Recently, ASCO updated its guidelines on the management of brain metastases (BM) in patients with HER2-positive (+) advanced breast cancer (BC). The update includes systematic review-based recommendations for systemic therapy as well as consensus-based recommendations for radiation therapy and/or surgery for HER2+ BC with BM.
The guidelines set out to address three questions:
• Does the approach to local therapy of BM differ in patients with HER2+ BC?
• How should systemic therapy be managed in patients with HER2+ BM only versus metastases to the brain and elsewhere?
• Should patients with HER2+ BC be screened for the development of BM?
Recommendations that pertain to systemic drug therapy will be discussed. However, memantine is utilized with local therapy, which includes whole-brain radiotherapy, to delay the time to cognitive decline. The guidelines recommend that memantine be administered when whole-brain radiation is performed (or up to 6 months later) and radiation to the hippocampus is avoided (termed hippocampal avoidance) if no metastases are present within 5 mm of the hippocampus. Nonetheless, there are no head-to-head trials comparing the efficacy and safety of local therapies alone compared with whole-brain radiation plus memantine with or without stereotactic radiosurgery.
Regarding systemic therapy, tucatinib in combination with capecitabine and trastuzumab may be offered to patients with HER2+ BC with BM who do not have symptomatic mass effect (i.e., no evidence of fatigue, drowsiness, nausea and vomiting, changes in personality or behavioral, or problems with vision) and whose disease has progressed on at least one previous HER2-directed treatment modality. Local therapy can be delayed until intracranial progression occurs. However, this is a weak recommendation based on low-quality evidence.
The guidelines discuss new evidence from the HER2CLIMB trial, which include a regimen of tucatinib, trastuzumab, and capecitabine in patients who had disease progression on trastuzumab, pertuzumab, and/or trastuzumab emtansine-based therapy. The HER2CLIMB trial demonstrated a statistically significant increase in overall progression-free survival (hazard ratio [HR] 0.48; 95% CI, 0.34-0.69). Among patients with BMs, central nervous system (CNS) progression-free survival (i.e., risk of intercranial progression or death) significantly improved, as did overall survival and overall response rate outcomes. It is important to note that this recommendation is limited to patients with asymptomatic BM who have not yet received local therapy. Patients had to meet the eligibility criteria for failure of prior treatment lines (i.e., trastuzumab and pertuzumab or trastuzumab emtansine). The HER2CLIMB protocol may also be considered for patients with metastasis <3 to 4 cm without symptomatic mass effect and with a favorable prognosis.
Patients who receive surgery and/or radiation therapy for BM and whose systemic disease is progressive at the time of BM diagnosis should be offered HER2-targeted therapy and second-line trastuzumab deruxtecan therapy, followed by the HER2CLIMB regimen of tucatinib, capecitabine, and trastuzumab if the BM are stable after local therapy.
The literature review update found that while neratinib plus capecitabine compared with lapatinib plus capecitabine in patients who had received second-line (or greater) systemic therapies and who had asymptomatic BMs did not demonstrate a significant difference in overall survival, there was evidence from secondary outcomes that neratinib has CNS activity. However, there is insufficient evidence to recommend neratinib plus chemotherapy beyond when patients have received second-line systemic therapy.
Although the guidelines mention a post hoc exploratory analysis of a cohort from the KAMILLA trial that examined the use of trastuzumab emtansine in patients who had received second-line (or greater) systemic therapies for HER2+ metastatic BC with BMs at baseline and demonstrated a response rate of 21.4%, the expert panel found insufficient evidence to make a recommendation. The main KAMILLA study had focused on the use of trastuzumab emtansine in patients with prior HER2-targeted therapy and chemotherapy who were asymptomatic or had untreated or controlled BM.
Also discussed in the guidelines is the NEfER-T trial, which compared neratinib plus paclitaxel to trastuzumab plus paclitaxel and found a statistically significant relative risk of 0.48 (95% CI, 0.29-0.79; P = .002) in a subgroup of patients who had not received prior treatment for symptomatic or progressive CNS metastases. Again, the guidelines found insufficient evidence to recommend the use of neratinib plus paclitaxel.
Finally, while the guidelines recommend that clinicians should have a low threshold for brain MRI testing in patients presenting with any neurologic symptoms, such as new-onset headaches, unexplained nausea or vomiting, or changes in motor or sensory function, they recommend that in patients without a known history or symptoms of BMs, there is insufficient evidence to recommend for or against performing routine surveillance with brain MRI and that this should undergo shared decision-making processes.
This guideline update serves as a tool to educate pharmacists about additional treatment options for HER2+ advanced BC with BM based on the HER2CLIMB trial and provide a rationale for the use of memantine in this population.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published November 9, 2022