Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Dr. Alan P. Lyss
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.