CDK4/6 Inhibition for Adjuvant Treatment of Early Stage Breast Cancer

Jeff A. Engle, PharmD, MS
Hematology/Oncology Clinical Pharmacist
M Health Fairview University of Minnesota Medical Center
Minneapolis, MN

Breast cancer is the most commonly diagnosed cancer in the United States accounting for an estimated 281,550 new diagnoses in 2021.¹ The good news is that greater than 90% of those diagnosed with breast cancer have early-stage disease where long-term remissions are possible.² Of those diagnosed, approximately 70% have cancers that are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) in which standard treatment depends on risk of recurrence and can include surgery, radiation, chemotherapy, and endocrine therapy.^3,4 Despite excellent disease free survival rates with adjuvant endocrine therapy, approximately 20% of patients may experience recurrence within 10 years of starting therapy, and the risk is higher in patients with high risk features.⁵ This highlights the importance of identifying patients at highest risk of recurrence and optimizing adjuvant therapy to minimize that risk.

Cyclin-dependent kinases 4 and 6 (CDK4/6) have been shown to be key promotors of tumor growth through the estrogen receptor pathway in HR+ breast cancer.6 Small molecule inhibition of CDK4/6 plays a significant role in decreasing breast cancer growth and prolonging survival in the treatment of advanced and metastatic HR+, HER2- breast cancer.^7-11 Three CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib) have been approved for the treatment of metastatic breast cancer based on improvements in progression free survival in large, Phase 3 clinical trials. These agents are now NCCN guideline recommendations as standard of care for first, second, and subsequent lines of therapy either alone or in combination with endocrine therapy for metastatic breast cancer.^4,12 Investigators are now researching whether the incorporation of CDK4/6 inhibitors along with adjuvant endocrine therapy can prevent recurrence and increase disease free survival in patients with early stage breast cancer. A summary of ongoing clinical trials assessing the adjuvant use of CDK4/6 inhibitors are below.

MonarchE Trial
The MonarchE trial is an open-label, randomized, Phase 3 trial aimed to determine the efficacy and safety of the addition of abemaciclib to endocrine therapy for the adjuvant treatment of HR+, HER2- high-risk early breast cancer.¹³ The trial enrolled adult patients with HR+ and HER2- early breast cancer with high risk features defined as four or more positive pathologic axillary lymph nodes or one to three positive axillary lymph nodes and at least one of the following: tumor size ≥ 5 cm, histologic grade 3, or centrally assessed Ki-67 ≥ 20%. Patients were randomized (1:1) to receive either abemaciclib 150 mg twice daily continuously plus endocrine therapy or endocrine therapy alone. Abemaciclib was continued for a maximum of two years and endocrine therapy was continued for five to 10 years as clinically indicated. The primary endpoint was invasive disease-free survival (IDFS) and key secondary endpoints included overall survival (OS) and safety.

A total of 5,637 patients were enrolled with a median age of 51 years and the majority being female (99.4%) and postmenopausal (56.5%). Approximately 60% of patients met inclusion criteria of four or more positive lymph nodes and over 95% had received prior chemotherapy and/or radiation therapy. Aromatase inhibitors were used as initial endocrine therapy in 68.3% of patients while 31.4% of patients received tamoxifen. There was a statistically significant difference in IDFS with events occurring in 136 (4.8%) of patients receiving abemaciclib plus endocrine therapy versus 187 (6.6%) of patients receiving endocrine therapy alone (HR 0.75, 95% CI 0.6-0.93; p=0.01). The two-year IDFS rates were 92.2% in the abemaciclib group versus 88.7% in the control group. Overall survival data were immature at the time of data cutoff. Patients receiving abemeciclib commonly developed diarrhea, fatigue, and neutropenia while patients in the control group commonly developed arthralgia, hot flush, and fatigue. Rates of arthralgia and hot flush were significantly reduced in the abemaciclib arm compared to endocrine therapy alone. Interstitial lung disease, venous thromboembolic events, and febrile neutropenia occurred in 2.7%, 2.3%, and 0.3% of patients receiving abemaciclib, respectively. Abemeciclib dose interruptions and reductions occurred in 56.9% and 41.2%, respectively while 16.6% of patients had to discontinue abemaciclib due to adverse effects. The authors concluded that the addition of abemaciclib to endocrine therapy as adjuvant treatment of early stage breast cancer significantly improves IDFS and should be considered for patients meeting the criteria for high risk of recurrence. The trial is still ongoing with future analyses planned.

