Medical Information

CDK4/6 inhibitors in the metastatic setting have demonstrated clinical benefit in the hormone receptor–positive breast cancer population, leading to curiosity of its activity in early-stage patients and setting the stage for a handful of informative clinical trials: PALLAS (NCT02513394), PENELOPE-B (NCT01864746), and monarchE (NCT03155997).1

Patients with breast cancer who have multimodal involvement—especially with 4 or more axillary lymph nodes (ALNs)—have at least a 30% risk of relapse at 10 years; those with 1 to 3 ALNs plus another poor prognostic factor are linked with a greater than 20% risk.2

Despite successes observed with endocrine therapy for this patient population, there is an unmet need for identifying those who have primary endocrine resistance and preventing or delaying their recurrence with additional treatment. “We still see patients who have endocrine-resistant disease who have recurrences that can occur very early, even within the first 2 to 3 years of endocrine therapy,” Sara M. Tolaney, MD, MPH, explained in a presentation during the 39th Annual Miami Breast Cancer Conference®.

Adjuvant treatment with the CDK4/6 inhibitor abemaciclib (Verzenio) is the most recent therapeutic advancement for patients with early-stage, node-positive, hormone receptor–positive, HER2-negative breast cancer, and it is one that should be utilized specifically in patients who would have met eligibility for the phase 3 monarchE trial.

The study was the basis for the October 2021 FDA approval of abemaciclib for use in combination with endocrine therapy for this patient population at high risk of recurrence and a Ki-67 score of at least 20% and has led to a monumental shift in clinical practice, Tolaney said.

“Adjuvant abemaciclib clearly does reduce risk of recurrence for [patients with] high-risk hormone receptor–positive breast cancer and is quite a milestone in development for agents in the early-stage setting where, to date, we just had endocrine therapies, but now we have an oral targeted agent that can help our patients,” Tolaney said in her lecture. Tolaney is chief of the Division of Breast Oncology, associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Tolaney expanded on the limitations of prior studies leveraging CDK4/6 inhibitors in this population, such as those examining palbociclib in her presentation.

PALLAS

The open-label, phase 3 PALLAS trial randomized 5600 patients with stage II to III hormone receptor–positive, HER2-negative breast cancer 1:1 to receive either the CDK4/6 inhibitor palbociclib (Ibrance) orally at 125 mg daily on a 3-weeks-on/1-week-off schedule for 2 years plus endocrine therapy (n = 2883) or endocrine therapy alone (n = 2877), which consisted of an aromatase inhibitor or tamoxifen, with or without a luteinizing hormone-releasing hormone agonist.3 Patients must have had prior surgery plus or minus chemotherapy with radiation; they also needed to be within 12 months of their cancer diagnosis and within 6 months of starting adjuvant endocrine therapy.

Patients were stratified by stage (IIA vs IIB/III), chemotherapy (yes vs no), age (≤50 vs >50), and geographic region (North America vs Europe vs other). Most patients between the 2 arms had stage IIB (33.4%) or stage III (48.8%) disease and had previously received chemotherapy (82.6%). A total of 58.7% had high-clinical-risk disease, which was described as having at least 4 ALNs or 1 to 3 ALNs with either T3/T4 and/or histologic grade 3 disease.

At 4 years, results showed that the invasive disease-free survival (iDFS) rate, the study’s primary end point, was similar between palbociclib/endocrine therapy and endocrine therapy alone at 84.2% and 84.5%, respectively (HR, 0.96; 95% CI, 0.81-1.14; log-rank P =.65).4,5

“Much to many of our surprise, there was not a benefit from use of adjuvant palbociclib, with in fact no difference in iDFS,” Tolaney said. “This was very shocking based on the very strong benefits in the metastatic setting. Some questioned [that] this study was negative because it didn’t have [only] high-risk patients.”

PENELOPE-B

Palbociclib was evaluated also in the phase 3 PENELOPE-B trial, which enrolled 1250 patients with hormone receptor–positive, HER2-negative breast cancer who did not have pathologic complete response after neoadjuvant chemotherapy, and had a clinical and pathologic stage (CPS)-estrogen receptor status and tumor grade (EG) score of 3 or higher or at least 2 with lymph node metastases (ypN).6

Following neoadjuvant chemotherapy, surgery plus or minus radiation, patients were randomized 1:1 to receive oral palbociclib at 125 mg once daily on days 1 to 21 every 28 days for 13 cycles (n = 631) or placebo (n = 619) on the same schedule. All patients received endocrine therapy concomitantly. Stratification factors included nodal status (ypN 0-1 vs ypN2-3), age (≤ 50 vs > 50 years), Ki-67 (> 15% vs ≤ 15%), region (Asian vs non-Asian), and CPS-EG score (≥3 vs 2 and ypN+).

Again, no iDFS benefit was observed with palbociclib. At a median follow-up of 42.8 months, the 4-year iDFS rate was 73.0% with the addition of palbociclib and 72.4% with endocrine therapy alone (stratified HR, 0.93; 95% CI, 0.74-1.17; P = .525).

