Advances in the Evolving Treatment Landscape for HR+ Breast Cancer: Highlights From SABCS 2024

Breast Cancer Treatment Landscape

The annual San Antonio Breast Cancer Symposium (SABCS) is a much-anticipated meeting in which the latest advances in breast cancer during the previous year are discussed. Here, I touch on some key clinical data on CDK4/6i presented at SABCS 2024.

The treatment landscape of breast cancer is constantly evolving. The use of CDK4/6i in the metastatic setting dates back to the series of PALOMA trials, whose results were published beginning in early 2015, giving rise to the approval of palbociclib plus fulvestrant for HR-positive/HER2-negative ABC following progression on ET and in combination with an AI as initial ET for metastatic disease. Since then, 2 additional CDK4/6i—abemaciclib and ribociclib—have also been approved in combination with an AI as initial treatment or fulvestrant as initial treatment or following progression on ET in the metastatic setting. Abemaciclib and ribociclib have also been approved for use in combination with an AI and/or ET as adjuvant therapy for patients with HR-positive/HER2-negative early breast cancer at high risk of recurrence.

Oral selective estrogen receptor degraders (SERDs) have been studied in both the metastatic and adjuvant settings and continue to be assessed for use in the treatment of breast cancer. Fulvestrant is currently indicated in (1) HR-positive/HER2-negative ABC in postmenopausal women not previously treated with ET, (2) HR-positive ABC in postmenopausal women after progression on ET, (3) HR-positive/HER2-negative ABC or MBC in postmenopausal women in combination with ribociclib, as initial endocrine-based therapy or following progression on ET, and (4) HR-positive/HER2-negative ABC or MBC in combination with palbociclib or abemaciclib in women with disease progression after ET. However, the efficacy of fulvestrant may be more limited in patients with ESR1 mutation, which is a common cause of acquired ET resistance, and this finding prompted additional research into oral SERD development. In 2023, elacestrant was approved as monotherapy in postmenopausal women or adult men with estrogen receptor–positive/HER2-negative ABC or MBC and ESR1 mutations after progression on ≥1 previous line of ET.

EMBER-3

Now, researchers are exploring potential treatment approaches by combining CDK4/6i with novel agents for patients who progress on AIs in the metastatic setting. The phase III EMBER-3 trial explored the efficacy and safety of the oral SERD imlunestrant with or without the CDK4/6i abemaciclib vs SoC therapy with fulvestrant or exemestane in patients with ER-positive/HER2-negative MBC after progression on AI with or without CDK4/6i (N = 874). In this study, 874 patients with estrogen receptor–positive/HER2-negative MBC were randomized to receive imlunestrant as monotherapy or in combination with abemaciclib or SoC therapy. The primary endpoints were PFS with imlunestrant vs SoC therapy among all patients, PFS with imlunestrant vs SoC therapy among patients with an ESR1 mutation and PFS with imlunestrant plus abemaciclib vs imlunestrant alone among all patients. Patients were stratified by prior CDK4/6i treatment (yes vs no), visceral metastasis (present vs absent), and geographic region (East Asia vs North America vs Western Europe vs other).

The most frequently reported adverse events (AEs) with single-agent imlunestrant were fatigue (22.6% vs 13.0% in the SoC therapy group), diarrhea (21% vs 12%), and nausea (17% vs 13%), with the majority being grade 1 AEs. When these AEs are compared with those associated with fulvestrant monotherapy, an increased incidence of gastrointestinal AEs were reported with imlunestrant because of oral administration (vs intramuscular injection with fulvestrant). However, 72% of patients receiving intramuscular fulvestrant reported injection-site reaction, which does not occur with oral therapies. In both the imlunestrant and SoC therapy arms, the number of patients who experienced grade 3 AEs such as anemia and neutropenia was minimal (both approximately 2%). Unfortunately, 1 patient in the imlunestrant group died from right ventricular heart failure thought to be related to treatment.

AEs leading to dose interruptions were reported in 10.4% of patients receiving imlunestrant vs 0.6% receiving SoC therapy. Of interest, in my clinical experience, patients who are receiving SoC therapy tend to require treatment holds because of arthralgias, but in EMBER-3, arthralgia was reported in fewer than 1% of patients. Permanent discontinuation was reported in 4.3% of patients receiving imlunestrant and in 1.2% of patients receiving SoC therapy.

Among patients receiving both imlunestrant and abemaciclib (combination arm), the most common AEs were diarrhea (86%), nausea (49%), neutropenia (48%), and anemia (44%). The safety profile reported with imlunestrant and abemaciclib was consistent with the known AE profile of abemaciclib, with no new or unexpected AEs. Dose interruptions of either imlunestrant or abemaciclib or both because of AEs were reported in 55% of patients, whereas AEs led to dose reductions in 39% of patients and permanent discontinuation in 6% of patients.

This study revealed a 38% risk reduction in disease progression or death with imlunestrant vs SoC therapy among patients with an ESR1 mutation, with an mPFS of 5.5 months in the imlunestrant arm vs 3.8 months in the SoC therapy arm (P <.001). In the ITT population, the mPFS was 5.6 months with imlunestrant vs 5.5 months with SoC therapy (P <.12). The mPFS with imlunestrant plus abemaciclib was 11.1 months vs 5.5 months with imlunestrant alone in patients with ESR1 mutations (hazard ratio: 0.53) and 9.4 months vs 5.5 months, respectively, in the ITT population (hazard ratio: 0.57; P <.001). These data suggest a benefit with the combination treatment regardless of ESR1 mutation status. These results are reassuring, as healthcare professionals have experience managing AEs associated with abemaciclib, and the addition of imlunestrant adds further benefit without a greater AE burden.

PATINA

Another key study presented at SABCS 2024 was the phase III PATINA trial, which assessed the addition of the CDK4/6i palbociclib to SoC ET plus trastuzumab with or without pertuzumab in patients with HR-positive/HER2-positive MBC after 6-8 cycles of chemotherapy with HER2-targeted treatment. The results of this study were impressive, with an mPFS of 44 months in patients who received SoC therapy with the addition of palbociclib vs 29 months in patients who received standard HER2-targeted therapy plus ET alone.

“The cyclin D1–CDK4 axis is essential for initiation and maintenance of growth in HER2-positive disease. The same axis drives resistance to the HER2 pathway blockade. This combined CDK4/6 and HER2 inhibition has shown to be synergistic and have a profound antitumor activity in preclinical models,” stated Otto Metzger, MD, during his presentation at SABCS 2024. The fact that these therapies can be combined to allow prolonged PFS and good tolerability is encouraging.

Consistent with the known safety profile of palbociclib, the most common AE was grade 3 neutropenia, which occurred in 63% of patients. Additional AEs were fatigue (28% vs 13% with SoC), stomatitis (21% vs 1%), and diarrhea (37% vs 12%). However, this AE profile is easily managed with dose reductions and supportive care. For example, fatigue is dose dependent, so for patients who do not tolerate palbociclib 125 mg, a dose reduction to 100 mg will typically improve symptoms of fatigue to grade 1 or better.?

Breast cancer research is ever evolving, with novel therapies helping patients live longer. The results from PATINA and EMBER-3 emphasize the potential of novel treatment strategies with CDK4/6i and/or SERDs to delay disease progression for patients with breast cancer.

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Your Thoughts

What are your clinical experiences with managing patients with breast cancer during treatment with a CDK4/6i or SERD? Get involved in the discussion by posting a comment below.