At a glance
Tucatinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer, in combination with trastuzumab and capecitabine
Treatment initiation and continuation of HER+ breast cancer patients are given medium or high priority during the COVID-19 pandemic in international guidelines
FDA approval of tucatinib
Tucatinib, a HER2-directed tyrosine kinase inhibitor was recently approved by the FDA for the treatment of patients with advanced unresectable or metastatic HER2+ breast cancer who have received at least one prior treatment, based on results of the HER2CLIMB study published in the New England Journal of Medicine [1,2] The oral drug is approved in combination with HER2 monoclonal antibody, trastuzumab and oral chemotherapy, capecitabine. The randomised, double-blind phase 2 trial included 612 patients with advanced HER+ breast cancer who had received prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1) . Patients with stable and treated or untreated brain metastases were also eligible for the trial of which 48% had brain metastases upon enrolment . The median progression-free survival (PFS) in patients who received tucatinib, trastuzumab, and capecitabine (tucatinib arm) was 7.8 months compared to 5.6 months in those who received placebo, trastuzumab, and capecitabine (placebo arm) representing a 46% risk reduction (HR=0.54; 95% CI: 0.42-0.71; p<0.00001) . Key secondary endpoints included overall survival (OS) and PFS in patients with a history or presence of brain metastases . Patients in the tucatinib arm had a 34% reduced risk of death (OS) at 2 years compared to placebo (HR=0.66; 95% CI: 0.50-0.87; p=0.0048) with a median OS of 21.9 months vs. 17.4 months, respectively . Among patients with brain metastases, those who received tucatinib had a 52% reduced risk of progression or death (PFS) at 1 year compared to those who did not (HR=0.48; 95% CI: 0.34-0.69; p<0.00001), with a median PFS of 7.6 months vs. 5.4 months, respectively . Common adverse events (AE)s experienced by patients in the tucatinib arm were diarrhoea, palmar-plantar erythrodysesthesia (PPE) syndrome, nausea, fatigue, and vomiting which were mostly grade 1 and 2 . Discontinuation of tucatinib due to AEs (hepatotoxicity and diarrhoea) occurred in 5.7% of patients.2 Serious AEs of grade 3 of higher in the tucatinib arm included PPE syndrome, diarrhoea, and hepatotoxicity .
The HER2CLIMB trial was particularly significant due to its inclusion of patients with active brain metastases which is uncommon in oncology trials. This high-risk population represents a large proportion of HER2+ breast cancer patients, and so the efficacy of tucatinib in this subgroup is a major advantage . The approval of tucatinib marks the first drug to be reviewed by an FDA initiative called ‘Project Orbis’, which enables collaborative review of oncology products among international partners with the aim of facilitating earlier patient access to new medicines and establishing greater global uniformity in standards of treatment . As a result, tucatinib was approved 4 months earlier than the FDA goal date despite challenging times amidst the COVID-19 pandemic . Tucatinib is also currently being investigated in an earlier line of treatment for advanced HER2+ breast cancer, in combination with T-DM1 in the HER2CLIMB-02 trial . Participants will have had prior treatment with taxane chemotherapy and trastuzumab in any setting and may or may not have active or stable brain metastases . Other novel HER2+ breast cancer treatments
Trastuzumab deruxtecan (DS-8201) was granted an accelerated approval by the FDA in December 2019 for the treatment of metastatic HER2+ breast cancer patients who have received at least 2 prior lines of therapy . It is an antibody-conjugate that consists of trastuzumab and a derivative of a topoisomerase I inhibitor, and is administered intravenously . Interestingly, DS-8201 has shown efficacy even in tumours with low HER2 expression that do not pass standard criteria for HER2-targeted therapy or are traditionally considered to be HER2 negative . A novel HER2 monoclonal antibody, margetuximab is currently being investigated in a phase 3 trial as an addition to chemotherapy vs. trastuzumab and chemotherapy . It is a derivative of trastuzumab that has been engineered to enhance affinity for the activating CD16A receptor . So far, the subgroup analysis for OS is not statistically different between the two treatment groups, however, there is enhanced benefit in patients who carry the low affinity CD16A-158F allele . Approximately 15-20% of breast cancers are HER2+ which are clinically more aggressive than other types of breast cancer . HER2+ metastatic breast cancer is usually treated with taxane chemotherapy, trastuzumab and pertuzumab in first-line and T-DM1 in second-line . There is currently no established third-line treatment option. Given the recent FDA approvals of tucatinib and DS-8201, they are likely to become the next standard of care in the heavily pre-treated HER2+ metastatic setting. Management of HER2+ breast cancer during COVID-19
As healthcare systems around the world have had to focus their resources on treating cases of COVID-19 and mitigate infection risk of all other patients, several breast cancer societies have published recommendations and guidelines to navigate physicians through the management of breast cancer patients during the pandemic.
