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Pharmacy Practice in Focus: Oncology
Antibody-drug conjugates have revolutionized metastatic breast cancer treatment and classification.
The development of antibody-drug conjugates (ADCs) has transformed the diagnosis and management of hormone receptor–positive (HR+) and HER2-negative (HER2–) metastatic breast cancer (MBC) in recent years. HR and HER2 status should be determined in all patients with invasive breast cancer at initial diagnosis and first occurrence of metastatic disease.1 HER2 testing is performed by either immunohistochemistry (IHC) or gene amplification (fluorescence in situ hybridization [FISH]). If HER2 results are equivocal, reflex testing should be performed with the alternative assay.
Image credit: David A Litman | stock.adobe.com
Recently, there has been an evolution in the landscape of HER2 identification (Table). Historically, IHC 0, IHC 1+, and IHC 2+/ISH negativity were classified as HER2–. HER2 positive (HER2+) status was determined with IHC 2+/ISH positivity or IHC 3+. Recent updates now classify HER2– status with IHC 0. HER2 positivity has the same historical identification.
The HER2-low category comprises a subset of cancers currently classified by the American Society of Clinical Oncology and the College of American Pathologists as HER2–. HER2 low refers to cancers with HER2 staining of IHC 1+ or IHC 2+/ISH negativity.2,3 The emerging HER2-ultralow classification is less than or equal to 10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining.4
IHC, immunohistochemistry; ISH, in situ hybridization.
There are 3 ADCs approved for HR+, HER2–, HER2-low, or HER2-ultralow disease: fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu; AstraZeneca and Daiichi-Sankyo), sacituzumab govitecan-hziy (SG, Trodelvy; Gilead Sciences), and datopotamab deruxtecan-dlnk (Dato-DXd, Datroway; Daiichi-Sankyo and AstraZeneca).
T-DXd is approved for adult patients with unresectable or metastatic HER2-low breast cancer after 1 or more lines of chemotherapy based on results from the DESTINY-Breast04 trial (NCT03734029).5 DESTINYBreast04 was a phase 3, open-label, randomized trial evaluating the efficacy and safety of T-DXd in 557 patients with previously treated unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH negativity) breast cancer. In this trial, patients were randomly assigned to receive either T-DXd or physician’s choice of chemotherapy. The median progression-free survival (PFS) among patients with HR+ cancer was 10.1 months with T-DXd vs 5.4 months with physician’s choice of chemotherapy; overall survival (OS) was 23.9 months and 17.5 months, respectively. Among HR+ and HR– patients, PFS and OS were improved with T-DXd at 9.9 months vs 5.1 months and 23.4 months vs 16.8 months, respectively.6
More recently, T-DXd received FDA approval for patients with HER2-ultralow MBC based on results from the DESTINYBreast06 trial (NCT04494425).5 In the phase 3, open-label DESTINY-Breast06 trial, 866 patients with HER2-low (IHC 1+ or IHC 2+/ISH negativity) or HER2-ultralow (IHC 0 with membrane staining), HR+ MBC who had received 1 or more lines of endocrine-based therapy and no previous chemotherapy for MBC were randomly assigned to T-DXd or physician’s choice of chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel). Patients were treatment naive for MBC, with 2 lines or more of endocrine therapy for MBC, or 1 line of endocrine therapy for MBC if disease progression occurred at 24 months or earlier from adjuvant endocrine therapy treatment, or 6 months or earlier from endocrine therapy with a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) for MBC. Results were consistent between patients with HER2-low expression and HER2-ultralow expression. T-DXd improved PFS in both HER2 low and HER2 ultralow compared with physician’s choice of chemotherapy at 13.2 vs 8.1 months and 13.2 vs 8.3 months, respectively.7
SG is approved for the treatment of relapsed/refractory (R/R) metastatic triple-negative breast cancer (mTNBC) in patients who have received 2 or more prior lines of therapy.8 In the phase 3 confirmatory ASCENT trial (NCT02574455), SG was studied in patients with R/R mTNBC. The trial enrolled patients with mTNBC (IHC 0 or 1+, or 2+/ISH negativity) who had received 2 or more chemotherapies for advanced disease. Patients were treated with SG or single-agent chemotherapy (eribulin, vinorelbine, gemcitabine, or capecitabine). Of the 529 patients, 71% were HER2 IHC 0+ and 29% were HER2 low. The median PFS with SG vs single-agent chemotherapy for HER2 IHC 0+ was 4.3 vs 1.6 months, and the median PFS with SG vs single-agent chemotherapy for HER2 low was 6.2 vs 2.9 months. The median OS with SG vs single-agent chemotherapy for HER2 IHC 0+ was 11.3 vs 5.9 months, and the median OS with SG vs single-agent chemotherapy for HER2 low was 14.0 vs 8.7 months.9
