Adjuvant CDK4/6 Inhibition Shows Potential in Early HR+/HER2- Breast Cancer, But More Data Are Needed

CDK4/6 inhibitors plus aromatase inhibitors have shown benefit as frontline treatment for patients with hormone receptor–positive, HER2-negative advanced breast cancer, but more data are needed to determine their role as adjuvant therapy before they are adopted into standard practice for patients with early-stage disease.

Hope S. Rugo, MD

All 3 FDA approved CDK4/6 inhibitors––palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)––plus aromatase inhibitors (AIs) have shown benefit as frontline treatment for patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer, but more data are needed to determine their role as adjuvant therapy before they are adopted into standard practice for patients with early-stage disease, explained Hope S. Rugo, MD, in a virtual presentation during the 38th Annual Miami Breast Cancer Conference®, an event hosted by Physician’s Education Resource®, LCC.

“What’s really remarkable about [the] data [with CDK4/6 inhibitors in the metastatic setting] is not only the benefits and the overall survival differences we’ve seen, but also the tolerability of these agents, which made it critical for us to learn how to move these agents into the early-stage setting,” said Rugo, a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Despite the use of adjuvant endocrine therapy, the risk of recurrence remains high in patients with HR-positive early breast cancer. Findings from the phase 3 GEICAM 9906 and GEICAM 2003-10 trials showed that patients with at least 4 positive nodes, 1 to 3 positive nodes and grade 3 histology, or 1 to 3 positive nodes and T3 disease had the highest risk of early recurrence with adjuvant chemotherapy and an AI, suggesting that these were the patients who stood to benefit the most from adjuvant CDK4/6 inhibition.1

“This led to important eligibility criteria in the positive, adjuvant trial MonarchE,” said Rugo.

In the phase 3 MonarchE trial, 5637 patients with HR-positive, HER2-negative breast cancer and at least 4 positive axillary lymph nodes (ALN) or 1 to 3 ALN and a tumor of at least 5 cm, grade 3 histology, or centrally tested Ki-67 of at least 20% were randomized to 150 mg of abemaciclib twice daily for up to 2 years plus 5 to 10 years of endocrine therapy as clinically indicated or endocrine therapy alone.2

Patients were divided such that those with at least 4 ALN or 1 to 3 ALN and grade 3 histology or a tumor of at least 5 cm were included in cohort 1 and those with 1 to 3 ALN and centrally tested Ki-67 of at least 20% were included in cohort 2.

In the phase 3 PALLAS trial, 5760 patients with stage II to III HR-positive, HER2-negative breast cancer were randomized to 125 mg of palbociclib daily, 3-weeks-on/1-week-off for 2 years plus endocrine therapy or endocrine therapy alone.3

Invasive disease-free survival (iDFS) served as the primary end point in both trials. The median follow-up was longer in the PALLAS trial, at 23.7 months vs 19.2 months in the MonarchE trial.

Of note, patients with stage II to III disease were enrolled in the PALLAS trial, whereas additional eligibility criteria were required for enrollment on MonarchE, said Rugo. As such, more patients in MonarchE received chemotherapy (95%) vs in PALLAS (82%-83%) and had N2 to N3 disease (59%-60% vs 38%, respectively). Similarly, a higher percentage of patients in MonarchE had grade 3 disease (38%-39%) vs in PALLAS (27%-29%).

Results from MonarchE demonstrated a 2-year iDFS rate of 92.3% with abemaciclib vs 89.3% with endocrine therapy (HR, 0.713; 95% CI, 0.583-0.871; P = .0009). Moreover, no statistically significant differences in iDFS benefit were reported between the 2 arms in the prespecified subgroup analysis, indicating consistent benefit with abemaciclib across all prespecified subgroups, said Rugo.

The 2-year distant recurrence-free survival (DRFS) rate was 93.8% with abemaciclib vs 90.8% with endocrine therapy alone (HR, 0.687; 95% CI, 0.551-0.858; P = .0009).

Additional data from MonarchE presented at the 2020 San Antonio Breast Cancer Symposium illustrated the prognostic value of Ki-67. In cohort 1––patients in whom Ki-67 was not an eligibility criterion––those with high Ki-67 experienced a marked improvement in 2-year iDFS with abemaciclib vs endocrine therapy alone, at 91.3% vs 86.1%, respectively. In patients with low Ki-67, the 2-year iDFS rates were 94.7% and 92.0%, respectively.4

“We kind of passed off on Ki-67, but [these data show that] if you have the same people doing your Ki-67 [testing] centrally, Ki-67 has an important prognostic impact and appears to define a group that has poorly endocrine responsive–disease that can be remarkably improved with the addition of the CDK4/6 inhibitor abemaciclib,” said Rugo.

