Updated results of the phase III ALTERNATIVE trial of dual HER2 inhibition with lapatinib/trastuzumab plus aromatase inhibitor (AI) therapy in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer were reported in the Journal of Clinical Oncology by Johnston et al.
The previously reported primary analysis showed significantly prolonged progression-free survival with lapatinib/trastuzumab plus AI vs trastuzumab plus AI. As stated by the investigators, “This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study.”
Study Details
Dual HER2 blockade with [lapatinib] plus [trastuzumab] plus AI showed superior [progression-free survival] benefit versus [trastuzumab] plus AI in patients with HER2-positive/HR-positive [metastatic breast cancer]. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.— Johnston et al
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In the trial, 355 postmenopausal women from sites in 29 countries who had received prior endocrine therapy and neo(adjuvant)/first-line trastuzumab plus chemotherapy were randomly assigned 1:1:1 to receive lapatinib/trastuzumab plus AI (n = 120), trastuzumab plus AI (n = 117), or lapatinib plus AI (n = 118). Patients in whom chemotherapy was intended were excluded from the trial. The primary endpoint was investigator-assessed progression-free survival with lapatinib/trastuzumab plus AI vs trastuzumab plus AI in the intent-to-treat population. Secondary endpoints included progression-free survival comparison of other study groups, overall survival, overall response rate, and clinical benefit rate.
Key Findings
The study met its primary endpoint. Median progression-free survival was 11 months (95% confidence interval [CI] = 8.3–13.8 months) in the lapatinib/trastuzumab plus AI group vs 5.6 months (95% CI = 5.4–8.3 months) in the trastuzumab plus AI group (hazard ratio [HR] = 0.62, 95% CI = 0.45–0.88, P = .0063). The benefit of dual HER2 blockade was consistent across predefined subgroups.
Median progression-free survival in the lapatinib plus AI group was 8.3 months (95% CI = 5.8–11.1 months; HR vs trastuzumab plus AI = 0.85, P = .316). For the lapatinib/trastuzumab plus AI, trastuzumab plus AI, and lapatinib plus AI groups, overall response rates were 31.7%, 13.7%, and 18.6%; median durations of response were 14.0 months, 8.4 months, and 11.1 months; and clinical benefit rates were 40%, 30%, and 34%, respectively.
Overall survival data were immature at the time of the current analysis. Median overall survival was 46.0 months in the lapatinib/trastuzumab plus AI group vs 40.0 months in the trastuzumab plus AI group (HR = 0.60, 95% CI = 0.35–1.04). Median overall survival was 45.1 months in the lapatinib plus AI group (HR vs trastuzumab plus AI group = 0.91, 95% CI = 0.55–1.51).
Common adverse events of any grade (mostly grade 1 or 2) in the three groups were diarrhea (69%, 9%, and 51%), rash (36%, 2%, and 28%), nausea (22%, 9%, and 22%) and paronychia (30%, 0%, and 15%). Grade 3 or 4 adverse events occurred in 34%, 22%, and 32% of patients. Serious adverse events occurred in 14%, 10%, and 17% of patients. Adverse events led to discontinuation of treatment in 3%, 6%, and 9% of patients.
The investigators concluded, “Dual HER2 blockade with lapatinib plus trastuzumab plus AI showed superior progression-free survival benefit vs trastuzumab plus AI in patients with HER2-positive/HR-positive metastatic breast cancer. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.”
Stephen R.D. Johnston, PhD, of The Royal Marsden NHS Foundation Trust, London, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The ALTERNATIVE study was supported by GlaxoSmithKline. Lapatinib is now an asset of Novartis Pharmaceutical Corporation, the current sponsor of this study. Support was also provided by the National Institute for Health Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust. For full disclosures of the study authors, visit ascopubs.org.
