The recent approval of several new HER2-targeted therapies has led to significant advances in the treatment of patients with HER2-positive metastatic breast cancer. During the 2021 Hematology/Oncology Pharmacy Association Annual Conference, Kelly Gaertner, PharmD, BCOP, BCPS, Clinical Pharmacy Specialist, Hematology/Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA, discussed data from recent clinical trials evaluating these agents, including their potential to improve outcomes in patients with brain metastases.
On December 20, 2019, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu), an antibody–drug conjugate, for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting. This approval was based on results of the phase 2 DESTINY-Breast01 trial, which showed a response rate of 61.4% following previous treatment with trastuzumab emtansine and a median overall survival (OS) of >2 years.
“The response rate of T-DXd [trastuzumab deruxtecan] was very impressive in such a heavily pretreated population, and the median PFS [progression-free survival] of 19.4 months was more than double what we would expect to see at this line of therapy,” said Dr Gaertner, who noted that patients had received a median of 6 previous regimens. “These are truly unprecedented results,” she added.
The most common grade ≥3 adverse events were nausea, fatigue, neutropenia, anemia, leukopenia, and lymphopenia, and approximately 15% of patients needed to discontinue treatment due to adverse events. With an additional 9 months of follow-up, the incidence of interstitial lung disease increased to 15.2%, with 5 (2.7%) fatal cases.
Neratinib plus Capecitabine
On February 25, 2020, the FDA approved the tyrosine kinase inhibitor (TKI) neratinib (Nerlynx), in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting. This approval was based on data from the phase 3 NALA trial, which enrolled patients with HER2-positive metastatic breast cancer who had received ≥2 previous HER2-directed regimens in the metastatic setting. Results showed an absolute benefit in PFS of 2.2 months with neratinib plus capecitabine compared with lapatinib plus capecitabine.
Dr Gaertner said that although median PFS, median OS, and median objective response rate did not differ significantly between the 2 study arms, a significant reduction in the incidence of intervention for central nervous system disease was observed.
The most notable side effect with neratinib is diarrhea, but the rate of discontinuation due to diarrhea was “fairly low in both arms,” she reported.
On April 17, 2020, the FDA approved the TKI tucatinib (Tukysa), in combination with capecitabine and trastuzumab for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received ≥1 previous anti–HER2-based regimens in the metastatic setting. This approval was based on data from the phase 2 HER2CLIMB study, which randomized patients to tucatinib, capecitabine, and trastuzumab (Herceptin) versus capecitabine plus trastuzumab. Patients enrolled in this study had received a median of 3 previous lines of therapy for metastatic disease, and 48% had a presence or history of brain metastases.
Results showed an absolute benefit in PFS of 2.2 months, corresponding to a 46% reduction in the risk for disease progression or death, and an absolute benefit in median OS of 4.5 months, corresponding to a 34% reduction in the risk for death. The objective response rate nearly doubled with the addition of tucatinib to capecitabine and trastuzumab compared with capecitabine and trastuzumab alone.
In patients with previously untreated, treated, stable, or progressing brain metastases, median PFS improved from 5.4 months to 7.6 months with the addition of tucatinib. An improvement in median OS was also seen in patients with all brain metastases.
“Because tucatinib is highly selective for HER2, with minimal inhibition of EGFR [epidermal growth factor receptor], we expect to see less gastrointestinal and skin toxicities compared with other currently available TKIs,” Dr Gaertner said.
On December 16, 2020, the FDA approved the monoclonal antibody margetuximab-cmkb (Margenza) in combination with chemotherapy for adult patients with metastatic HER2-positive breast cancer who had received ≥2 previous HER2-directed regimens, at least one of which was for metastatic disease. This approval was based on results of the phase 3 SOPHIA trial, which randomized patients with HER2-positive advanced breast cancer to receive margetuximab plus chemotherapy (capecitabine, eribulin [Halaven], gemcitabine [Gemzar], or vinorelbine [Navelbine]) versus trastuzumab plus chemotherapy. Patients enrolled in this trial had received ≥2 previous lines of HER2-directed therapy.
Analysis of the overall population showed a “modest” benefit in median PFS with margetuximab versus trastuzumab and no improvement in median OS, said Dr Gaertner. However, exploratory analysis showed enhanced PFS and OS in patients with CD16A-158F allele.
Grade ≥3 adverse events occurred in >50% of patients in both arms, respectively. The FDA label for margetuximab carries a black box warning for left ventricular dysfunction and embryo-fetal toxicity.