A panel at the 2020 San Antonio Breast Cancer Symposium discussed 3 new drug approvals from the past year, highlighting changes in the treatment landscape across multiple breast cancer types.
The breast cancer treatment landscape has evolved in the past year, with notable FDA approvals providing new options for patients with certain types of breast cancer. In a session on day 1 of the San Antonio Breast Cancer Symposium (SABCS), which is taking place virtually from December 8-11, 2020, FDA physicians and a Penn Medicine researcher discussed the approvals and clinical implications of sacituzumab, fam-trastuzumab deruxtecan-nxki, and tucatinib; all of which have been approved in the year since SABCS 2019.
The discussion was moderated by Julia Beaver, MD, chief of medical oncology in the Oncology Center of Excellence at the FDA. Speaking on sacituzumab was Christy Osgood, MD, a pediatric oncologist at the FDA; Preeti Narayan, MD, a medical oncologist at the FDA, discussed trastuzumab deruxtecan’s approval; and tucatinib’s approval was discussed by Mirat Shah, MD, a medical oncologist on the breast, gynecological, and supportive oncology team at the FDA. Angela DeMichele, MD, MSCE, co-leader of the breast cancer research program at Penn Medicine, discussed the current treatment landscape, and how these new drugs meet patient needs.
Sacituzumab in Metastatic Triple-Negative Breast Cancer
Sacituzumab, a drug granted accelerated FDA approval on April 22, 2020, is the first antibody drug conjugate (ADC) approved for the treatment of metastatic triple-negative breast cancer (mTNBC). The accelerated approval, which includes the treatment of patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease, was based on results from the single-arm IMMU-132-01 trial (NCT 01631552).
“Patients with metastatic triple negative breast cancer have limited treatment options and need new safe and effective therapies, particularly for patients who are heavily pretreated,” Osgood explained. “This accelerated approval addresses this unmet medical need.”
The current treatment algorithm for TNBC includes targeted or immune therapy for patients who qualify based on genetic testing, but only about half qualify, DeMichele explained. The other half of patients undergo either chemotherapy, which has just a 15% to 20% response rate and a median progression-free survival (PFS) of 2-3 months, or clinical trials. The 5-year survival for distant disease is just 11%, meaning there is a need for better options, DeMichele said. Sacituzumab is one of those options for patients who have undergone 2 prior therapies for mTNB.
“This is an exciting class of drugs called antibody drug conjugates, and I think that it's worth really getting to know how these drugs works because we have several approved for breast cancer and many more that are coming down the line,” DeMichele said.
The 3 key components of an ADC are the antibody, which can have independent functions on its own in addition to docking onto the cell; the linker, which has to be stable enough to avoid off-target effects but must be cleaved to let the payload enter the cell; and the payload, the cytotoxic agent. Sacituzumab contains an anti-Trop-2 antibody, hydrolyzable linker, and a payload of SN-38. The drug-antibody ratio is what mainly determines the efficacy of the agent, and sacituzumab’s 7.6:1 ratio is high.
Sacituzumab is expected to receive full approval based on results of the confirmatory ASCENT trial (NCT02574455), which was halted early due to compelling evidence of efficacy. Median PFS was 5.6 months in the sacituzumab group vs 1.7 months in the physician’s choice chemotherapy group. Median overall survival (OS) was 12.1 months in the sacituzumab group vs 6.7 months in the chemotherapy group.
Neutropenia is the most notable toxicity, seen in 63% of patients in the trial, with 17% of patients experiencing grade 4 neutropenia. The payload, SN-38, is inactivated and detoxified by the enzyme UGT 1A1, and the UGT 1A1*28 allele have increased toxicity, especially in homozygotes, which includes about 10% of North Americans, DeMichele noted. Therefore, it is important to test patients ahead of the start of treatment.
Despite the toxicities, the drug is likely to gain full approval, and other studies are examining it in mTNBC in combination with checkpoint inhibitors and PARP inhibitors; in hormone receptor-positive/HER2-negative disease; and in the adjuvant and neoadjuvant settings.
Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer
Fam-trastuzumab deruxtecan-nxki (T-DXd) is an ADC comprising an immunoglobulin (IgG1) antibody linked to a topoisomerase I inhibitor (DXd) conjugate that received accelerated FDA approval on December 19, 2019 for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
“This accelerated approval occurred at a time when therapies in the third-line metastatic setting for HER2-positive breast cancer were limited, and therefore represent an important approval for an area with unmet need,” Narayan said.
