Targeted treatments ‘moving the bar’ in metastatic breast cancer

 

Research exploring novel targeted agents for patients with metastatic breast cancer is mounting and spurring excitement in the oncology field.

“There really is a lot to be excited about,” Gregory A. Vidal, MD, PhD, medical oncologist at West Cancer Center and Research Institute and associate professor in the department of hematology/oncology at The University of Tennessee Health Science Center, told Healio. “We are seeing research push boundaries in this patient setting with more targeted chemotherapeutic options that are ‘moving the bar’ a bit in terms of response rates from what we normally expect in the late-line treatment setting.”

Gregory Vidal, MD, PhD

Treatments in metastatic breast cancer are mainly taxane-based, including paclitaxel and docetaxel. Other treatment options include oral capecitabine as well as the platinum-based agents, carboplatin and cisplatin.

“These are the main agents used for these patients,” Vidal said. “Anthracyclines are another option, but most patients have already used these in the curative treatment setting. Since toxicity is related to cumulative doses, its use in metastatic setting can be limited. Chemotherapy agents generally have better activity when used in the first-line as compared with later-lines setting where PFS, OS and response rates significantly decrease.”

Triple-negative disease

In metastatic breast cancer, tumor types are classified into different subgroups and treatment response varies based upon the tumor type. Metastatic triple-negative breast cancer involves an aggressive tumor type for which effective treatment options are limited.

“Triple-negative breast cancer remains the greatest unmet need in terms of effective treatments,” Vidal said. “These patients traditionally do terribly, with the average median OS at about 12 months. As compared to the other breast cancer subtypes, metastatic triple negative breast cancer are poorly acting tumors, and we do not yet fully understand why they are behaving this way. If we can offer these patients additional treatment options with lower toxicities, then we can move the bar further in terms of disease control and survival outcomes. Overall, I am hopeful as there is a lot of research being conducted in this patient population.”

In a phase 1/2 single-group trial published in The New England Journal of Medicine, investigators assessed the safety and efficacy of sacituzumab govitecan (IMMU-132, Immunomedics Inc.) in 108 patients (median age, 55 years; 75.9% white) with metastatic triple-negative breast cancer who previously underwent a median of three anticancer treatments. Results showed a response rate of 33.3% (95% CI, 24.6-43.1), which included three complete responses and 33 partial responses. Median duration of response was 7.7 months (95% CI, 4.9-10.8).

“Sacituzumab is an antibody drug conjugate that showed a response rate above 30% in the late-line setting among women with metastatic triple-negative breast cancer, which is something that was never seen before,” Vidal said.

In the phase 3 KEYNOTE-355 trial, presented during the ASCO20 Virtual Scientific Program, researchers found that the addition of pembrolizumab (Keytruda, Merck) to various chemotherapy agents significantly improved PFS among women with inoperable metastatic triple-negative breast cancer. No new safety concerns were reported.

“This was a very important trial, but more success is needed in the metastatic triple-negative breast cancer treatment setting,” Vidal said. “Checkpoint inhibitors have essentially revolutionized the way we treat cancers across the board, and they have now found their place in the triple-negative breast cancer setting. Other agents have shown promise in altering the way the immune system recognizes cancer cells and interacts with it, which can help with controlling and treating this disease — there really is a lot to be excited about.”

“Another important combination presented at ASCO involved a PARP inhibitor, veliparib (ABT-888, AbbVie), combined with chemotherapy ( SWOG S1416) in patients with metastatic triple negative breast cancer with an alteration of the homologous recombination pathway, but not having BRCA mutation, showed prolongation in PFS,” he said. “Two PARP inhibitors have already been approved in metastatic breast cancer, but there are other PARP inhibitors currently approved in the ovarian cancer setting that are not yet approved in breast cancer and are certainly being studied.”

HER2-positive, ER-positive disease

Data on various agents in the HER2-positive metastatic breast cancer setting were also presented during the ASCO20 Virtual Scientific Program. In a phase 3 randomized study that analyzed a large subset of patients with brain metastases from HER2-positive breast cancer enrolled in HER2CLIMB, investigators found tucatinib (Tukysa, Seattle Genetics) plus trastuzumab (Herceptin, Genentech) and capecitabine significantly extended OS and improved PFS.

“Tucatinib showed not only improvement in PFS but also OS for patients with brain involvement who are HER2-positive,” Vidal said. “This was another well-conducted study showing benefit in the metastatic breast cancer setting.”

Another study presented during the ASCO20 Virtual Scientific Program showed pyrotinib (Hengrui Therapeutics) plus capecitabine extended PFS among certain patients with HER2-positive metastatic breast cancer. The combination also had a manageable toxicity profile.

“This study out of China involving the use of an oral tyrosine kinase inhibitor that targets HER2, showed significant PFS in these patients,” Vidal said.

Even more treatments are showing promise in the HER2-positive metastatic breast cancer setting, Vidal noted.

“The anti-HER2-drug conjugate, trastuzumab deruxtecan [T-DXd; Enhertu, AstraZeneca] was approved in December 2019 for HER2-positive breast cancer for third-line treatment. [T-DXd] also showed very good response in the HER2-low patient population and is being actively studied in this setting now. It will be exciting to see the data in this patient population,” he said.

“Sacituzumab is also being investigated in a large phase 3 trial in the ER-positive metastatic breast cancer setting,” Vidal added. “This was based on previous phase 2 data showing efficacy in the ER-positive setting. There is a lot to look forward to in the treatment of metastatic breast cancer.”

 

 

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