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Initial Pertuzumab Plus Trastuzumab ± Chemotherapy Followed by Trastuzumab Plus Emtansine for ERBB2+ Metastatic Breast Cancer
TAKE-HOME MESSAGE
- This study was a secondary analysis of a phase II randomized clinical trial wherein patients with ERBB2-positive metastatic breast cancer were randomly assigned to receive pertuzumab plus trastuzumab with or without chemotherapy. Among patients treated without chemotherapy, the 2-year overall survival rate was 79.0% versus 78.1% among those treated with chemotherapy; however, progression-free survival was significantly shorter when chemotherapy was omitted.
- These results suggest that chemotherapy-free anti-ERBB2 treatment is a reasonable option for selected patients with metastatic breast cancer, as the overall survival outcomes are similar to those achieved with chemotherapy.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved.
OBJECTIVE
To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes.
DESIGN, SETTING, AND PARTICIPANTS
This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022.
INTERVENTIONS
Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B).
MAIN OUTCOMES AND MEASURES
Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL).
RESULTS
A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B.
CONCLUSIONS AND RELEVANCE
The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach.
Additional Info
Disclosure statements are available on the authors' profiles:
Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial
JAMA Oncol 2023 Aug 10;[EPub Ahead of Print], J Huober, P Weder, K Ribi, B Thürlimann, JC Thery, Q Li, L Vanlemmens, S Guiu, E Brain, J Grenier, F Dalenc, C Levy, AM Savoye, A Müller, V Membrez-Antonioli, MA Gérard, J Lemonnier, H Hawle, D Dietrich, E Boven, H BonnefoiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The standard first-line therapy for patients with ERBB2 (formerly HER2)–positive (ERBB2+) metastatic breast cancer (MBC) consists of dual antibody therapy plus taxane-based chemotherapy, based on the CLEOPATRA trial. Although, in clinical practice, in an effort to minimize toxicity, patients generally receive chemotherapy for a few months and then continue on trastuzumab plus pertuzumab (HP) alone (with the addition of hormonal therapy for triple-positive tumors), initial exposure to chemotherapy remains challenging for patients. The current study evaluated the outcomes of a chemotherapy-free treatment approach with HP alone compared with standard chemotherapy plus HP therapy in patients with ERBB2+ MBC. Both treatment groups received trastuzumab emtansine at progression. Although the median progression-free survival duration was longer in the chemotherapy group, the median overall survival duration was comparable between the two groups. Several completed trials point to the possibility that there may be a subset of patients with ERBB2+ breast cancer who do not require chemotherapy in combination with ERBB2-targeted treatment. For example, in the neoadjuvant NeoSphere trial, 17% of the patients achieved a pathological complete response with HP therapy alone. Additionally, the PERTAIN trial provides some insight into responses in patients who do not receive chemotherapy upfront. This trial was intended to evaluate the efficacy and safety of first-line pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in patients with triple-positive MBC and reported a statistically significant 3-month prolongation of progression-free survival duration with the addition of pertuzumab. However, the use of induction chemotherapy was left to the discretion of the investigator, and, in this group, an overall survival duration of more than 5 years was reported in the group of patients who did not receive induction chemotherapy, suggesting that there may be a group of patients who can do very well without chemotherapy upfront. The identification of these patients remains a challenge. Recently, at the American Society of Clinical Oncology 2023, the PHERGain trial, which used a response-adapted design to identify early responders to HP therapy alone, was reported. Promising results were noted with the use of PET scans to identify patients who respond well to neoadjuvant treatment that did not include chemotherapy. Going forward, it will be essential to personalize treatment approaches with further investigations into the use of novel approaches, such as biomarker-based strategies, gene expression profiles, and imaging responses, to help clarify which patients with ERBB2+ breast cancer can be spared chemotherapy.