Updates in HER2-Targeted Therapy for the Treatment of Metastatic Breast Cancer

Kelly Gaertner, PharmD BCOP BCPS
Oncology Clinical Pharmacy Specialist
Allegheny Health Network
Pittsburgh, PA

Danielle Roman, PharmD BCOP
Manager, Clinical Pharmacy Services
Allegheny Health Network
Pittsburgh, PA

Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related mortality in women.¹ Approximately 15%–20% of breast cancers overexpress the human epidermal growth factor receptor 2 (HER2) protein.² Compared with other subtypes of breast cancer, hormone receptor–negative, HER2-positive disease has a greater likelihood of metastasizing to the brain.^3-5 In the absence of systemic HER2-targeted therapy, HER2-positive breast cancer (HER2BC) has historically been associated with more aggressive disease and a worse prognosis. For patients with unresectable or metastatic HER2BC, the combination of docetaxel, pertuzumab, and trastuzumab has been established as the preferred initial therapy on the basis of progression-free survival (PFS) and overall survival (OS) benefits demonstrated in the phase 3 CLEOPATRA study.^6,7 In the phase 3 EMILIA trial, ado-trastuzumab emtansine showed an improvement in PFS and OS in the second-line setting following receipt of trastuzumab and a taxane.⁸ Although these therapies have significantly extended survival outcomes for patients with metastatic HER2BC, disease progression continues to remain inevitable in most cases. Subsequent treatment options have primarily included trastuzumab plus chemotherapy, or capecitabine plus lapatinib or trastuzumab, with no previously established standard of care in the third-line setting. This article summarizes recent therapy updates and emerging treatments for metastatic HER2BC.

New Approvals

Fam-trastuzumab deruxtecan-nxki (Enhertu) is a new addition to the armamentarium for the treatment of metastatic HER2BC. The U.S. Food and Drug Administration (FDA) granted the drug accelerated approval on December 20, 2019, for patients with HER2-positive unresectable and/or metastatic breast cancer after at least two prior anti-HER2-based regimens in the metastatic setting. This antibody-drug conjugate (ADC), similar to ado-trastuzumab emtansine, consists of an HER2-directed antibody and cytotoxic drug joined by a cleavable linker. Fam-trastuzumab deruxtecan differs in several important ways from other currently available ADCs: notably, the inclusion of a potent topoisomerase I inhibitor as the cytotoxic drug, a higher drug-to-antibody ratio, and the ability of the cytotoxic portion to easily cross the cell membrane, which potentially allows for a more potent effect on nearby tumor cells regardless of target expression.⁹

The FDA approval of fam-trastuzumab deruxtecan was based on the results of the DESTINY-Breast01 trial.⁹ This was an open-label multicenter single-arm phase 2 study of fam-trastuzumab deruxtecan in females with HER2-positive unresectable or metastatic breast cancer who had received previous treatment with trastuzumab and ado-trastuzumab emtansine. The efficacy analysis was based on 184 patients who received the recommended dose of 5.4 mg/kg. The majority of patients were heavily pretreated, receiving a median of six prior lines of therapy (range 2–27). Thirteen percent of patients enrolled had stable, treated brain metastases. The primary endpoint of overall response rate was 60.9% by independent central review, primarily driven by partial responses (54.9%). The median PFS was 16.4 months, and median duration of response was 14.8 months. This benefit was observed across all subgroups, including patients with brain metastases. The most common adverse effects that occurred in 20% or more of the study population were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. Interstitial lung disease (ILD) developed in 13.6% of patients, of which the majority of cases were grade 1–2; however, four ILD-related deaths occurred during the study. The median time to onset was 4.1 months (range 1.2–8.3).¹⁰

