The TULIP trial

The TULIP trial represents a pivotal phase 3 study conducted to assess the efficacy of trastuzumab duocarmazine (T-Duo) in patients suffering from metastatic breast cancer with HER2 overexpression. In this trial, 437 patients meeting specific criteria, including having undergone two prior treatments or prior T-DM1 therapy in the metastatic setting, were enrolled. The patients were randomized to receive either T-Duo or the physician’s selected treatment.

Previously reported data at ESMO 2021 demonstrated a favourable outcome in centrally evaluated progression-free survival (PFS), which served as the primary endpoint. However, the final results presented in this report concerning the secondary endpoint, overall survival (OS), did not exhibit a statistically significant improvement, despite observing a numerical increase. The safety profile of the treatment remained consistent with earlier findings, though concerns were raised regarding ocular toxicity. Notably, 78% of patients experienced eye-related issues, ranging from dry eyes to keratitis or conjunctivitis, leading to dose reductions and discontinuation in approximately 20% of cases.

A critical question arises regarding the positioning of T-Duo among existing HER2-targeted agents, especially in light of the absence of demonstrable OS benefits. T-Duo was developed for administration after first-line taxane therapy with pertuzumab and trastuzumab, and second-line treatment with T-DM1. However, the landscape of HER2-targeted therapies has rapidly evolved, with the emergence of trastuzumab deruxtecan (T-DXd) altering the treatment paradigm for first- and second-line settings. T-DXd has replaced T-DM1 in cases of rapid relapse during first-line treatment.

The study also highlighted a subset of patients (13%) in the TULIP trial with treated or stable brain metastasis. Detailed information on the progression of this relevant subgroup remains to be investigated.

Considering the challenges posed by ocular toxicity and evolving treatment paradigms, the future of T-Duo necessitates careful consideration. Exploring combination therapies might be a possibility, although recent phase 1 trials were halted due to unsatisfactory results and toxicity concerns. Alternatively, investigating the potential of T-Duo post-T-DXd treatment could provide a valuable avenue for further research, potentially identifying a specific niche for this compound within the evolving landscape of HER2-targeted therapies.

Reference

Aftimos P. – Trastuzumab duocarmazine versus physician’s choice therapy in pre-treated HER2-positive metastatic breast cancer: Final results of the phase III TULIP trial. ESMO2023 #386MO