Recommendations by the American Society of Breast Surgeons and European Society of Medical Oncology (ESMO) are categorised by priority based on patient condition for outpatient visits, imaging, surgical oncology, medical oncology and radiation oncology [10,11]. The American College of Surgeons’ guidelines for triage of breast cancer patients is divided into three phases based on the context of the institution’s resources and prevalence of the COVID-19 pandemic in their region [1.2] Generally, implementation of telemedicine is recommended where possible to reduce hospital visits and diagnostics and imaging services are reserved for symptomatic and metastatic cases [10,11]. As HER2+ breast cancer is associated with poorer prognosis, treatment initiation or continuation of these patients are categorised as medium or high priority [10,11]. For early HER2+ breast cancer patients, adjuvant post-operative radiotherapy, neoadjuvant and adjuvant chemotherapy in combination with targeted HER2 therapy are high priority [10,11]. Completion of neoadjuvant chemotherapy with or without anti-HER2 therapy that has already initiated, and adjuvant T-DM1 in high-risk HER2+ breast cancer patients are also considered high priority [10,11]. For some patients, adjuvant anti-HER2 therapy may be discontinued after 6 months instead of 12 months . For metastatic HER2+ patients, early-line trastuzumab or pertuzumab plus chemotherapy is given high priority as these are likely to improve outcomes [10,11]. Despite the current recommendations, the full impact of COVID-19 on breast cancer treatment delivery is yet to be understood. For instance, deferred screening and lack of specialist staff resources may negatively affect patient outcomes and quality of care, respectively. The American Society of Clinical Oncology and ESMO have set up registries to collect information from oncology healthcare professionals’ experiences which may improve patient care and help to inform future practice guidelines [13,14]. Interestingly, the American Cancer Society Cancer Action Network initiated a survey to help understand the main concerns of cancer patients and survivors, and barriers to their care and treatment during the pandemic . As the total case number and fatality rate of COVID-19 is relatively lower in Asia compared to other parts of the world, the impact of COVID-19 on the management of cancer patients and the healthcare system in Hong Kong is likely less severe provided the current situation does not worsen. References  FDA Press Release. FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-drug-under-international-collaboration-treatment-option-patients-her2 (2020).  Murthy, R. K. et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N. Engl. J. Med. 382, 597–609 (2020).  Altaha, R., Crowell, E., Hobbs, G., Higa, G. & Abraham, J. Increased risk of brain metastases in patients with HER-2/neu-positive breast carcinoma. Cancer 103, 442–443 (2005).  ClinicalTrials.gov. Randomized, Double-blind, Phase 3 Study of Tucatinib or Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Subjects With Unresectable Locally-advanced or Metastatic HER2+ Breast Cancer (HER2CLIMB-02). https://clinicaltrials.gov/ct2/show/NCT03975647 (2020).  FDA Press Release. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA (2019).  Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N. Engl. J. Med. (2019).  Rugo, H. S. et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J. Clin. Oncol. 37, 1000–1000 (2019).  Krishnamurti, U. & Silverman, J. F. HER2 in breast cancer: a review and update. Adv. Anat. Pathol. 21, 100–107 (2014).  Pernas, S. & Tolaney, S. M. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther. Adv. Med. Oncol. 11, (2019).  Dietz, J. R. et al. Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium. Breast Cancer Res. Treat. 181, 487–497 (2020).  ESMO. ESMO management and treatment adapted recommendations in the COVID-19 era: Breast cancer. https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-pandemic/breast-cancer-in-the-covid-19-era.  COVID 19 Pandemic Breast Cancer Consortium. COVID-19 Guidelines for Triage of Breast Cancer Patients. American College of Surgeons https://www.facs.org/covid-19/clinical-guidance/elective-case/breast-cancer (2020).  ASCO Survey on COVID-19 in Oncology (ASCO) Registry. ASCO https://www.asco.org/asco-coronavirus-information/coronavirus-registry (2020).  ESMO. Collaborating on registries, studies and surveys. https://www.esmo.org/covid-19-and-cancer/collaborating-on-registries-studies-and-surveys.  American Cancer Society Cancer Action Network (ASC CAN). COVID-19 Pandemic Impact on Cancer Patients and Survivors. (2020).