In terms of tolerability, the primary treatment-emergent adverse effects (AEs) with abemaciclib were low-grade diarrhea and neutropenia, said Rugo. Of note, venous thromboembolic disease, including pulmonary embolism, was reported in 2.3% and 0.9% of patients who received abemaciclib, respectively, vs 0.5% and 0.1% of patients who received endocrine therapy alone, respectively.

Interstitial lung disease (ILD) and febrile neutropenia were also “moderately increased” in patients who received abemaciclib, said Rugo, who added that ILD was “primarily low grade and not the kind of ILD we’ve seen with antibody-drug conjugates.”

In terms of treatment discontinuation, only 17.2% of patients discontinued abemaciclib because of AEs, which is “markedly different from what we saw in PALLAS,” Rugo added.

The primary reason for discontinuation was diarrhea (5.1%); however, the majority of patients discontinued treatment within the first 5 months of treatment, which with dose holds and reductions and diet changes can increase the tolerability of the drug, said Rugo.

“Abemaciclib improved iDFS and reduced the risk of distant recurrence in patients with high-risk HR-positive, HER2-negative early breast cancer, but we need longer follow-up to establish a change in the standard of care,” said Rugo. “I would consider using abemaciclib in clinical practice only in patients with very high-risk disease––4 or more positive nodes––based on these encouraging data for a group of patients we know have a high risk of recurrence,” said Rugo.

Results from PALLAS showed no difference in 3-year iDFS with the addition of palbociclib, at 88.2% vs 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; P = .51). No difference in DRFS was reported either, at 89.3% with palbociclib vs 90.7% with endocrine therapy alone (HR, 1.00; 95% CI, 0.79-1.27; P = .9997).

“Based on this, the futility boundary was crossed and the IDMC [Independent Data Monitoring Committee] recommended stopping palbociclib and unblinding the patients in [the palbociclib arm],” said Rugo.

Notably, 42.2% of patients discontinued palbociclib prematurely; 64.2% of discontinuations were attributed to AEs. No significant difference in discontinuation of endocrine therapy was reported between the 2 arms.

“PALLAS [enrolled] lower-risk patients and had a high discontinuation rate. To quote George Sledge, [MD, of Stanford University] from ESMO 2020, ‘it is a certainty that one cannot benefit from a drug one does not take’,” said Rugo.

The phase 3 PENELOPE-B study also evaluated adjuvant CDK4/6 inhibition with palbociclib. The trial was much smaller than MonarchE and PALLAS, enrolling 1250 patients with HR-positive, HER2-negative breast cancer. Eligible patients did not have a pathologic complete response to neoadjuvant chemotherapy and had a CPS-EG score of at least 3 or at least 2 with positive nodes.

Patients were randomized to 125 mg of palbociclib daily, 3-weeks-on/1-week-off for 13 cycles or placebo.

“Most patients at surgery had a T2 or greater tumor, a quarter of the patients had Ki-67 of greater than 15%, and a remarkably low number of patients received ovarian ablation,” said Rugo.

At a median follow-up of 42.8 months, no difference in iDFS was reported between arms (HR, 0.93; 95% CI, 0.74-1.17; P = .525). The 2-year iDFS rate was 88.3% with palbociclib vs 84.0% with placebo. The 4-year iDFS rates were 73.0% and 72.4%, respectively.5

“This has brought up the question of whether the short exposure in a disease that has a long natural history is not enough for these patients with high-risk breast cancer and whether we’re going to see a narrowing of the benefit with abemaciclib over time,” said Rugo.

In terms of tolerability, some patients required dose reductions with palbociclib, but a much lower rate of treatment discontinuation was observed in PENELOPE-B compared with PALLAS, added Rugo.

“We await with great excitement the data from the NATALEE trial with 3 years of exposure [to ribociclib],” concluded Rugo.


  1. Rugo H. Hormone-receptor positive high-risk, early-stage breast cancer: are CDK4/6 inhibitors the standard of care? Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; Virtual.
  2. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high risk, early breast cancer (monarchE). Ann Oncol. 2020;31(4). Abstract: LBA5_PR. doi:10.1016/j.annonc.2020.08.2238
  3. Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212-222. doi:10.1016/S1470-2045(20)30642-2
  4. Harbeck N, Johnston S, Fasching P, et al. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE. Can Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-PD2-01
  5. Loibl S, Marmé F, Martin M, et al. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancer and with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B. Can Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS1-02
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