“There was one intriguing finding that emerged, which was there was some early separation of the curves, suggesting that at 2 years there seemed to be some trend toward benefit of palbociclib,” Tolaney said. “[However,] then you see these curves come back together at 4 years. [This was a purely exploratory finding, but] it made some wonder if maybe after discontinuation of palbociclib, you just see a delay in events but [no evidence] leading to cure in patients.”

monarchE

Following these results, data from the phase 3 monarchE trial with abemaciclib proved to be encouraging. Investigators enrolled 5637 patients with hormone receptor–positive, HER2-negative, high-risk, early-stage breast cancer with pre-/postmenopausal status and with or without prior neoadjuvant and/or adjuvant chemotherapy.7 Patients did not have metastatic disease and were at most 16 months from surgery to randomization.

The trial was split into 2 cohorts. Cohort 1 included those with high-risk disease based on clinical pathological features (≥4 ALNs or 1 to 3 ALNs and at least having grade 3 disease or a tumor size ≥ 5 cm). Cohort 2 included patients with high-risk disease based on Ki-67 status (1-3 ALNs, Ki-67 expression ≥ 20%, no grade 3 disease, and tumor size < 5 cm).

Patients were randomized 1:1 to receive abemaciclib at 150 mg twice daily plus endocrine therapy or endocrine therapy alone for an on-study treatment period of 2 years; the follow-up period for endocrine therapy was 3 to 8 years.

Patients were stratified by prior chemotherapy use, menopausal status, and region. Aside from the primary end point of iDFS, secondary outcome measures included iDFS in high–Ki-67 populations, distant relapse-free survival (DRFS), overall survival (OS), pharmacokinetics, and patient-reported outcomes.

The intention-to-treat (ITT) population comprised both cohort 1 and 2 populations. Approximately 60% of patients on study had 4 or more positive lymph nodes; the Ki-67 breakdown was less than 20% (34.2%), 20% or higher (44.3%), and unavailable (21.5%).

Data showed that the addition of abemaciclib led to a 30.4% reduction in the risk of invasive disease progression or death (HR, 0.696; 95% CI, 0.588-0.823; nominal P = .0001). The 2- and 3-year iDFS rates were 92.7% and 88.8% with abemaciclib vs 90.0% and 83.4% with endocrine therapy alone; the absolute difference in iDFS rates at 3 years was 5.4%.

Additionally, the benefit was seen across all patient subgroups, Tolaney noted, adding that a piecewise analysis was conducted to examine the effect of abemaciclib treatment over time.

“There was an increasing magnitude of benefit with increase in effect size from year 1 to year 2 again showing larger benefits with longer follow-up,” she said. The piecewise HR for iDFS beyond 2 years was 0.596 (95% CI, 0.397-0.855); for DRFS, this was 0.692 (95% CI, 0.448-1.032).

When specifically analyzing the Ki-67–high group in the ITT population, data showed that abemaciclib led to a 33.7% reduction in the risk of developing an iDFS event (HR, 0.663; 95% CI, 0.524-0.839; nominal P = .0006). The 2- and 3-year iDFS rates with abemaciclib were 91.9% and 86.8%, respectively; these rates were 87.9% and 80.8% with endocrine therapy alone, respectively.

In cohort 1, the 3-year iDFS rates were 86.1% with abemaciclib and 79.0% with endocrine therapy alone in Ki-67–high patients (n = 2003; HR, 0.626; 95% CI, 0.488-0.803). When examining the Ki-67–low subgroup (n = 1914), the 3-year iDFS rates were 91.7% and 87.2%, respectively (HR, 0.704; 95% CI, 0.506-0.979).

“When you look at outcomes in both low– and high–Ki-67 patients, you see that Ki-67 is not a predictive biomarker of benefit to abemaciclib because you’re seeing, again, benefit in both the low– and high–Ki-67 patients,” Tolaney said. “You see a larger absolute difference in the high–Ki-67 patients at about 7% with about a 4.5% difference in the low–Ki-67 patients. But what you see is that Ki-67 is clearly prognostic, with high Ki-67 having more recurrences compared with those patients who have low Ki-67.”

Furthermore, preliminary OS findings did not show a benefit to adding abemaciclib in the ITT population (HR, 1.091; 95% CI, 0.818-1.455) but a benefit was seen in the Ki-67 subgroup (HR, 0.767; 95% CI, 0.511-1.152).8 There was a comparable number of deaths in both arms at 3.4% with abemaciclib and 3.2% with endocrine therapy alone.

The safety profile with abemaciclib in monarchE demonstrated consistent findings with prior analyses. At a median duration of abemaciclib therapy at 23.7 months, incidence of venous thromboembolism (VTE) was higher with the CDK4/6 inhibitor at 2.5% vs 0.6% with endocrine therapy alone; interstitial lung disease rates were 3.2% and 1.3%, respectively.

Based on these data, the FDA approved abemaciclib in October 2021 for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early-stage breast cancer at high risk of recurrence and a Ki-67 score of at least 20%, as determined by an FDA-approved test.9 The agency also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to be used as a companion diagnosis.