PALLAS Trial
PALLAS is an open-label, randomized, Phase 3 trial aimed to determine the efficacy and safety of the addition of palbociclib to endocrine therapy for the adjuvant treatment of early breast cancer.¹⁴ Patients were enrolled within 12 months of being diagnosed with histologically confirmed HR+, HER2- stage II or III invasive breast cancer and within 6 months of initiating adjuvant endocrine therapy. Study participants were randomly assigned (1:1) to receive either palbociclib 125 mg once daily on days 1-21 followed by 7 days off every 28 days for a maximum of two years, plus endocrine therapy or endocrine therapy alone. The choice of endocrine therapy was based on provider and patient choice and consisted of tamoxifen or an aromatase inhibitor for a duration of at least five years. The primary outcome of the study was IDFS with key secondary outcomes being OS and safety.

A total of 5,760 patients with a median age of 52 years, predominantly female (99.4%), and premenopausal (53.5%) were enrolled in the study. Aromatase inhibitors and tamoxifen were used in 67.2% and 32.5% of patients, respectively. One hundred seventy patients in the palbociclib group and 181 patients in the endocrine therapy alone group experienced an IDFS event which did not differ significantly between the two groups. The 3-year IDFS rate was 88.2% in the palbociclib group and 88.5% in the endocrine therapy alone group (HR 0.93, 95% CI 0.76-1.15; p=0.51). Overall survival data were immature at the time of data cutoff. The patients receiving palbociclib plus endocrine therapy most commonly experienced neutropenia, leukopenia, fatigue, and arthralgia while patients receiving endocrine alone most commonly experienced arthralgia, hot flush, and fatigue. Early discontinuation of palbociclib occurred in 42.2% of trials participants with 27.1% due to adverse effects. The authors concluded that the addition of two years of palbociclib with standard endocrine therapy did not improve IDFS versus endocrine therapy alone and couldn’t be recommended for adjuvant treatment of stage II-III, HR+, HER2- breast cancer.

Penelope-B Trial
The Penelope-B trial is a randomized, double-blind, placebo controlled, Phase 3 trial studying the use of palbociclib in combination with endocrine therapy for patients with high risk residual disease following neoadjuvant chemotherapy.15 Patients were enrolled if they had HR+, HER2- early breast cancer who had residual disease in either the breast or the lymph nodes following neoadjuvant chemotherapy and was considered high risk based on a clinical pathological staging-estrogen receptor grading (CPS-EG) score of ≥ 3 or 2 with ypN+. CPS-EG is a validated prognostic staging system for breast cancer patients with residual disease following neoadjuvant chemotherapy.16-17 Patients were randomized to receive either palbociclib 125 mg daily on days 1-21 followed by seven days off every 28 days for a maximum of 13 cycles plus endocrine therapy or placebo plus endocrine therapy. Endocrine therapy was continued for at least five years. The primary endpoint of the study was IDFS with key secondary endpoints including OS and safety.

A total of 1,250 patients were enrolled in the study with a median age of 49 years and many patients had a CPS-EG score of ≥ 3 (59.4%) and a Ki-57 ≤ 15% (74.5%). At the time of analysis, there were 152 (24.1%) and 156 (25.2%) IDFS events in the palbociclib and placebo arms, respectively, which didn’t demonstrate a statistically significant difference (HR 0.93, 95% CI 0.74-1.17, p=0.525). Overall survival didn’t differ significantly between the two groups (HR 0.87, 95% CI 0.61-1.23, p=0.42) with the three-year OS being 93.6% with palbociclib and 90.5% with placebo. The most common adverse effects in the palbociclib group were leukopenia, neutropenia, and fatigue while leukopenia, fatigue, hot flush, and arthralgia were most common in the placebo group. In the palbociclib arm, 47.6% of patients required a dose reduction and 17.5% of patients discontinued early with only 3% discontinuing due to adverse effects.

The authors concluded there was no benefit of the addition of palbociclib for one year to endocrine therapy in patients with residual disease following neoadjuvant chemotherapy based on the IDFS.

Discussion
There is an unmet need for improvements to adjuvant-based therapies based on high rates of recurrence for patients initially treated for HR+, HER- early breast cancer. The CDK4/6 inhibitors have proven highly efficacious and safe in the treatment of advanced breast cancer, so it’s reasonable to consider their incorporation into earlier lines of therapy. The conflicting results observed in MonarchE, PALLAS, and Penelope-B make it difficult to determine whether CDK4/6 inhibition combined with adjuvant endocrine therapy provides substantial benefit to incorporate into clinical practice. Differences in the trial design and the CDK4/6 medications themselves may help to explain the differing results.

