Findings from two clinical trials, conducted in patients withheavily pretreated HER2-positive metastatic breast cancer (MBC), show better outcomes with investigational agents. The results have been presented at San Antonio Breast Cancer Symposium (10-14 December 2019, San Antonio, Texas, US) and simultaneously published in The New England Journal of Medicine. In HER2CLIMB, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival (PFS) and overall survival (OS) than adding placebo. In DESTINY-Breast01, trastuzumab deruxtecan showed durable antitumour activity.
The HER2CLIMB results
Standard-of-care treatment for patients with HER2-positive MBC is first-line trastuzumab plus pertuzumab and a taxane, followed by second-line trastuzumab emtansine for patients who have disease progression. After progression during treatment with trastuzumab emtansine, commonly used regimens include tyrosine kinase inhibitors such as lapatinib with trastuzumab or capecitabine, trastuzumab with chemotherapy, or participation in a clinical trial.
With improvement in systemic therapies, the incidence of brain metastases has increased such that brain metastases may develop in up to half of patients. Treatment for brain metastases in patients with HER2-positive MBC includes local therapies, such as neurosurgical resection and stereotactic or whole-brain radiation therapy.
Tucatinib is an investigational, oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of epidermal growth factor receptor, which may alter the toxicity profile. In a phase Ib dose-escalation trial, tucatinib in combination with trastuzumab and capecitabine showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.
The HER2CLIMB is a phase II trial that evaluated tucatinib combined with trastuzumab and capecitabine in patients with HER2-positive MBC (who had or did not have brain metastases) previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The patients were randomly assigned to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary endpoint was PFS among the first 480 patients who underwent randomisation. Secondary endpoints, assessed in the total population (612 patients), included OS, PFS among patients with brain metastases, confirmed objective response rate (ORR), and safety.
The PFS rate at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio [HR] for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; p < 0.001), and the median duration of PFS was 7.8 months and 5.6 months, respectively.
The OS rate at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (HR for death, 0.66; 95% CI, 0.50 to 0.88; p = 0.005), and the median OS was 21.9 months and 17.4 months, respectively.
Among the patients with brain metastases, PFS rate at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (HR 0.48; 95% CI, 0.34 to 0.69; p < 0.001), and the median PFS was 7.6 months and 5.4 months, respectively.
Common adverse events in the tucatinib group included diarrhoea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhoea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
The study team concluded that tucatinib plus trastuzumab and capecitabine is an active combination in heavily pretreated patients with HER2-positive MBC, including those with previously untreated, treated and stable, or treated and progressing brain metastases. The risks of diarrhoea and elevated aminotransferase levels were higher with tucatinib.
The HER2CLIMB study was funded by Seattle Genetics.
The DESTINY-Breast01 results
The authors wrote in the study background that no uniformly accepted standard of care has been defined in patients with HER2-positive MBC after the administration of second-line therapy with antibody-drug conjugate trastuzumab emtansine. The currently available options have limited benefit.
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate that is composed of a humanized monoclonal antibody specifically targeting HER2, with the same amino acid sequence as trastuzumab, a cleavable tetrapeptide-based linker, and a potent topoisomerase I inhibitor as the cytotoxic drug (payload). Trastuzumab deruxtecan was designed to improve on the critical attributes of currently available antibody-drug conjugates. In a phase I dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan; median response duration was 20.7 months.
DESTINY-Breast01is atwo-part, open-label, single-group, multicentre, phase II study that evaluated trastuzumab deruxtecan in adult patients with pathologically documented HER2-positive MBC who had received previous treatment with trastuzumab emtansine. In the first part of the study, the study team evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose. In the second part, the investigators evaluated the efficacy and safety of the recommended dose.
The primary endpoint was the ORR, according to independent central review. Key secondary endpoints were the disease-control rate, clinical-benefit rate, duration of response and PFS, and safety.
Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan, 5.4 mg per kilogram of body weight.
In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0).
The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of PFS was 16.4 months (95% CI, 12.7 to not reached).
During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anaemia (8.7%), and nausea (7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients; grade 1 or 2 - 10.9%; grade 3 or 4 - 0.5%; and grade 5 - 2.2%).
The authors concluded that in this global, phase II study, trastuzumab deruxtecan had a high level of clinical activity in patients with HER2-positive MBC who had undergone extensive previous therapies. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring.
The study DESTINY-Breast01 was funded by Daiichi Sankyo and AstraZeneca.
- Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. NEJM; Published online 11 December 2019. DOI: 10.1056/NEJMoa1914609
- Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. NEJM; Published online 11 December 2019. DOI: 10.1056/NEJMoa1914510