The recommended dose of fam-trastuzumab deruxtecan is 5.4 mg/kg administered by intravenous infusion every 3 weeks until disease progression occurred or an unacceptable level of toxicity was reached. Dose interruption or reduction recommendations exist for neutropenia, febrile neutropenia, left ventricular dysfunction, and ILD/pneumonitis. Black-box warnings exist for embryo-fetal toxicity and ILD/pneumonitis; patients should therefore be closely monitored for signs and symptoms, including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Prompt investigation with radiographic imaging, consultation with a pulmonologist, interruption of the drug, and possibly initiation of corticosteroids (based on grade) are recommended for suspected ILD. Similar to other HER2-targeting drugs, fam-trastuzumab deruxtecan may increase the risk of developing left ventricular dysfunction; however, only three cases of asymptomatic left ventricular ejection fraction (LVEF) decrease were reported in DESTINY-Breast01.⁹ LVEF should be assessed prior to initiation of fam-trastuzumab deruxtecan and at regular intervals during treatment as clinically indicated.¹⁰

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend fam-trastuzumab deruxtecan for metastatic HER2BC in accordance with FDA labeling.¹¹ Ongoing trials are focused on initiation of fam-trastuzumab deruxtecan earlier in the disease course (DESTINY-Breast0212 and DESTINY-Breast0313) and on the potential role of this agent in patients with HER2 low-expressing breast cancer.¹⁴

Neratinib (Nerlynx) is an oral tyrosine kinase inhibitor (TKI) initially approved by the FDA for extended adjuvant treatment of early-stage HER2BC.¹⁵ In the phase 3 NALA study, the combination of neratinib and capecitabine was compared to lapatinib and capecitabine in patients with HER2-positive metastatic breast cancer who had received at least two prior lines of therapy in the metastatic setting.16 Patients were randomized 1:1 to 21-day cycles of either neratinib 240 mg orally daily continuously plus capecitabine 750 mg/m² orally twice daily on days 1 through 14 or lapatinib 1,250 mg orally daily continuously plus capecitabine 1,000 mg/m² twice daily on days 1 through 14. Though PFS was significantly improved in the neratinib arm (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63–0.93; p = .006), OS benefit with neratinib did not reach statistical significance (HR, 0.88; 95% CI, 0.72–1.07; p = .2086). PFS and OS rates at 12 months with neratinib versus lapatinib were 28.8% versus 14.8% and 72.5% versus 66.7%, respectively.¹⁶ Furthermore, the neratinib plus capecitabine combination delayed the time to intervention for symptomatic central nervous system disease (overall incidence, 22.8% vs. 29.2%; p = .043).

Although grade 3 diarrhea was more prevalent with neratinib than with lapatinib (24.4% vs. 12.5%), adverse events leading to treatment discontinuation were less common with neratinib (10.9% vs. 14.5%). On the basis of the NALA trial, the FDA approved the combination of neratinib plus capecitabine on February 24, 2020, for treatment of advanced or metastatic HER2BC after two or more prior anti-HER2-based regimens in the metastatic setting.¹⁵ The combination was also added to the NCCN guidelines as an option among the other recommended regimens for HER2-positive metastatic breast cancer.¹¹

Another exciting HER2-directed therapy to emerge recently is tucatinib, an oral TKI that selectively inhibits HER2.¹⁸ This high specificity for the HER2 domain with negligible inhibition of the epidermal growth factor receptor distinguishes tucatinib from other currently approved HER2-targeted small-molecule TKIs and affects the toxicity profile.^17,18 Tucatinib was evaluated in combination with capecitabine and trastuzumab in the phase 3 HER2CLIMB study.¹⁸ Patients with HER2-positive advanced breast cancer were included if they had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Patients with brain metastases were included; those with leptomeningeal disease were not. A total of 612 patients were randomized 2:1 to receive either tucatinib 300 mg or placebo orally twice daily continuously, in combination with trastuzumab and capecitabine. Patients were heavily pretreated, with a median of three prior lines of therapy for metastatic disease (range 1–14). Approximately half (47.5%) had brain metastases. With regard to the primary endpoint of PFS in the first 480 randomized patients, the median PFS was 7.8 months with tucatinib versus 5.6 months with placebo (HR, 0.54, 95% CI, 0.42–0.71; p < .001) at 1 year. For patients with brain metastases, the median PFS was extended with the addition of tucatinib to 7.6 versus 5.4 months (HR, 0.48, 95% CI, 0.34–0.69; p < .001). Regarding safety, the most common adverse events of any grade that occurred more frequently with tucatinib included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, vomiting, and stomatitis.¹⁸

