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In the last few years there has been tremendous progress in the treatment of metastatic HER2-positive breast cancer.

"We are getting a lot of therapeutic options coming into this space," said Shridar Ganesan, MD, PhD, a physician-scientist at the Rutgers Cancer Institute of New Jersey. "Trastuzumab [Herceptin] was the first, but we now have a wealth of effective therapeutics that in combination can change the natural history of this disease."

As more options have entered the space, work has been done to try to establish clear sequencing of these options.

"The main treatment option in the frontline setting remains the combination of chemotherapy, typically taxanes, with HER2-targeting agents, most often trastuzumab and pertuzumab [Perjeta]," Ganesan said.

This standard was established with the phase III CLEOPATRA trial, which showed that this regimen significantly improved overall survival (OS) compared with trastuzumab and docetaxel alone (HR 0.68, 95% CI 0.56-0.84, P<0.001); demonstrated that these improvements were maintained after a median of 8 years' follow-up.

One of the few exceptions to the use of this regimen in the frontline may be for patients with hormone-receptor positive disease, according to Kelly E. McCann, MD, PhD, of the University of California Los Angeles' Jonsson Comprehensive Cancer Center.

"I do have rare patients who have very slow-growing ER [estrogen receptor]-positive, HER2-positive breast cancers that respond well to just a HER2-targeted therapy plus endocrine therapy," McCann said. "We typically use chemotherapy with trastuzumab and pertuzumab for six cycles, and then continue the HER2-targeting agents plus hormone blockade as maintenance. If a patient with ER-positive, HER2-positive breast cancer has a very prolonged response to maintenance HER2-targeting therapy plus endocrine therapy, I might switch out the endocrine therapy at the time of progression rather than switch to a new cytotoxic regimen."

Ganesan added that he might also consider hormone therapy rather than trastuzumab for certain patients who have hormone-receptor positive, HER2-positive disease that either cannot tolerate or do not want chemotherapy.

Second-Line Established

The debate over the most effective second-line option seems to have been ended with the release of the DESTINY-Breast03 trial results.

"The trial compared two antibody drug conjugates -- trastuzumab deruxtecan (T-DXd, Enhertu) and trastuzumab emtansine (TDM-1; Kadcyla) -- and results made it pretty clear that T-DXd was the superior drug in terms of median progression-free survival [PFS] in the second-line setting," McCann said.

Updated results showed that in addition to significantly improved PFS (HR 0.33, 95% CI 0.26-0.43, P<0.0001), T-DXd also significantly improved OS compared with TDM-1 (HR 0.64, 95% CI 0.47-0.87, P=0.0037).

McCann and Ganesan noted though that T-DXd may not be the best second-line option for every patient.

"T-DXd is not a 'free ride' and patients can experience significant pulmonary toxicity, neutropenia, and other side effects," Ganesan said. "In some cases, TDM-1 may be better tolerated; it may be the best option in certain situations where patients have significant lung disease or a history of pulmonary fibrosis, for example."

Another second-line exception to the use of T-DXd is in patients with central nervous system (CNS) involvement.

"If someone has brain metastases, I would recommend the HER2CLIMB regimen of tucatinib [Tukysa] with trastuzumab and capecitabine," McCann said.

HER2CLIMB showed that the tucatinib combination was associated with significantly lower risk of progression or death in patients with HER2-positive disease and brain metastases.

"That brings up the question of whether or not to actively look for brain metastases, because traditionally we've waited for symptoms before ordering brain imaging," McCann said. "Since we could be choosing second-line therapy based on presence of brain metastases, I think it is reasonable to do a baseline screening MRI after progression on first line."

Ganesan said that screening for brain metastases in asymptomatic women is currently not routine practice, but that could change as data on screening strategies become available.

Third-Line and Beyond

Beyond the second-line there are more unanswered questions. Both the tucatinib combination regimen studied in HER2CLIMB and the antibody drug conjugate TDM-1 can be used as third-line options in metastatic HER2-positive disease. However, more research is needed to determine the activity of TDM-1 after use of T-DXd.

The FDA approved margetuximab (Margenza) in combination with chemotherapy for third-line use in patients with metastatic HER2-positive breast cancer, although the National Comprehensive Cancer Network (NCCN) guidelines recommended it in the fourth-line or later. This approval was based on the SOPHIA trial of patients with HER2 immunohistochemistry 3+ or ISH-amplified HER2-positive disease; the study showed statistically significant improved PFS with margetuximab compared with trastuzumab plus chemotherapy, though the absolute clinical benefit was not impressive. showed no improvement in OS.

"I have never prescribed margetuximab outside of the SOPHIA trial because the difference in median PFS of margetuximab versus trastuzumab was only 1 or 2 months," McCann said. "Margetuximab is an antibody that was rationally designed to stimulate more of an immune response than trastuzumab, but this ultimately didn't translate into the clinical efficacy we'd hoped for."

Combination neratinib (Nerlynx) plus capecitabine is also approved as a third-line treatment, but recommended in the fourth-line or later per NCCN guidelines. The phase III found that the pan-HER tyrosine kinase inhibitor neratinib plus capecitabine significantly improved PFS and time to intervention for CNS disease compared with lapatinib (Tykerb) plus capecitabine.

Finally, trastuzumab in combination with chemotherapy is another option for these patients.

"The guidelines can tell us to do this therapy first, this second, and this third, but you have to look at every patient and carefully understand how much disease they have, where that disease burden is, and that patient's tolerance to therapy," Ganesan said. "These factors always have to be taken into consideration. The overwhelming aim in these later lines is to balance the possible benefit of doing a good job reducing disease burden and helping them feel better with the possible toxicities of these therapeutics."

It is also important to remember that the landscape of treatment will continue to shift, possibly even in the first-line.

"What I am saying today," Ganesan said, "may not be the same as what I am saying a year from now, and that kind of rapidly changing treatment landscape is great."

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