Trodelvy-Keytruda Combo Shows Promise in First-Line Metastatic TNBC
The ASCENT-04 trial shows Trodelvy plus Keytruda extends progression-free survival by 3.4 months in PD-L1-positive metastatic triple-negative breast cancer. Meanwhile, the ToPCourT trial investigates trilaciclib combined with pembrolizumab and chemotherapy for advanced TNBC. These developments signal evolving treatment approaches for this aggressive breast cancer subtype.
The combination of Trodelvy (sacituzumab govitecan) and Keytruda (pembrolizumab) has demonstrated a clinically meaningful improvement in progression-free survival for patients with PD-L1-positive metastatic triple-negative breast cancer (mTNBC), according to results from the ASCENT-04 trial. The trial showed the combination extended progression-free survival from 7.8 months with traditional chemo-immunotherapy to 11.2 months, a 3.4-month improvement with a hazard ratio of 0.65. This development represents a significant shift in the first-line treatment landscape for this aggressive form of breast cancer.
For several years, the standard of care for PD-L1-positive mTNBC has been chemotherapy combined with Keytruda. However, antibody-drug conjugates like Trodelvy have shown robust activity in pretreated triple-negative breast cancer, improving both progression-free and overall survival compared to standard chemotherapy. The ASCENT-04 trial compared Trodelvy and Keytruda to chemotherapy and Keytruda in patients with previously untreated, metastatic triple-negative breast cancer who had tumors that were PD-L1 positive.
The 3.4-month improvement in progression-free survival is particularly critical because approximately half of patients who initiate first-line treatment for metastatic triple-negative disease never receive a second line of therapy, with about one-third dying before getting second-line treatment. Survival in metastatic triple-negative breast cancer has been quite limited, usually ranging between 18 to 20 months.
Triple-negative breast cancer is defined as breast cancer that lacks expression of progesterone receptor, estrogen receptor, and amplification of human epidermal growth factor receptor type 2 (HER2). It accounts for approximately 15% of all breast cancers and has a poorer prognosis compared to hormone receptor-positive and HER2-positive subtypes. Due to the lack of targetable receptors, cytotoxic chemotherapy remains the backbone of treatment with limited options after disease progression in the advanced setting.
Meanwhile, another clinical trial called ToPCourT is evaluating a different combination approach. This open-label, single-arm, phase II trial will assess the efficacy of trilaciclib in combination with pembrolizumab, gemcitabine, and carboplatin in patients with locally advanced unresectable or metastatic TNBC who have received three or less prior lines of therapy. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor that protects myeloid and lymphoid cell lines when administered before chemotherapy by transiently arresting them in the G1 phase.
The primary endpoint of the ToPCourT trial is overall response rate according to RECIST 1.1, with secondary objectives including progression-free survival, duration of response, and overall survival. Trilaciclib was previously evaluated in patients with metastatic TNBC in a randomized phase II study with gemcitabine and carboplatin, which demonstrated an improvement in overall survival despite not showing the same myeloprotection seen in lung cancer studies.