On the basis of the results of the HER2CLIMB study, tucatinib (Tukysa) was approved by the FDA on April 17, 2020, in combination with trastuzumab and capecitabine for patients with advanced unresectable or metastatic HER2BC following receipt of at least one prior anti-HER2-based regimen in the metastatic setting.^19,20 Notably, the labeled indication specifically includes patients with brain metastases, and tucatinib is a welcome addition to the treatment options for this particular patient population.²⁰ Tucatinib is approved at a dose of 300 mg orally with or without food twice daily continuously, in combination with capecitabine 1,000 mg/m² orally twice daily on days 1 through 14 and trastuzumab at standard dose every 21 days.20 Dose interruption or reduction recommendations exist for diarrhea and hepatotoxicity. Patients should be counseled on the potential for severe diarrhea and appropriate management. Hepatic function should be monitored every 3 weeks or as clinically indicated. Empiric dose reductions of tucatinib are indicated in the setting of severe hepatic impairment and concurrent use with a strong CYP2C8 inhibitor. Tucatinib is associated with other clinically relevant drug-drug interactions, and a thorough drug interaction screen is recommended prior to initiation.²⁰

Emerging Therapies

Margetuximab is a monoclonal antibody derived from the parent compound of trastuzumab. Though both margetuximab and trastuzumab bind to the same epitope of HER2 and demonstrate similar affinity and antiproliferative activity, margetuximab’s Fc region is engineered to increase affinity for the activating Fc receptor (FcR) CD16A while decreasing affinity for the inhibitory FcR CD32B.^21-23 The randomized phase 3 open-label SOPHIA trial evaluated margetuximab in patients with metastatic HER2BC who had received one to three prior lines of therapy, including pertuzumab, in the metastatic setting. Patients were randomized 1:1 to margetuximab 15 mg/kg or trastuzumab intravenously every 3 weeks, in addition to capecitabine, eribulin, gemcitabine, or vinorelbine. Initial results were presented at the 2019 American Society of Clinical Oncology annual meeting.²² In the intention-to-treat (ITT) analysis of 536 patients, margetuximab showed an improved PFS versus trastuzumab, with a median of 5.8 months versus 4.9 months (HR, 0.76; 95% CI, 0.59–0.98; p = .033). The subset of patients with CD16A genotypes containing a 158F allele (a population that has been found to be less responsive to trastuzumab) saw an even greater PFS benefit with margetuximab, with a median of 6.9 months versus 5.1 months (HR, 0.68; 95% CI, 0.52–0.90; p = .005). Data from the second interim OS analysis were presented at the 2019 San Antonio Breast Cancer Symposium. After a median follow-up of 15.6 months, the median OS in the ITT population was 21.6 months with margetuximab versus 19.8 months with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69–1.13; p = .326).²³ Again, the outcomes were more pronounced in the patients with CD16A 158F allele, with a median OS of 23.7 months with margetuximab versus 19.4 months with trastuzumab (HR, 0.79; 95% CI, 0.61–1.04; p = .087). Though the OS data on margetuximab are not yet mature, preliminary outcomes are promising, and it is hoped that they will lead to another option for HER2-directed therapy.

Conclusion

The recent advances in the treatment of HER2-positive metastatic breast cancer provide promising options for many patients who have exhausted first- and second-line therapies for this breast cancer subtype. Fam-trastuzumab deruxtecan, as well as the combinations of neratinib and capecitabine and of tucatinib, capecitabine, and trastuzumab, have gained recent FDA approvals for treating metastatic HER2BC. Margetuximab may add to future treatment paradigms. Further discussions and ongoing studies will seek to define the optimal sequencing of these recent approvals, as well as the use of fam-trastuzumab deruxtecan for patients with HER2-low- expressing breast cancer.

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