CDK4/6 Inhibitors Could Fill Treatment Void for Patients with HR+/HER2- Early Breast Cancer

Joyce O'Shaughnessy, MD

CDK4/6 inhibitors have the potential to fill an unmet need in the treatment of patients with early-stage breast cancer, especially for those who develop primary resistance to endocrine therapy, according to a presentation by Joyce O'Shaughnessy, MD, at the 21st Annual International Congress on the Future of Breast Cancer^® East.¹

“We still have a lot of work to do in hormone receptor [HR]–positive/HER2-negative breast cancer,” O'Shaughnessy, the Celebrating Women Chair in breast cancer research, Baylor University Medical Center, Texas Oncology, US Oncology, said during the presentation. “We have the issue of primary endocrine therapy resistance. Some of those patients are chemotherapy sensitive, but some of them are [also] cross-resistant to chemotherapy. In the first couple years of being diagnosed with HR-positive/HER2-negative breast cancer, patients start recurring in spite of optimal single-agent endocrine therapy. In the first 2-3 years after a diagnosis of HR-positive/HER2-negative breast cancer, [there] are the highest annual odds of recurrence. Those are the patients with primary endocrine therapy–resistant disease that we do not have good tools for.”

The CDK4/6 inhibitors palbociclib (Ibrance) and abemaciclib (Verzenio) have previously displayed striking data in the metastatic setting, O'Shaughnessy explained. Thus, investigators made it a priority to evaluate the agents in the adjuvant setting. The agents are similar, though abemaciclib inhibits significantly more kinases compared with palbociclib and can also be given continuously because it is not as myelosuppressive, she noted.

Palbociclib Not the Answer for HR+/HER2- Early Breast Cancer

The phase 3 PALLAS trial (NCT02513394) compared the efficacy of palbociclib plus adjuvant endocrine treatment with that of endocrine treatment alone among patients with stage II-III HR-positive/HER2-negative breast cancer. Eligible patients underwent prior surgery, with or without chemotherapy or radiotherapy, were within 12 months of their diagnosis, and were within 6 months of starting adjuvant endocrine treatment. Palbociclib was administered at a dose of 125 mg daily for 3 weeks on and 1 week off, plus standard endocrine therapy. Patients in the control group received standard endocrine therapy alone. The primary end point was invasive disease-free survival (iDFS).²

At a median follow-up of 31 months, no significant difference was observed in terms of 4-year iDFS. The 4-year iDFS was 84.2% and 84.5% in the combination and monotherapy arms, respectively (HR, 0.96; 95% CI, 0.81-1.14; P = .65).

In the phase 3 PENELOPE-B trial (NCT01864746) patients with HR-positive/HER2-negative breast cancer with residual disease received palbociclib plus endocrine therapy or placebo plus endocrine therapy following neoadjuvant chemotherapy and surgery. Similar to PALLAS, at a median follow-up of 42.8 months, no significant difference in iDFS was reported between the 2 arms (HR, 0.93; 95% CI, 0.74-1.17; P = .525).³

“The curves have come together at 4 years,” O'Shaughnessy said. “There was this intriguing split in the curve early on, but it came back together. This raises the question, in a high-risk population, of whether a longer duration of therapy might have benefitted these patients.”

Abemaciclib Shows Greater Promise

In the phase 3 monarchE trial (NCT03155997), patients with high-risk HR-positive/HER2-negative early breast cancer were randomly assigned 1:1 to received either abemaciclib plus standard of care endocrine therapy or endocrine therapy alone. Patients were divided into cohorts based on high-risk clinical pathological features (cohort 1) or high-risk Ki-67 scores (cohort 2). Patients in the investigational arm were treated with abemaciclib 150 mg twice daily continuously without a break.⁴

At a median follow-up of 27 months, patients in the intent-to-treat population who received abemaciclib experienced a 30.4% reduction in the risk of experiencing an iDFS event compared with those who received endocrine therapy alone (HR, 0.696; HR, 95% CI, 0.588-0.823; P = .0001). There was also an absolute difference in the 3-year iDFS rates of 5.4% that favored the abemaciclib arm. The distant recurrence–free survival risk was reduced by 31.3% in abemaciclib arm (HR, 0.687; 95% CI, 0.571-0.826; P < .0001) with an absolute difference of 4.2% between the 3-year rates.