Narayan cited 2 studies used to support the accelerated approval: the phase II DESTINY-Breast01 (NCT03248492) and a phase I study of 50 HER2-positive breast cancer patients that provided supportive safety data. The phase I trial also included HER2-low disease patients, Narayan noted. HER2-low disease is estimated to make up about 40% of all HER2-negative breast cancers, yet there are no therapies designed for it, she said. Therefore, it is an area that needs further development, and T-DXd is one of several ADCs being tested in that population.
Ahead of T-DXd’s accelerated approval, available third-line therapies for metastatic HER2-positive breast cancer had about 15% to 30% response rates, compared with T-DXd’s overall response rate of 60%.
T-DXd joins combination tucatinib, capecitabine, and trastuzumab treatment; and neratinib, capecitabine, and trastuzumab treatment in third-line HER2-positive breast cancer options, DeMichele explained. She also noted that at the time of the approval, tucatinib was not yet approved.
“I think the reason it got that accelerated approval clearly is because of this remarkable overall rate of 60% of progression free survival 16.4 months, clearly superior to what had been approved previously in the third-line setting with neratinib-capecitabine-trastuzumab, DeMichele said. It also showed a higher response rate than tucatinib-capecitabine-trastuzumab, but she clarifies that there shouldn’t be cross-trial comparison.
“It's going to be very important for a randomized trial to be conducted in order to really understand the ultimate benefit of T-DXd in the third line, as well as its impact on overall survival,” DeMichele said.
Tucatinib in Advanced HER2-positive Breast Cancer with Brain Metastases
Tucatinib, an oral tyrosine kinase inhibitor (TKI) of HER2, was fully approved on April 17, 2020 in combination with trastuzumab and capecitabine for advanced unresectable or metastatic HER2-positive breast cancer. The indication includes patients with brain metastases who have received one or more prior anti-HER2-based regimens in the metastatic setting. CNS metastases occur in roughly 30%-50% of HER2-positive breast cancer patients.
Approval was based on results from the HER2CLIMB trial (NCT02614794) on patients with HER2-positive unresectable or metastatic breast cancer. Patients with treated and stable brain metastases, treated and progressing metastases, and untreated metastases were all eligible.
Compared with patients on a regimen trastuzumab and capecitabine, those given tucatinib, trastuzumab, and capecitabine had a longer median PFS (5.6 months vs 7.8 months, respectively. The median OS in the tucatinib group was 21.9 months, compared with 17.4 months in the placebo group. In patients with brain metastases, about half the total patient population, median PFS was 7.6 months in the tucatinib group vs 5.4 months in the placebo group.
While there were several options for third-line treatment before tucatinib’s approval, no therapy had shown an improvement in overall survival in the third-line setting, Shah pointed out. Tucatinib was granted orphan drug designation by the FDA, a program that offers incentives for drug companies to develop drugs for rare conditions or diseases that affect less than 200,000 people in the United States per year, for breast cancer with brain metastases.
“Although breast cancer is not rare in the US, having breast cancer and brain metastases is more rare,” Shah said. “And additionally, this defines a group of patients with a distinct therapeutic need.”
New approaches to meeting this need, including TKIs and ADCs, are exciting because penetrating the CNS has proven tricky, DeMichele said. Through different mechanisms, these drugs allow that penetration to occur.
DeMichele stresses the importance of ongoing and future research trying to prevent HER2-positive CNS disease. She cites several trials that have shown some patients to develop CNS-only recurrences after neoadjuvant chemotherapy. “This is an unmet need, and we need to think about bringing these agents that penetrate the CNS into the neoadjuvant settings,” she said.
A Dynamic Year
DeMichele sees 2020, despite its other health crises, a year when the breast cancer treatment landscape truly changed thanks to FDA pathways that have sped up drug approvals. All 3 of the drugs discussed in the session were developed within the past 5 years. And ADCs in particular are an emerging and important group of drugs that have shown adaptability across breast cancer subtypes, she said.
“What's really remarkable is the rapid timeline, and I think it's really been a tremendous advance that the FDA has figured out a mechanism to enable these drugs to be to be developed and approved in such a short timeline,” DeMichele said.