SG is also indicated for patients with metastatic HR+, HER2– (IHC 0, IHC 1+, or IHC 2+/ISH negativity) breast cancer who have received endocrine-based therapy and at least 2 additional lines of systemic therapy based on the TROPiCS-02 trial (NCT03901339).8 TROPiCS-02 is a phase 3 study evaluating SG in HR+/HER2– locally advanced inoperable or MBC. The inclusion criteria included patients with HER2-low and HR+/HER2– (IHC 0 or 1+, or 2+/ISH negativity) disease with at least 1 endocrine therapy, taxane, and CDK4/6i in any setting and at least 2, but no more than 4, lines of chemotherapy for metastatic disease. Patients were treated with SG or single-agent chemotherapy (eribulin, vinorelbine, gemcitabine, or capecitabine). Of the 543 patients, 40% were HER2 IHC 0+ and 52% were HER2 low. The median PFS with SG vs single-agent chemotherapy for HER2 IHC 0+ was 5.0 vs 3.4 months, and the median PFS with SG vs single-agent chemotherapy for HER2 low was 5.8 vs 4.2 months. The median OS with SG vs single-agent chemotherapy for HER2 IHC 0+ was 13.6 vs 10.8 months, and the median OS with SG vs single-agent chemotherapy for HER2-low was 15.4 vs 11.5 months.10,11
Dato-DXd is the newest ADC to the market in this setting. The phase 3 TROPION-Breast01 trial (NCT05104866) evaluated Dato-DXd compared with physician’s choice of chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine). In the trial, the median PFS improved from 4.9 months with investigator’s choice to 6.9 months in the Dato-DXd arm. The median PFS by the investigator was similar at 6.9 vs 4.5 months, respectively. Dato-DXd did not achieve statistical significance in the final OS analysis in patients with inoperable or metastatic HR+, HER2-low, or HER2– (IHC 0, IHC 1+, or IHC 2+/ISH negativity) breast cancer previously treated with endocrine-based therapy and at least 1 systemic therapy.11 Based on these results, Dato-DXd is approved for patients with unresectable or metastatic HR+, HER2– (IHC 0, IHC 1+ or IHC 2+/ISH negativity) breast cancer who have received prior endocrine-based therapy and chemotherapy in the metastatic setting.12
With 3 unique ADCs approved in the metastatic HER2– or HER2-low setting, paying close attention to biomarker status and what treatments the patient has previously received is crucial. For patients with HR+ MBC, first-line treatment with a CDK4/6i in combination with endocrine therapy remains the standard of care. In the absence of other targetable mutations, T-DXd is National Comprehensive Cancer Network (NCCN) Category 1 preferred and may be considered for patients with HER2– or HER2-low (IHC 0, IHC 1+, or IHC 2+/ISH negativity) disease. If a patient is not a candidate for T-DXd, SG is also NCCN Category 1 preferred. In subsequent lines of therapy, Dato-DXd is also an option.1
The most common treatment-related adverse events (TRAEs) associated with T-DXd in the DESTINYBreast04 trial were nausea, fatigue, and alopecia; grade 3 or higher AEs included neutropenia, anemia, and fatigue. Patients should receive antiemetic prophylaxis with a 3- or 4-drug regimen. Drug-related interstitial lung disease (ILD)/pneumonitis occurred in 12.1% of patients, with 0.8% experiencing grade 5 events.5,6 The safety profile of T-DXd was consistent in DESTINY-Breast06 with no new safety concerns.7
In the ASCENT trial, the most common TRAEs associated with SG were neutropenia, diarrhea, nausea, fatigue, and alopecia.9 Safety was consistent in Tropics-02, with grade 3 or higher AEs including neutropenia, diarrhea, and febrile neutropenia.9 Patients receiving SG should also receive a 3- or 4-drug antiemetic regimen, as well as granulocyte colony-stimulating factor support as needed for primary or secondary neutropenia prophylaxis. Atropine may be given in the infusion center for acute anticholinergic adverse effects secondary to SG’s cytotoxic payload, SN-38, the active metabolite of irinotecan, and patients should receive appropriate education on the use of an antidiarrheal medication with the first loose bowel movements.8
In the TROPION-Breast01 trial, Dato-DXd was associated with nausea, stomatitis, alopecia, and neutropenia. Grade 3 or higher AEs in this trial included neutropenia, anemia, and thrombocytopenia.11 Stomatitis/oral mucositis events were mostly low grade; however, patients should be educated to hold ice chips or ice water in their mouth throughout the infusion. In addition, patients should be prescribed a corticosteroid mouthwash. Ocular surface events, such as dry eye and keratitis, also occurred in low grades. Patients should be educated to use lubricating eye drops 4 times a day and as needed and should be referred to an ophthalmologist before initiating treatment and annually while on treatment.12 Notably, the incidence of ILD/pneumonitis was 3.3%.11
Megan May, PharmD, BCOP, FHOPA, FAPO, is a clinical oncology pharmacy specialist at Baptist Health Lexington in Kentucky.
Rose DiMarco, PharmD, BCPS, BCOP, is assistant director of pharmacy—oncology and infusion at Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.
The advent of ADCs has revolutionized the care of patients with MBC. Identifying patients with HER2-low status adds a level of complexity and a new treatment option. Data on how best to sequence these agents are needed, and future studies will attempt to answer that question. Although the ADCs are promising new treatment options, they each have unique AEs that require careful monitoring and patient education, highlighting the pharmacist’s critical role in treatment with ADCs.
