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CDK4/6 inhibitors changed the treatment of hormone receptor (HR)-positive/HER2-negative metastatic breast cancer, with combination endocrine therapy and CDK4/6 inhibition becoming the standard of care in these patients. There may be several different options as next line of therapy for these patients, and choosing the right one depends on characteristics of the progressing disease.

"After a patient progresses on combination hormone therapy, we usually thought about moving on to chemotherapy," said Nancy Chan, MD, of the NYU Langone Laura and Isaac Perlmutter Cancer Center in New York City. "Recently though, we have had advances in the use of targeted therapies."

The next step after progression is now typically to test patients for a specific mutation, such as PIK3CA. When upregulated, the PI3K/AKT/mTOR pathway may be a key factor in the patient's disease progression, Chan said.

One of the first trials to target this pathway was which looked at the use of everolimus in patients with HR-positive, HER2-negative advanced breast cancer previously treated with an aromatase inhibitor (AI). Median progression-free survival was 6.9 months with everolimus compared with 2.8 months with placebo. These patients had no prior treatment with a CDK4/6 inhibitor.

There is now an FDA-approved targeted therapy for patients with PIK3CA mutations. Alpelisib (Piqray) was approved based on the SOLAR-1 trial that examined the drug in patients with or without PIK3CA mutations. In the group of patients positive for the mutation, the median progression-free survival was almost doubled with alpelisib plus fulvestrant (Faslodex) compared with fulvestrant alone (11.0 vs 5.7 months).

"Patients able to tolerate hormone therapy plus alpelisib targeted specifically to the PIK3CA mutation can have a really long duration of response," Chan said. "This provides more time for a patient to delay the start of chemotherapy."

While everolimus had efficacy in patients with or without the PIK3CA mutation, alpelisib's activity was specific to those with the mutation. Chan said that, in most cases, patients with the mutation would be treated with alpelisib. However, she did note that a major side effect of alpelisib is risk for high glucose levels.

"If you have someone with diabetes, starting this drug may be more difficult," Chan said. "We work really closely at NYU with an endocrinologist before we even start a patient with diabetes on this drug. We take precautions, but if the tumor has the mutation we want to at least try this drug because it is efficacious."

Lending further support to the use of alpelisib after CDK4/6 progression were the results from the BYLieve study. This study looked at patients who had immediate prior treatment with a CDK4/6 inhibitor plus an AI (Cohort A) or a CDK4/6 inhibitor plus fulvestrant (Cohort B). Median progression-free survival was 7.3 months for Cohort A and 5.7 months for Cohort B. In Cohort A, 50.4% of patients were alive without progression at 6 months, the study's primary endpoint.

Another drug in development to target the PI3K/AKT/mTOR pathway is capivasertib, Chan noted. Capivasertib is a selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION study tested fulvestrant with or without capivasertib in postmenopausal women with estrogen receptor-positive, HER2-negative metastatic disease. Median progression-free survival was more than doubled with capivasertib plus fulvestrant. A phase III study is in progress with the drug, which Chan predicted could be important, if approved.

HER2 Status

With its recent approval, trastuzumab deruxtecan (Enhertu) is now an option for women with the newly defined category of HER2-low breast cancer who have progressed on CDK4/6 inhibitors. Patients who were previously classified as HER2-negative could now be eligible for treatment with trastuzumab deruxtecan.

"Up to 50% of HR-positive breast cancers in the metastatic setting will have HER2-low expression," Chan noted.

Another antibody drug conjugate, sacituzumab govitecan (Trodelvy) is also effective in the metastatic setting for patients with HR-positive, HER2-negative breast cancer, Chan said.

"Even if they don't have the PIK3CA mutation but they are progressing on a CDK4/6 inhibitor, these patients now have two additional new drugs to potentially benefit from," she said.

Chan noted that clinicians should be cautious of the use of trastuzumab deruxtecan in patients with a history of pneumonitis.

"This is a specific side effect that we know about 10% of patients will experience," she said. "If I have a patient with a history of lung disease, I have the patient see a pulmonologist before starting the drug, and I proceed with a lot of caution."

Other Options

About one-third of patients who have been on an AI or tamoxifen will develop a mutation in the actual estrogen receptor, an ESR1 mutation, Chan said.

"That means the receptor is always turned on and an AI or tamoxifen may not be effective," Chan said.

In that setting, fulvestrant is the only approved selective estrogen receptor degrader found to be effective. For patients with an ESR1 mutation, fulvestrant can be used in combination with a CDK4/6 inhibitor.

Another option for patients who have progressed after treatment with a CDK4/6 inhibitor is to change endocrine therapies and CDK4/6 inhibitors, Chan said.

Results of the MAINTAIN trial showed a significant progression-free survival benefit when patients with HR-positive/HER2-negative metastatic breast cancer changed endocrine therapy and received ribociclib (Kisqali) after progression. Patients treated with ribociclib plus endocrine therapy had a median progression-free survival of 5.29 months compared with 2.76 months with endocrine therapy alone.

"The landscape is changing very rapidly," Chan said, pointing to the importance of clinicians staying up-to-date on the most recent data and communicating and interacting with other clinicians.

"The most important factor in how we choose the next line of treatment is knowing the patient sitting in front of us," Chan said. "Clinical judgement is still a very important part of how we treat breast cancer. We have to use it to determine how to sequence and use all the new drugs available."

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