response rate, the trial’s translational component may prove its most enduring contribution. The team performed integrated analyses of tumor biopsies and blood samples to understand why some patients responded and others did not. Responders carried tumors characterized by a TNF and interferon-enriched inflammatory microenvironment, a molecular signature indicating that the intended biology, the sensitization of tumor cells to cytokine-driven killing, was actually occurring in patients. Responders also showed increased tumor antigenicity, meaning their cancers displayed more molecular features that the immune system could recognize as foreign, together with enhanced diversity of T cell receptor clones, a sign that a broader repertoire of T cells had been mobilized against the tumor.

Resistance, by contrast, had a coherent fingerprint of its own. Non-responding tumors were dominated by a niche of immune suppressor cells, specifically tumor-associated macrophages and regulatory T cells, orchestrated by the chemokine receptors CCR4, CCR6, CCR7 and CCR8. These receptors guide the trafficking of immune cells, and their enrichment points to a microenvironment in which suppressive myeloid and regulatory populations crowd out effector T cells, absorbing the benefits of checkpoint release. This finding suggests that patients who fail the tolinapant-pembrolizumab combination might in future be candidates for additional agents that deplete or reprogram macrophages and regulatory T cells, potentially creating triple or quadruple combinations tailored to the biology of each tumor.

The trial was funded by Cancer Research UK and Astex Pharmaceuticals, now part of Taiho Oncology, with drug supplied through Astex and Merck Sharp & Dohme’s investigator-initiated studies program. It was conducted across UK centers including The Royal Marsden, Cambridge University Hospitals and the Institute of Cancer Research’s Drug Development Unit, with laboratory work spanning the Meier Lab, the Centre for Evolution and Cancer and collaborating groups in Australia and Sweden. The study also reflects a growing trend in early-phase oncology: rather than treating phase I trials as pure safety exercises, the investigators embedded deep molecular profiling from the outset, so that every patient’s response contributed to a mechanistic map of the drug’s action.

For the field, the results constitute clinical proof of concept that dual blockade of IAP proteins and PD-1 can sensitize tumors to immunotherapy. They also deliver a practical dividend in the form of candidate biomarkers. The TNF and interferon signature, antigenicity measures and T cell receptor clonality could be developed into diagnostic tests to select patients most likely to benefit, while the CCR-driven suppressor niche signature could identify those who need combination strategies beyond PD-1 blockade. Larger trials will be required to confirm efficacy, define which tumor types gain the most, and validate the biomarkers prospectively. But the ASTEROID data provide a compelling early answer to a question that has frustrated oncologists for a decade: how to make immunotherapy work for the many patients whose tumors currently ignore it. By targeting the machinery tumors use to silence inflammatory cell death, tolinapant appears to reopen a channel that cancer had carefully closed, and the 33 percent response rate, including in a notoriously immunotherapy-resistant breast cancer subtype, is the kind of signal that reshapes research agendas.

Subject of Research: A phase I trial of the IAP antagonist tolinapant combined with pembrolizumab in advanced solid tumors

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

Article References: Tiu, C., Yau, W., Tenev, T., Lionarons, D., Leung, C., Sanchez-Perez, V., Codacci-Pisanelli, G., Lai, X., Zachariou, A., Hussain, A., Prout, T., Parmar, M., Baikady, B., Goicoechea, M., Layzell, S., Guppy, N., Roxanis, I., Lund, T., Dos Reis, D. C., … Meier, P. (2026). IAP antagonist tolinapant (ASTX660) in combination with pembrolizumab in advanced solid tumors: a phase I trial. Nature Communications. https://doi.org/10.1038/s41467-026-77552-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77552-7

Keywords: tolinapant, ASTX660, pembrolizumab, IAP antagonists, immunotherapy, phase I trial, advanced solid tumors, ER-positive breast cancer, immunogenic cell death, PD-1 blockade, tumor microenvironment, biomarkers