Additionally, among patients in the intent-to-treat population who received neoadjuvant chemotherapy, the 2-year iDFS rate also favored the abemaciclib arm compared with the endocrine therapy arm at 87.2% and 80.6%, respectively (HR, 0.61; 95% CI, 0.47-0.80; log-rank P < .001). The 2-year distant disease–free survival rates were 89.5% and 82.8%, respectively (HR, 0.61; 95% CI, 0.46-0.81; log-rank P < .001).

Similarly, patients in the intent-to-treat population with high Ki-67 (≥ 20%) experienced a 33.7% reduction in the risk of developing an iDFS event when they were treated with abemaciclib (HR, 0.663; 95% CI, 0.524-0.839; P = .0006). The absolute difference in 3-year iDFS rates between the arms was 6.0%.

Notably, patients treated with abemaciclib in cohort 1 who also had high Ki-67 experienced a 37.4% reduction in the risk of developing an iDFS event (HR, 0.626; 95% CI, 0.488-0.803; P = .0002). The absolute difference in 3-year iDFS rates between the arms was 7.1%.

“The FDA wanted to take a look at the highest-risk population,” O'Shaughnessy said. “The cohort 2 patients were a protocol amendment and started enrolling a bit after cohort 1, so the follow-up was not as great. The [cohort 1 patients enrolled from the beginning] were a very high anatomic risk group, and the FDA wanted to look at those that were highly proliferative in addition. Basically, [we found] that the higher the risk, the higher the impact of abemaciclib. This is the group that led to the FDA [approval] for adjuvant abemaciclib.”

High Ki-67 is prognostic of a worse outcome, but it is not predictive of abemaciclib benefit, O'Shaughnessy stressed. Patients derived a benefit from treatment with abemaciclib regardless of Ki-67 score.

In October 2021, the FDA approved abemaciclib for the adjuvant treatment of adult patients with HR-positive/HER2-negative, node-positive early breast cancer at a risk of recurrence and a Ki-67 score of at least 20%.⁵

The Future of CDK4/6 inhibitors in HR+/HER2- Early Breast Cancer

CDK4/6 inhibitors are currently under investigation in patients with HR-positive/HER2-negative early breast cancer in multiple ongoing clinical trials. The phase 3 ADAPTlate trial (NCT04565054) is evaluating delayed extended abemaciclib in patients with high-risk disease. Adjuvant abemaciclib is also being examined in high-risk patients in the phase 3 POETIC-A trial (NCT04584853) Finally, the phase 2 CARABELA trial (NCT04293393) is investigating neoadjuvant abemaciclib plus endocrine therapy among patients with intermediate or high-risk disease.¹

Neoadjuvant treatment with CDK4/6 inhibitors such as abemaciclib has the potential for clinical utility, O'Shaughnessy noted. In the phase 2 neoMONARCH trial (NCT02441946), 66.1% of patients who received abemaciclib plus anastrozole experienced complete cell cycle arrest (Ki-67 < 2.7%) at 2 weeks compared with 58.8% and 14.8% among patients who received abemaciclib monotherapy and anastrozole monotherapy, respectively.⁶ Similarly, in the phase 2 PALLET trial (NCT02296801), 90% of patients who received palbociclib plus letrozole achieved complete cell cycle arrest at week 14 compared with 59% who received letrozole monotherapy (P < .001).⁷

“If you have a patient who you know is going to be a good candidate [for the monarchE regimen], but they are not surgical candidates at that moment, and they are either not chemotherapy candidates or the biology of [their] disease is such that you do not feel they will benefit from chemotherapy, I have been starting the monarchE treatment with an aromatase inhibitor plus abemaciclib preoperatively to down size, get them to surgery, and then continue the adjuvant therapy,” O'Shaughnessy said.

References

1. O'Shaughnessy J. Incorporating CDK4/6 inhibitors into management of early breast cancer. Presented at: 21st Annual International Congress on the Future of Breast Cancer^® East: July 15-16, 2022; New York, NY.
2. Gnant M, Cueck 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
3. 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;39(14):1518-1530. doi:10.1200/JCO.20.03639
4. 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):P1571-1581. doi:10.1016/j.annonc.2021.09.015
5. FDA approves abemaciclib with endocrine therapy for early breast cancer. News release. FDA. October 12, 2021. Accessed July 18, 2022. bit.ly/3uXYXGe
6. Hurvitz SA, Martin M, Press MF, et al. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer. Clin Cancer Res. 2020;26(3):566-580. doi:10.1158/1078-0432.CCR-19-1425
7. Johnston S, Puhalla S, Wheatley D, et al. Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. J Clin Oncol. 2019;37(3):178-189. doi:10.1200/JCO.18.01624