T-DM1 is less effective than trastuzumab-pertuzumab-docetaxel in older patients with HER2+ metastatic breast cancer, but comes with a lower rate of grade ≥3 adverse events
The combination of trastuzumab, pertuzumab and docetaxel (HPD) is recommended as the first-line treatment for patients with HER2+ advanced breast cancer (BC). However, this regimen negatively impacts the quality of life in patients aged ≥65 years. To address this issue, a phase III clinical trial compared T-DM1 to HPD in this older patient population. This trial failed to show non-inferiority for T-DM1 vs. HPD in terms of overall survival (OS) and progression-free survival (PFS). However, the incidence of grade 3 adverse events was lower with T-DM1 thanwith HPD, warranting further investigation.
Dual HER2 blockade with trastuzumab and pertuzumab in combination with docetaxel (HPD) is the established standard of care first line treatment for patients with HER2+ metastatic breast cancer (mBC). However, for patients aged ≥65, HPD can be mentally and physically intolerable, severely impacting their quality of life. Therefore, there is a need for a new standard treatment with reduced toxicity and non-inferior efficacy in this older patient group. The trial at hand evaluated the efficacy and safety of T-DM1 compared to HPD in older patients with HER2+ metastatic BC (mBC).
Methods
This phase 3 trial included patients aged ≥65 years with HER2+ mBC, who did not yet receive prior chemotherapy (ECOG PS: 0-2). In total, 148 patients were randomly assigned (1:1) to receive HPD q3w (trastuzumab 6 mg/kg [loading dose 8 mg/kg]; pertuzumab 420 mg [loading dose 840 mg] and docetaxel 60 mg/m2) (N= 75) or T-DM1 3.6 mg/kg q3w (N= 73) until disease progression. The primary endpoint of the study consisted of OS, with PFS, safety, and deterioration of activities of daily living as secondary objectives.
Results
In the preplanned first interim analysis, 135 patients were assessed, with a median age of 72 years in the T-DM1 arm and 71 in the HPD arm. T-DM1 did not demonstrate non-inferiority to HPD in terms of OS (median not reached in both arms, HR[95%CI]: 1.263[0.677-2.357]; p=0.953). T-DM1 also failed to show non-inferiority to HPD in PFS, with a numerically higher median PFS in the HPD arm (median PFS: 15.6 vs. 11.3 months; HR[95%CI]: 1.358[0.907-2.033]; p= 0.1336).
The safety profile was generally better for patients in the T-DM1 arm, with a lower incidence of grade ≥3 neutropenia (0% vs. 30.1%) and leukopenia (0% vs. 26.0%) compared to HPD. In contrast, thrombocytopenia was more common in the T-DM1 arm than with HPD (16.9 vs. 0%, respectively). The incidence of grade ≥3 non-haematological adverse events was generally lower in the T-DM1 arm than in the HPD arm (fatigue: 5.6% vs. 22.9%, diarrhoea: 0% vs. 11.4%, appetite loss: 8.5% vs. 11.4%, febrile neutropenia: 0% vs. 10.0%). This had a positive impacting the quality of life in older patients with HER2+ mBC. Of note, grade ≥3 increased AST (15.3% vs. 0%) and ALT (16.7% vs. 2.7%) were more frequent in the T-DM1 arm. cancer.
Conclusion
T-DM1 was not non-inferior to HPD in terms of PFS and OS. However, T-DM1 did come with a better tolerability than HDP, both in terms of frequency and severity of adverse events. Based on these results, HPD will continue to be the standard of care as the first-line treatment for older patients with HER2+ mBC. However, given the heterogeneity in health conditions among older patients with BC, conducting subset analyses based on age or geriatric assessment may help identify specific subpopulations for whom T-DM1 could be considered as an optional treatment.
Reference
Shimomura A, Tamura K, Sasaki K, et al. A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. Presented at SABCS 2023; Abstract RF02-04.
