CDK4/6 Inhibitors Show Hints of Activity in Early-Stage HR+/HER2- Breast Cancer

CDK4/6 inhibitors in combination with endocrine therapy have transformed the treatment of patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, said Halle Moore, MD, who added that, although not yet approved, some data indicate the treatment strategy can provide a survival advantage to patients in the adjuvant setting.

“The addition of CDK4/6 inhibitors to endocrine treatment improved progression-free survival [PFS] in a number of settings,” said Moore, director of Breast Medical Oncology in the Department of Hematology and Oncology and co-director of the Cleveland Clinic Comprehensive Breast Cancer Program at the Taussig Cancer Institute of Cleveland Clinic, in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

“Increasingly, [this strategy] is being shown to improve overall survival [OS] in HR-positive breast cancer. [Although] the toxicity profiles differ between the medications and we are still awaiting the survival outcomes for early-stage disease, the data with abemaciclib [Verzenio] are very encouraging [in the early-stage setting],” added Moore, who is also an associate professor of medicine at the Cleveland Clinic Lerner College of Medicine.

The virtual meeting covered systemic therapies in HER2-positive and triple-negative breast cancer, how standards of care are evolving in HR-positive breast cancer, and recent advances with short-course radiotherapy in the paradigm.

In the interview, Moore, who co-chaired the event, discussed the data that support the use of CDK4/6 inhibitors plus endocrine therapy in HR-positive, HER2-negative breast cancer, how to select between available CDK4/6 inhibitors in the metastatic setting, and the current state of this treatment approach for patients with early-stage disease.

OncLive^®: How have the data from the MONALEESA-3 (NCT02422615) and MONALEESA-7 (NCT02278120) trials supported the integration of ribociclib (Kisqali) into the treatment of patients with HR-positive, HER2-negative breast cancer?

Moore: The MONALEESA trials looked at the addition of ribociclib to endocrine treatment for advanced breast cancer. The MONALEESA-3 trial [evaluated ribociclib] in combination with fulvestrant [Faslodex] vs fulvestrant alone in postmenopausal women who had HR-positive, HER2-negative advanced breast cancer. The participants in that trial could have had up to 1 prior hormonal treatment for metastatic disease, but no prior chemotherapy for their advanced breast cancer.

That study, as have other studies looking at CDK4/6 inhibitors in combination with fulvestrant, showed a significant improvement in PFS with the addition of ribociclib to fulvestrant. This study also showed an OS improvement in a previous publication and then in a recent update during the 2021 ASCO Annual Meeting. [The data showed] a persistent advantage in OS in this setting with the addition of ribociclib to fulvestrant.

MONALEESA-7 was a trial that specifically looked at premenopausal women. In that study, participants received goserelin for ovarian function suppression with tamoxifen or an aromatase inhibitor [AI] with or without ribociclib. [The results showed] a PFS and OS advantage with the inclusion of ribociclib.

Now, we need to be careful with the use of tamoxifen in combination with ribociclib because both drugs can prolong QT intervals, which can increase the risk for cardiac arrhythmias. In general, when we are using ribociclib for the treatment of premenopausal women, we would prefer to use ovarian ablation or an AI over tamoxifen.

How do the findings from the PALOMA-3 trial (NCT01942135) with palbociclib (Ibrance) compare with those observed with ribociclib?

The PALOMA-3 trial was also updated at the 2021 ASCO Annual Meeting. This trial looked at the addition of palbociclib to fulvestrant in the treatment of pre or postmenopausal women with HR-positive, HER2-negative advanced breast cancer. Participants in this trial had progression after endocrine therapy in the metastatic or adjuvant settings, which was different from some of the other trials in this setting. Participants were allowed to have had up to 1 line of chemotherapy for their metastatic disease.

The study also previously showed an improvement in PFS. At earlier follow-up, there was a nonsignificant improvement in OS with a hazard ratio of about 0.81. At the 2021 ASCO Annual Meeting, [data with] a median follow-up of 73 months were presented. The hazard ratio remained similar but was found to be significant.

Interestingly, if we look specifically at patients who had not had prior chemotherapy, the hazard ratio for OS was about 0.72, which was very similar to what was observed in the studies using ribociclib. The outcomes appear to be similar and some of the differences seem to be accounted for by differences in the study populations.

What data support the use of abemaciclib in the early-stage setting for patients with HR-positive, HER2-negative breast cancer?

