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Director, Glen Family Breast Center
Hematology and Medical Oncology
Winship Cancer Institute
Kevin Kalinsky, MD, MS, has disclosed that his spouse/partner has ownership interest in and has received salary from Grail and that he has received consulting fees from Amgen, AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, and Seattle Genetics; and has received funds for research support paid to his institution from Acetylon, Amgen, Calithera, CytomX, Genentech/Roche, Immunomedics, Incyte, Lilly, Novartis, Pfizer, Seattle Genetics, and Zentalis.
In 2020, the treatment of advanced triple-negative breast cancer (TNBC) rapidly evolved with the FDA’s approvals of pembrolizumab plus chemotherapy and sacituzumab govitecan. The latter marked the first approval of an antibody–drug conjugate for this challenging subtype of non–HER2-associated disease, and was notable because this agent prolongs overall survival (median OS: 12.1 vs 6.7 months with chemotherapy; P < .0001). Where do these new agents fit into the treatment sequence for advanced TNBC—and how does that sequence change for the approximately 10% of patients harboring germline BRCA1/2 mutations?
Sequencing Immune Checkpoint Inhibitors (ICIs) and Sacituzumab Govitecan in Advanced TNBC With Wild-type vs Mutated BRCA
First-line Treatment Depends on PD-L1 Expression, Not BRCA Status
It is important to perform upfront PD-L1 testing to determine if the patient is eligible for atezolizumab plus nab-paclitaxel (using the SP142 assay) or pembrolizumab plus nab-paclitaxel, paclitaxel, or gemcitabine (using the 22C3 pharmDx assay). If the patient has PD-L1–positive disease, then I would choose chemotherapy plus ICI, regardless of whether the patient is BRCA wild‑type or carries a BRCA mutation. If the patient has PD-L1–negative disease, then I would select chemotherapy or, if a BRCA mutation is identified, a PARP inhibitor.
Later-line Treatment Influenced by BRCA Status, Relapse Timing, and Toxicities
TNBC With Mutated BRCA
If the patient carries a BRCA mutation and has not previously received a PARP inhibitor, then I would consider a PARP inhibitor for second-line treatment, followed by sacituzumab govitecan in the third line.
The caveat here is that if the patient progressed within 12 months of (neo)adjuvant therapy, I would consider sequencing sacituzumab govitecan as a second-line therapy. The decision depends, first, on the extent of disease. PARP inhibitors are associated with excellent response, but that response is not always durable. If the goal is to achieve and maintain response, then I would sequence sacituzumab govitecan before the PARP inhibitor. The second factor is patient preferences on administration, because PARP inhibitors are oral agents, whereas sacituzumab govitecan is administered as an intravenous infusion.
Does the efficacy of sacituzumab govitecan differ for patients with vs without BRCA mutation? At SABCS 2020, Hurvitz and colleagues presented an analysis of biomarkers predicting response to sacituzumab govitecan. The greatest benefit was seen in patients with moderate to high Trop-2 expression, although all patients experienced some benefit, and the number of patients with low Trop-2 expression was small. BRCA mutation status was not associated with benefit. However, the analysis was limited by the low rate of germline BRCA mutations (approximately 10%) in the study population.
After progression on sacituzumab govitecan, I would consider chemotherapies such as eribulin, gemcitabine, capecitabine, or vinorelbine.
TNBC With Wild-type BRCA
For patients who are BRCA wild-type, I would decide between second-line treatment with chemotherapy vs sacituzumab govitecan. If the patient had progressed within 12 months of (neo)adjuvant therapy, I would likely select sacituzumab govitecan and reserve chemotherapy for third-line treatment. If the patient did not have an early relapse, then I would sequence chemotherapy before sacituzumab govitecan. I would select the chemotherapy based on pre-existing toxicities; for example, if the patient has neuropathy, then I would be hesitant about giving a taxane or eribulin as a next step.
Although we now have 3 approved immunotherapy agents, metastatic TNBC continues to represent an unmet need. Even in the first-line setting, I would look into whether the patient is eligible for a clinical trial. There are multiple exciting areas of investigation in this disease, such as whether sacituzumab govitecan could be combined with ICIs or administered in earlier lines, and even as (neo)adjuvant therapy. Still other antibody–drug conjugates are under investigation in TNBC and for HER2-low disease, such as ladiratuzumab vedotin and trastuzumab deruxtecan, respectively. I am hopeful that there will soon be other antibody–drug conjugates approved for this challenging disease.
Want to hear more from the experts on how to leverage novel immunotherapies for managing patients with early-stage through metastatic TNBC? Download the slides from a dynamic live Webinar featuring Dr. Heather McArthur and her colleagues, Dr. Kevin Kalinsky and Dr. Rita Nanda (on-demand Webcast coming soon).