However, Tolaney explained that the challenge in applying these data to clinical practice is that the 55% of patients on study who had at least 4 ALNs were Ki-67 low. “This is challenging because we know these patients are at high risk of recurrence and we know that there was benefit in both low– and high–Ki-67 patients with abemaciclib in monarchE,” she said. “The other challenge that we have is the low analytical validity of Ki-67 testing where there re data that have been put together by the international [Ki-67 BC] Working Group suggesting unacceptable analytical validity particularly within this range of 5% to 30%, which is where the 20% cutoff falls for selection of patients for abemaciclib based on the FDA criteria.”

Recommendation updates have been issued by the American Society of Clinical Oncology for selection of adjuvant chemotherapy and targeted therapy for patients with early-stage breast cancer (FIGURE).10

FIGURE. ASCO Recommendation Update on Adjuvant Chemotherapy and Targeted Therapy in Early-Stage Breast Cancer

Two years of abemaciclib (150 mg twice daily) plus endocrine therapy may be offered to patients with hormone receptor–positive, HER2-negative, node-positive, early-stage breast cancer with a high risk of recurrence and a Ki-67 score of ≥ 20% as determined by an FDA-approved test.Abemaciclib for 2 years plus endocrine therapy for at least 5 years may be offered to the broader intention-to-treat population of patients with resected hormone receptor–positive, HER2-negative, node-positive, early-stage breast cancer at high risk of recurrence, defined as having at least 4 positive ALNs or as having 1-3 ALNs and ≥ 1 of the following features:Histologic grade 3 diseaseTumor size ≥ 5 cmKi-67 index ≥ 20%Although exploratory analyses suggested similar hazard ratios in favor of abemaciclib regardless of Ki-67 status, there were relatively few Ki-67–low tumors in monarchE.When discussing treatment options with patients, the potential benefits (improved iDFS) should be weighed against the potential harms (treatment toxicity, financial cost).

ALN, axillary lymph node; ASCO, American Society of Clinical Oncology; iDFS, invasive disease-free survival.

To break it down, Tolaney recommends abemaciclib to patients who would have met the eligibility criteria for monarchE: “[such as] those patients with 4 or more positive nodes or [who] have 1 to 3 positive nodes and a tumor over 5 cm or is high grade.”

When weighing the risk factors of VTE with abemaciclib plus endocrine therapy, she also emphasized using the proper partners of endocrine therapy. “The risk is higher with use in combination with tamoxifen, with about 4% of patients in monarchE getting tamoxifen and abemaciclib experiencing a VTE,” she said. “In my general practice, I have been recommending abemaciclib more for use with aromatase inhibition and using it more cautiously with tamoxifen.”

Tackling Germline BRCA Mutations

A clinical scenario is how to potentially fit in CDK4/6 inhibition into treatment for patients with early-stage breast cancer who also harbor a germline BRCA mutation. Data from the phase 3 OlympiA study (NCT02032823) showed that 1 year of adjuvant treatment with the PARP inhibitor olaparib (Lynparza) led to a 42% reduction in the risk of invasive disease or death compared with placebo in patients with high-risk, HER2-negative early-stage breast cancer (stratified HR, 0.58; 95% CI, 0.41-0.82; P < .001).11 In this population, 18% of patients had hormone receptor–positive disease.

“We don’t have data from monarchE to look at outcome differences for germline BRCA vs wild-type patients in that study, but we do have some suggestions in the metastatic setting that patients who have germline BRCA mutations tend to have less benefit from CDK4/6 inhibition than patients who have wild-type disease,” Tolaney said, citing data from an analysis presented at the 2021 San Antonio Breast Cancer Symposium.12

Therefore, olaparib should be recommended to most patients with germline BRCA-mutant disease vs abemaciclib, unless they have particularly high-risk features where sequential therapy may be considered. However, Tolaney concluded that data on that approach are not currently available.

References：

1 Tolaney SM. Advances in the treatment of HR+ early-stage breast cancer: identifying patients for targeted therapy. Presented at: 39th Annual Miami Breast Cancer Conference®; March 3-6, 2022; Miami Beach, FL.

2 Pagani O, Francis PA, Fleming GF, et al. Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: results from TEXT and SOFT. J Clin Oncol. 2020;38(12):1293-1303. doi:10.1200/JCO.18.01967

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 Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib in HR+/HER2- early breast cancer: final results from 5,760 patients in the randomized phase III PALLAS trial. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-07. Accessed March 4, 2022. https://bit.ly/3ttbWy5

5 Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi:10.1200/JCO.21.02554

6 Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—the Penelope-B trial. J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639

7 Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015

8 Harbeck N, Rastogi P, Shahir A, et al. Letter to the editor for ‘Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study’. Ann Oncol. 2022;33(2):227-228. doi:10.1016/j.annonc.2021.10.015

9 FDA approves abemaciclib with endocrine therapy for early breast cancer. FDA. Updated October 13, 2021. Accessed March 3, 2022. https://bit.ly/3Kj0KLi

10 Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(6):685-693. doi:10.1200/JCO.20.02510

11 Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Eng J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

12 Safonov A, Bandlamudi C, Tallón de Lara P, et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS4-08. Accessed March 4, 2022. https://bit.ly/3pzTH8P

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