Next Generation of Combo Regimens Being Explored in ER+ Breast Cancer

Combinations of checkpoint inhibitors and endocrine therapy are an area of intriguing exploration in estrogen receptor (ER)–positive breast cancer, according to Hung Khong, MD.

“Most studies [looking at these types of combinations] have focused on triple-negative breast cancer,” said Khong. “However, there is no evidence that ER-positive disease doesn't respond to immunotherapy. In fact, there is evidence to the contrary that [indicates] ER-positive breast cancer does respond to immunotherapy.”

Khong also emphasized that such a combination approach could prove to be more tolerable than combination regimens that include chemotherapy. Other types of potential combination therapies include the use of CDK4/6 inhibitors with endocrine therapy, he cited.

In an interview with OncLive during the virtual Institutional Perspectives in Cancer (IPC) on Breast Cancer, Khong, an associate member of Moffitt Cancer Cancer, discussed the potential to combine endocrine therapy with immunotherapy in patients with ER-positive breast cancer, and other intriguing therapies poised to improve transform the pipeline.

OncLive: Could you provide some background to combining antiestrogen treatment and immunotherapy in patients with ER-positive, HER2-negative breast cancer?

Khong: When [oncologists] combine immunotherapy together with a different drug for breast cancer treatment, they tend to combine it with chemotherapy. The I-SPY 2 study combined pembrolizumab (Keytruda) with paclitaxel, followed by doxorubicin and cyclophosphamide, for patients with ER-positive disease in the neoadjuvant setting. However, we know that in the neoadjuvant setting for ER-positive disease, endocrine therapy worked just as well or better than chemotherapy—not worse. However, [oncologists] are so used to chemotherapy that every time we think about neoadjuvant therapy, we think about combining [immunotherapy with] chemotherapy. There are many studies showing that endocrine therapy works just as well, but with less toxicity. 

There is a reason why we do a combination of endocrine therapy and chemotherapy; it is scientific. [There are different types of] endocrine therapies, the 2 major ones being tamoxifen and aromatase inhibitors (AIs). Tamoxifen has been shown to shift the T cells from a Th1 to Th2 phenotype; therefore, that will be detrimental for a cancer treatment in combination with chemotherapy.

However, AIs have been shown to do the opposite. They shift the T-cell response from Th2 to Th1, which is important for anti-cancer immunity. Also, AIs have been shown to modulate the new system in a different way. Because they shift the T cells from the Th2 to the Th1 phenotype, they enhance interferon gamma production. Then, as we know, interferon gamma is a major factor to help regulate PD-L1 expression on tumor cells.

Therefore, AIs may potentially upregulate PD-L1 expression, but it has other pro-immune activity. Therefore, combining an AI with a PD-1 blocker is assumed to be a reasonable, scientific rationale to treat patients.

What other key combinations in ER-positive breast cancer would you like to discuss?

For ER-positive tumors, we know that CDK4/6 inhibitors [could be an appropriate partner] for good combinations. Right now, CDK4/6 inhibitors are used mainly for patients with metastatic disease, but there are a lot of studies that have been done in the neoadjuvant or adjuvant setting. Therefore, combining endocrine therapies and CDK4/6 inhibitors together, [and CDK4/6 inhibitors in combination with PD-1/PD-L1 inhibitors] is something that we're looking into.

Could you discuss the phase 1/1b trial examining LSZ102 in combination with ribociclib (Kisqali) or alpelisib (Piqray) in ER-positive breast cancer?

Alpelisib has been approved in combination with fulvestrant (Faslodex) in the treatment of patients with metastatic ER-positive breast cancer. Alpelisib [needs to be carefully discussed with] patients because alpelisib does have more substantial AEs compared with endocrine therapy alone or in combination. Therefore, we have to look at the risk-benefit ratio and discuss [using the agent] with our patients.

Could you expand on the AEs with some of the other agents that are available?

With everything we do, or any recommendations [we make], we have to always look at the recent benefits. We should never look at the risks alone, [nor should] we look at the benefit alone—we have to look at the balance [when deciding on a treatment for our patients]. Immunotherapy in combination with endocrine therapy doesn’t usually [add much in terms of toxicity] because the 2 agents have different mechanisms of action, so I don't expect anything worse than the AEs of each drug alone.

What is the biggest challenge in ER-positive breast cancer treatment?

Actually, there are a lot of challenges in this space because people always believe that ER-positive disease is more indolent, less suppressive and, therefore, have better prognoses than patients with HER2-positive or triple-negative breast cancer. However, that is not correct because ER-positive disease has a long duration of recurrence—much more compared with TNBC.

TNBC [if it comes back], it usually returns within the first 2 years. After 5 years of diagnosis, rarely does the cancer recur after that. However, ER-positive disease can recur at a steady rate every year for the next 25 to 30 years. That is a major issue, with the long-term recurrence of ER-positive disease. That is a reason why we want to combine immunotherapy to endocrine therapy; we want long-term control.