The monarchE study [NCT03155997] looked at the use of abemaciclib in early-stage breast cancer. This study [evaluated] women with high-risk HR-positive, HER2-negative breast cancer. High-risk was defined by N2 or N3 disease or any lymph node involvement, plus a T3 tumor, high-grade tumor, or a Ki67 score of at least 20%. In this population, the addition of 2 years of abemaciclib to standard endocrine treatment for breast cancer, in addition to surgery, standard chemotherapy, and radiation, improved invasive disease-free survival with a hazard ratio of about 0.75. That included an improvement in distant relapse-free survival with a hazard ratio of about 0.72.

These findings were significant and indicate that [abemaciclib] might be an important treatment for reducing recurrence risk in women with high-risk, estrogen receptor [ER]–positive disease, although we are awaiting a survival benefit. Notably, this treatment is not yet FDA approved in this setting.

How are you selecting between CDK4/6 inhibitors in this disease state?

In the early-stage setting, these drugs are not yet [FDA] approved; however, there are some pretty compelling data for the use of abemaciclib. The studies with palbociclib [in the adjuvant setting], which used 1 to 2 years of therapy, have not yet shown a significant benefit with the addition of palbociclib. If we are going to use these drugs in the adjuvant setting, abemaciclib is the only one that has the data to support that use.

In the metastatic setting, we look at adverse effect profiles since we don’t have strong data to say that one [CDK4/6 inhibitor] is superior to another; they have not been directly compared in this setting.

We know that abemaciclib can [cause] more gastrointestinal toxicities; we see a lot of diarrhea, as well as some nausea and vomiting. [However, abemaciclib confers] less myelosuppression [vs other CDK4/6 inhibitors]. For some patients, [myelosuppression] might be a bigger concern with ribociclib and palbociclib.

[The CDK4/6 inhibitors] have fairly similar toxicity profiles, although ribociclib can [cause] QT prolongation. [Ribociclib] might be avoided in patients on other medications that can [cause QT prolongation]. Ribociclib may be more cost-effective; we have found that pricing is often better.

These decisions can be individualized. We may also look at which clinical trial [population] was most similar to the patient that we’re treating at that time to try to use the [CDK4/6 inhibitor] that was best studied in that setting.

What research is being done with CDK4/6 inhibitors to further expand their utility in practice?

Right now, a number of clinical trials are focusing on new combinations looking at some of the novel endocrine agents, such as the oral selective ER downregulators, in combination with CDK4/6 inhibitors. We have a trial open at [Cleveland Clinic] looking at that right now.

We recently finished participating in a trial looking at a novel selective ER modulator in combination with a CDK4/6 inhibitor for ESR1-mutant ER-positive metastatic breast cancer. Looking at novel endocrine backbone combinations is definitely an area where the field is moving right now.

Also, the CDK4/6 inhibitors are being studied in other settings, such as in HER2-positive disease and in combination with chemotherapy.

Are there nuances to utilizing PI3K inhibitors in HR-positive breast cancer?

Alpelisib [Piqray] is the [PI3K inhibitor] approved for the treatment of advanced breast cancer. It is approved [for patients] when a PIK3CA mutation is present on the tumor in combination with fulvestrant. That’s mainly where we have been using it.

[Alpelisib] does have some toxicities. It can increase blood sugar. Many patients will need to have pretty intensive management that may require metformin or other treatments for elevated blood sugars. [Treatment with alpelisib] requires a little extra monitoring, but we have seen improvements in PFS with this combination.

Ongoing studies are looking at [alpelisib] in combination with other endocrine treatments.

During the IPC webinar, Chirag S. Shah, MD, of Cleveland Clinic, discussed the evolving approach to radiation therapy in breast cancer. Could you highlight some of the key points that were made during the presentation?

Dr. Shah spoke a lot about hypofractionation of radiation. [Put] simply, that is giving radiation in fewer fractions or few numbers of treatments. [Dr. Shah] also talked about short-course radiotherapy. He shared with us that the outcomes with a shorter course of radiation therapy in select patients with early-stage breast cancer can be similar to those with more traditional, 5-to-7-week courses of radiation.

He talked about a variety of different schedules, including shortening [the radiation course] to 3 weeks of treatment and a newer approach where treatments are given once a week for 5 weeks. That [comprises] 5 treatments over 5 weeks, which can be much more convenient for a patient who has to travel for their treatment or has other transportation issues.

His main takeaway was that these shorter course [approaches to] radiation are becoming a standard of care for patients in the breast-conservation and post-mastectomy settings.