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Managing TNBC

CE / CME

Cases and Challenges in the Optimal Treatment of Triple-Negative BC

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: May 08, 2023

Expiration: May 07, 2024

Jeremy M. Force
Jeremy M. Force, DO
CME/CE Information

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Updates to Second- and Subsequent Lines of Treatment for Metastatic TNBC

Patients with TNBC who progress on first-line treatment for metastatic disease historically had very few treatment options and very poor prognosis. An advance in this setting is the approval of sacituzumab govitecan, a novel antibody-drug conjugate (ADC) that targets TROP-2 to deliver a potent, cytotoxic topoisomerase 1 inhibitor into tumor cells.30,31 TROP-2 is a desirable surface target because it is highly expressed in TNBC (about 88%) compared with other breast cancer types and minimally expressed in normal tissues. The cytotoxic component of sacituzumab govitecan, SN-38, delivers a more than 100-fold potent drug than its parent compound irinotecan, and the drug also has a bystander effect on TROP-2 negative tumor cells.31

The phase III ASCENT trial showed the benefit of sacituzumab govitecan vs single-agent chemotherapy, the historical standard of care. Patients enrolled in ASCENT had metastatic TNBC and progression after 2 or more prior therapies, at least 1 of which was for metastatic disease.32 On the primary endpoint, treatment with sacituzumab govitecan vs chemotherapy was associated with significant improvement in PFS in patients without baseline brain metastatic disease. In the final survival analysis, risk of progression or death was reduced by 59% with sacituzumab govitecan (Figure 3). Treatment with sacituzumab govitecan was also associated with significant improvement in OS and a 24-month OS rate of 22.4% (vs 5.2% with chemotherapy).32,33

Figure 3. Phase III ASCENT: PFS and OS with sacituzumab govitecan in patients with metastatic TNBC without brain metasteses with ≥2 prior treatment regimens.32

Of importance, benefit was seen across all patient subgroups, including older patients, patients with prior ICI or liver metastases, any BRCA1/2 status or TROP-2 expression level, and those with brain metastases.32 Clinical benefit with sacituzumab govitecan was seen in patients who relapsed with metastatic TNBC as well as in patients without TNBC at their initial diagnosis (eg, due to change in HR/HER2 expression), which represented almost one third of patients in each treatment arm.34 Patients reported more improvement in quality of life from baseline with sacituzumab govitecan vs chemotherapy on measures of physical functioning, fatigue, and pain.35

Of equal importance, a subanalysis of patients in ASCENT with 1 prior line of treatment for metastatic TNBC and progression 12 or more months after (neo)adjuvant chemotherapy found sacituzumab govitecan was also effective as second-line treatment. Treatment was associated with median OS double that with single agent chemotherapy (HR for death: 0.51; 95% CI: 0.28-0.91).36 Sacituzumab govitecan is recommended by the NCCN and ASCO as a second-line approach, following 1 line of treatment for metastatic TNBC.10,16, No TROP-2 measurement is necessary prior to treatment with sacituzumab govitecan.10,11

The most frequent treatment-related side effects with sacituzumab govitecan are neutropenia, diarrhea, nausea and vomiting, fatigue, and alopecia. The majority of gastrointestinal effects, fatigue, and alopecia were mild (grade 1) in clinical trials. In contrast, grade 3 or 4 neutropenia predominated, and is the most frequent serious adverse event. Both neutropenia and diarrhea are expected effects with the SN-38 payload of the ADC.32,37,38 Table 4 summarizes recommended management of sacituzumab govitecan toxicities.37-40 When starting patients on sacituzumab govitecan, it is helpful to educate them about the potential for hair loss (and offer a prescription for a wig) and to recognize the side effects that require urgent intervention. There is a risk for hypersensitivity reactions with the drug, and patients should know to call if symptoms develop within 24 hours of starting treatment. Symptoms include swelling, skin rash or itch, breathing problems, dizziness, chills or fever, and hypotension. Patients also should call immediately for black or bloody stools, symptoms of dehydration, nausea preventing fluid intake, and vomiting or diarrhea within 24 hours of prophylaxis.38-40 

Table 4. Management of Common and Potentially Severe Toxicities Associated with Sacituzumab Govitecan.37-40

 

Expert Insights From Dr Force: Treating Myelosuppression and Diarrhea Associated With Sacituzumab Govitecan

 

T-DXd for HR-Negative/HER2-Low Metastatic Disease
As mentioned previously, the concept of HER2-low, defined as HER2 expression of IHC 1+ or IHC 2+/negative ISH, is newly relevant because of the potential for trastuzumab-targeting ADCs to benefit such patients.10 Phase III DESTINY-Breast04 compared treatment with T-DXd to standard of care chemotherapy in patients with HER2-low metastatic breast cancer (including TNBC) after 1 or 2 prior lines of treatment and demonstrated clinical benefit with higher objective response rates and longer PFS and OS.41 Among patients who were HR-negative/HER2-low, T-DXd (n = 40) vs chemotherapy (n = 18) was associated with a 54% reduction in risk of progression (HR 0.46; 95% CI: 0.24-0.89) and 52% reduction in risk of death (HR 0.48; 95% CI: 0.24-0.95). Median OS was 18.2 months vs 8.3 months.41

Based on this study, T-DXd is now NCCN-recommended for second- or subsequent-line treatment of recurrent, metastatic disease.10 T-DXd is FDA approved for HER2-low breast cancer after chemotherapy in the metastatic setting or with recurrence during or ≤6 months after completing adjuvant therapy.42 

 

Expert Insights From Dr Force: Survival Advantage With T-DXd vs Chemotherapy in HER2-Low Metastatic Breast Cancer

 

Patients With Germline BRCA Mutations 
Cells with mutated BRCA1/2 have a defective homologous DNA repair pathway. PARP inhibitors disrupt alternative DNA damage repair mechanisms of tumor cells, which may lead to apoptosis and potentially reduction or stoppage of tumor growth in cancer cells with an already defective homologous DNA repair pathway.43 Given the prevalence of BRCA mutations in TNBC, the PARP inhibitors olaparib and talazoparib were studied in patients with BRCA-mutated, metastatic TNBC. 

The phase III OlympiAD trial compared olaparib vs standard of care single-agent chemotherapy for treatment of BRCA-mutated, high-risk, HER2-negative breast cancer and ≤2 lines of chemotherapy in metastatic disease. In the final survival analysis, olaparib vs chemotherapy was associated with significant improvement in PFS, the primary endpoint (HR 0.58; 95% CI: 0.43-0.80; P <.001). Median PFS was about 3 months longer with olaparib (7.0 vs 4.2 months), but no difference in OS was seen between treatments in the overall patient population or in patients with TNBC.44,45 The phase III EMBRACA trial compared talazoparib with single-agent chemotherapy for locally advanced or metastatic BRCA-mutated breast cancer.46 In EMBRACA, treatment with talazoparib vs chemotherapy was associated with a significant improvement in PFS, with median PFS of 8.6 vs 5.6 months (HR 0.54; 95% CI: 0.41-0.71; P <.001), but not OS in the final analysis.46,47 In the subset of patients with TNBC in EMBRACA, both PFS and clinical benefit rate were significantly improved with talazoparib.48

How should T-DXd dosing be modified in a patient with HER2-low metastatic breast cancer who develops grade 2 interstitial lung disease (ILD)?

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