Navigating treatment options in HER2-positive breast cancer
Healio spoke with Amy Tiersten, MD, professor of medicine with Mount Sinai Hospital, about the treatment landscape in HER2-positive breast cancer.
She highlighted FDA approvals, interesting therapies in the pipeline and the role of endocrine therapy for the treatment of breast cancer.
Healio: Have there been any potential practice-changing FDA approvals for HER2-positive breast cancer?
Tiersten: Historically HER2-positive breast cancers were considered to have a poor prognosis compared with other subtypes. Anti-HER2 monoclonal antibodies have significantly improved outcomes, but maximal effect is in combination with chemotherapy. Standard first-line therapy for HER2-positive advanced disease includes chemotherapy plus trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech). Antibody-drug conjugates combine both these approaches by combining antibodies to HER2/neu protein with cytotoxic (chemotherapy) payload of highly potent agents. The highly potent chemotherapy is attached to antibody by a linker that prevents premature release of the payload at nontarget tissue, so it has fewer toxicities traditionally associated with chemotherapy. The first antibody-drug conjugate used in breast cancer was trastuzumab emtansine (Kadcyla, Genentech), which combines a potent microtubule inhibitor (mertansine) with trasutuzmab. Trastuzumab deruxtecan (Enhertu; Daiichi-Sankyo, AstraZeneca), combines a topoisomerase inhibitor (exatecan) with trastuzumab. This has been a very exciting time for advances in the treatment of HER2/neu-positive breast cancer. In late 2019, trastuzumab deruxtecan was approved for the treatment of metastatic HER2/neu-positive breast cancer based on a phase two single arm trial that showed an extremely high response rate (61%) with a median duration of response of 21 months in the third-line setting. In 2021, a subsequent trial (DESTINY-Breast03) compared trastuzumab deruxtecan to trastuzumab emtansine in the second-line setting, showing a huge advantage for trastuzumab deruxtecan (median PFS of 25 months with trastuzumab deruxtecan and 7.2 months with trastuzumab emtansine). Approximately 10% of patients receiving trastuzumab deruxtecan had low-grade interstitial toxicity, which was less than had been reported with the original trial. Trastuzumab deruxtecan is currently being studied in the frontline metastatic setting (DESTINY-Breast09) as well as in the adjuvant setting in patients with residual disease following neoadjuvant therapy (DESTINY-Breast05).
Another exciting development in the treatment of metastatic HER2/neu-positive breast cancer is the FDA approval of tucatinib (Tukysa, Seagen) in early 2020. Tucatinib is a small-molecule tyrosine kinase inhibitor and is used in combination with trastuzumab and capecitabine (Xeloda, Hoffmann La Roche) in patients who have had at least one line of prior therapy for metastatic disease. The phase three HER2CLIMB trial showed that the addition of tucatinib to trastuzumab and capecitabine improved PFS and OS. But what was most exciting about this trial was the benefit seen in patients with brain metastases. Unlike many other trials, patients were eligible for this trial who had untreated brain metastases. At 1 year, 40% of tucatinib patients — but no patients in the placebo arm — were alive and free of central nervous system progression. Tucatinib reduced the risk of intracranial progression or death by 68%. Tucatinib is now being studied in patients with earlier stage disease in the Compass HER2 RD trial, which is a randomized trial of trastuzumab emtansine vs. trastuzumab emtansine plus tucatinib in patients with residual disease after neoadjuvant therapy.
Another new anti-HER2 drug called margetuximab (Margenza, MacroGenics) received FDA approval in late 2020 for the treatment of more heavily pretreated metastatic HER2-positive breast cancer in combination with chemotherapy after showing an improvement in PFS as compared with trastuzumab plus chemotherapy.
Healio: What are some treatments in the pipeline you are anticipating?
Tiersten: Many other antibody-drug conjugates are under study presently, including trastuzumab duocarmazine (SYD985), which was recently compared with chemotherapy of physician’s choice plus trastuzumab in a randomized trial (TULIP trial) and shown to be significantly more effective in the third-line setting.
In addition, some of the antibody-drug conjugates also appear to have benefit in patients with breast cancer who have low HER2 expression (IHC 1+/2+/FISH-). This represents 40% to 50% of all breast cancers.
Immune check-point inhibitors, which are presently only FDA approved in patients with triple-negative breast cancer, are also being studied in combination with chemotherapy and trastuzumab and pertuzumab in the frontline metastatic setting. At Mount Sinai, we are currently participating in NRG-B004, which is a randomized trial comparing paclitaxel plus trastuzumab plus pertuzumab with paclitaxel (Abraxane, Abraxis Bioscience) plus trastuzumab plus pertuzumab with atezolizumab (Tecentriq, Genentech). Other future directions include novel immune-stimulating antibody-drug conjugates such as BDC-1001 and DF1001.
Healio: When should endocrine therapy be considered?
Tiersten: As far as the role of endocrine therapy in combination with anti-HER2-based therapies, it’s important to note that about 50% of breast tumors expressing HER2 are also HR-positive. Crosstalk between HER2 and ER signaling pathways may contribute to endocrine resistance in these HR-positive, HER2-positive tumors. However, anti-HER2 agents in combination with endocrine therapy can restore endocrine sensitivity. Thus, simultaneous inhibition of both HER2 and ER pathways is considered more effective. The TAnDEM trial found that in patients with HR-positive, HER2-positive metastatic breast cancer, the addition of trastuzumab to an aromatase inhibitor in the first-line setting was associated with an improved PFS of 4.8 months compared with 2.4 months on aromatase inhibitor alone. Endocrine therapy with trastuzumab is, thus, a reasonable option for first-line treatment of HR-positive, HER2-positive metastatic breast cancer as it is less toxic and allows for dual-targeted therapy.
An ongoing trial at Mount Sinaii, the ASPPIRE trial, is examining the efficacy of trastuzumab, pertuzumab, anastrozole (Arimidex, Ani Pharmaceuticals) and palbociclib (Ibrance, Pfizer) as frontline therapy for HR-positive, HER2-positive metastatic breast cancer.
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