The PALLAS trial included all patients with stage II-III disease whereas MonarchE utilized lymph node status as well as tumor size, grade, and Ki-67 as a marker of high risk of recurrence and Penelope-B utilized the CPS-EG staging system specific to patients who received eoadjuvant chemotherapy with higher values indicating higher risk of recurrence. This led to more patients in the palbociclib arm of the PALLAS trial having stage II disease (51.1% vs. 25.4%) and node negative disease (12.7% vs. 0.2%) compared to the abemaciclib arm in MonarchE. Patients in MonarchE with stage IIIC disease derived a significant benefit with the addition of abemaciclib though these subgroup analyses need to be interpreted cautiously due to sample size. In Penelope-B, 5.1% of patients in the palbociclib arm had node negative disease while specific staging data was not reported. Another difference in the patient population among trials was that patients in MonarchE had higher Ki-67 proliferation rates compared to Penelope-B (not reported in PALLAS) though the subgroup analysis of Penelope-B didn’t suggest a difference in patients with high versus low Ki-67 tumors and Ki-67 was not reported in the subgroup analyses for MonarchE.

Differences observed among the clinical trials in early discontinuation and duration of treatment may also contribute to the differing results. Observed safety profile varied among agents yet no new safety concerns were observed. Notably, diarrhea with abemeciclib,

myelosuppression with palbociclib, and the trials had varying rates of discontinuation in intervention arms due to toxicity. The PALLAS study had 42.2% of patients discontinue palbociclib early with 27.1% of the patients discontinuing due to adverse effects. MonarchE and Penelope-B had discontinuation rates due to adverse effects of 16.6% and 3%, respectively. The median follow-up time also differed at the time of reporting. Median follow-up duration was 15.5 months for MonarchE, 23.7 months for PALLAS, and 42.8 months for Penelope-B. Therefore, differences in the time on therapy and the amount of follow up at the time of reporting may contributing to the differing results.

Although these medications are in the same therapeutic class, the specific agents differ in pharmacology and administration. Abemaciclib is dosed continuously and a preclinical study found continuous CDK4/6 inhibition with abemaciclib led to sustained cell-cycle disruption and apoptosis whereas short-term inhibition led to cell-cycle rebound.¹⁸ Abemaciclib has also shown a 14 times higher affinity for CDK4, which is more highly expressed in breast tumor, compared to CDK6 while palbociclib was found to be equipotent against CDK4 and 6.^19,20 In the absence of head-to-head clinical trials, it’s unclear if these differences in pharmacology and administration translate to a difference in clinical outcomes.

The use of CDK4/6 inhibitors in the adjuvant treatment of early stage breast cancer has yet to become standard of care based on the results of these trials. The differing results among these clinical trials may be due to study design, drug pharmacology, or some other factor. Longer follow up on previous trials, and the ongoing NATALEE trial (NCT03701334)²¹ which looks at the use of three years of ribociclib with endocrine therapy in HR+, HER2- early breast cancer may shed additional light on the benefit of CDK4/6 inhibition in this patient population.

Disclosure: JAE is on the speaker bureau for Eli Lilly and Company.

REFERENCES

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33
2. Cardoso F, Spence D, Mertz S, et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). Breast. 2018;39:131-138
3. Howlander N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014 Apr 28;106(5):dju055
4. National Comprehensive Cancer Network. Breast Cancer (Version 4.2021). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 15, 2021
5. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level metaanalysis of the randomised trials. Lancet. 2015 Oct 3;386(10001):1341-1352
6. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77-R77
7. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR1/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884
8. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646
9. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925-36
10. Turner NC, Slamon, DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926-36
11. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307-16
12. Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020 Dec;31(12):1623-49
13. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, nodepositive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020 Dec 1;38(34):3987-98
14. 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 Feb;22(2):212-22
15. Loibl S, Marme 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 May 10;39(14):1518-30
16. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:1956-62
17. Marme F, Lederer B, Blohmer JU, et al. Utility of the CPS1EG staging systemin hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with neoadjuvant chemotherapy. Eur J Cancer. 2016;53:65-74
18. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37
19. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017 Sep 1; 23(17): 5218–24 20. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38
20. A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (NATALEE). Accessed June 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03701334