The TRILINX trial revealed Xevinapant's toxicity was so high that it forced reductions in standard, effective treatments like cisplatin and radiation. This compromised the foundational therapy, leading to worse patient outcomes and demonstrating a key risk in adding novel agents to established regimens.
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While platinum chemotherapy is considered the standard treatment after a patient progresses on a first-line ADC-IO combination, experts admit this is a standard "based on nothing." There is no clinical trial data to prove its efficacy in this specific setting; it serves only as a placeholder for new clinical trials.
The failure of an adjuvant trial for the TKI pazopanib was likely caused by a protocol change that reduced the dose to manage transaminitis. While well-intentioned to improve tolerability and adherence, the lower dose was sub-therapeutic. This serves as a critical lesson that managing side effects by compromising dose can nullify a drug's potential efficacy.
Corvus Pharmaceuticals is already planning frontline combination trials for its T-cell lymphoma drug. The drug's favorable safety profile is the critical enabler, allowing it to be paired with chemotherapy and used as a long-term maintenance therapy to prolong remissions—a strategy unavailable to more toxic drugs.
An expert argues the path to curing metastatic cancer may mirror pediatric ALL's history: combining all highly active drugs upfront. Instead of sequencing treatments after failure, the focus should be on powerful initial regimens that eradicate cancer, even if it means higher initial toxicity.
Initial studies combining menin inhibitors with venetoclax/azacitidine showed high remission rates but also high mortality. Using each agent at its full, 28-day dose caused severe, fatal myelosuppression, forcing protocol amendments to shorten drug exposure to manage toxicity.
Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.
The failure of the TROPiCS-04 trial for sacituzumab govitecan may not indicate the TROP2 ADC class is ineffective. Experts suggest problems with dosing and toxicity management (e.g., neutropenia) during the trial could be the real culprit, arguing that the drug class still holds promise.
Clinical trials combining potent ARPIs like abiraterone and enzalutamide have consistently failed. Once the androgen receptor pathway is maximally suppressed by one agent, adding another with a similar mechanism provides no further clinical advantage, much like hammering a nail that is already flush with the wood.
The TRILINX trial found that adding Xevinapant to local chemoradiation did not improve local control but was associated with a higher rate of distant cancer failures. This counterintuitive outcome highlights the risk of unintended, detrimental systemic effects when developing combination therapies for localized disease.
Xevinapant's Phase III failure, after a promising Phase II trial, was partially attributed to the broader, more heterogeneous patient population. This group experienced greater toxicity than the Phase II cohort, suggesting early-phase safety profiles may not scale, ultimately compromising the efficacy of the entire treatment regimen.