CDK4/6 Inhibitors Continue to Build Traction in Early-Stage ER+/HER2- Breast Cancer

Joyce A. O’Shaughnessy, MD

Neoadjuvant and adjuvant treatment with CDK4/6 inhibitors has shown encouraging preliminary evidence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer, but confirmation of durable benefit is needed in the adjuvant setting before they are brought into routine clinical practice, explained Joyce A. O’Shaughnessy, MD, during a presentation at the 20th Annual International Congress on the Future of Breast Cancer^® West, a virtual program hosted by Physicians’ Education Resource^®, LLC.

O’Shaughnessy is the chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care^® in Community Outreach.

In the neoadjuvant setting, the phase 2 NeoPalAna trial (NCT01723774) enrolled pre- and postmenopausal patients with stage II and III ER-positive, HER2-negative breast cancer. Patients received 4 weeks of anastrozole followed by 16 weeks of anastrozole plus palbociclib (Ibrance) followed by a 3- to 5-week treatment-free interval before surgery.¹

The results showed that the complete cell cycle arrest (CCAC; Ki-67 <2.7%) rate increased from 28% after 4 weeks of anastrozole to 87% after 2 weeks of treatment with the combination. However, Ki-67 rebounded at the time of surgery, except in patients who stayed on palbociclib, suggesting that continuous treatment with palbociclib is necessary to maintain the response.

In the phase 2 FELINE trial (NCT02712723), patients were randomized to placebo plus letrozole, intermittent letrozole plus ribociclib (Kisqali), or continuous letrozole plus ribociclib. There was no difference in the preoperative endocrine prognostic index 0 score. However, the rate of patients with a Ki-67 of 2.7% or less at surgery was 71.4% with the addition of ribociclib vs 63.3% with letrozole alone (P = .4225). Moreover, the addition of ribociclib led to a higher rate of node negativity vs letrozole alone, at 46.5% vs 35.5%, respectively (P = .3024).²

However, as in the NeoPalAna trial, during the period of being off ribociclib prior to surgery, the Ki-67 rebounded in a subset of patients.

“There was a group [whose Ki-67 remained] very suppressed, so it’s just a proportion of the patients that are having a rebound in their Ki-67,” said O’Shaughnessy. “This really raises the question of how long we need to keep the preoperative or adjuvant therapy going in order to continue the [Ki-67] suppression,” said O’Shaughnessy.

The phase 2 NeoMONARCH trial (NCT02441946) enrolled postmenopausal patients with stage I, II, IIIA, or IIIB, hormone receptor (HR)–positive, HER2-negative breast cancer. Patients were randomized to anastrozole, anastrozole plus abemaciclib (Verzenio), or abemaciclib alone.³

The results demonstrated that the percent changes in Ki-67 from baseline to week 2 were 92.86%, 90.52%, and 62.78% in the abemaciclib/anastrozole, abemaciclib alone, and anastrozole alone arms, respectively.

Moreover, the rates of CCCA, which O’Shaughnessy termed a “very good end point,” were 67.8%, 57.7%, and 14.3%, respectively.

“Clearly, we’re getting much greater suppression of proliferation with the preoperative CDK4/6 inhibitors, regardless of which [agent you use],” said O’Shaughnessy.

The final neoadjuvant study O’Shaughnessy highlighted, the phase 2 CORALLEEN trial (NCT03248427), randomized postmenopausal patients with stage I to IIIA, HR-positive, HER2-negative disease with luminal B biology to doxorubicin and cyclophosphamide plus paclitaxel or letrozole plus ribociclib for 6 months.⁴

The study, which adopted the Prosigna risk of recurrence (ROR) score as the primary end point, showed no absolute difference in the ROR score between arms from baseline to surgery.

“The CDK4/6 inhibitor doesn’t look any worse than chemotherapy, but we can’t really say it’s any better,” said O’Shaughnessy.

“Are we ready to use [these agents] preoperatively? I would say probably not yet because we don’t know the duration the CDK4/6 inhibitor [should be given]. We really need the adjuvant data to know whether we [should] give them preoperatively,” said O’Shaughnessy.

In the adjuvant setting, O’Shaughnessy called attention to 3 trials. The first, the phase 3 PALLAS trial (NCT02513394), randomized patients with stage II to III, HR-positive, HER2-negative breast cancer to 2 years of palbociclib plus endocrine therapy or endocrine therapy alone.⁵

At a median follow-up of 23.7 months, the 3-year invasive disease-free survival (IDFS) rate was 88.2% with palbociclib/endocrine therapy vs 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; P = .51).4 The 3-year distant relapse-free survival (DRFS) rate was 89.3% and 90.7%, respectively (HR, 1.00; 95% CI, 0.79-1.27; P = .9997).

“There was no benefit from the palbociclib. It’s a bit of a mystery why that is,” said O’Shaughnessy.

In the phase 3 monarchE trial (NCT031559970), patients with node-positive, high-risk, early HR-positive, HER2-negative breast cancer were randomized to 2 years of abemaciclib plus standard endocrine therapy or endocrine therapy alone.

“[monarchE] enrolled the highest-risk patients. The [trial investigators] really selected patients who were going to recur within 2 or 3 years,” said O’Shaughnessy.

The primary results indicated that at a median follow-up of 19.1 months, abemaciclib/endocrine therapy reduced the risk of invasive disease by 25.3% vs endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided P = .0096). The 2-year IDFS rates were 92.2% in the abemaciclib/endocrine therapy arm vs 88.7% in the endocrine-alone arm.⁶

Additional results demonstrated that the addition of abemaciclib to endocrine therapy had a significant impact on DRFS across all prespecified subgroups, reducing the risk of distant recurrence by 28.3% (HR, 0.717; 95% CI, 0.559-0.920; P = .0085). The 2-year DRFS rates were 93.6% with abemaciclib/endocrine therapy vs 90.3% with endocrine therapy alone.

Updated findings from monarchE demonstrated that the risk of developing an IDFS event was reduced by 28.7% with abemaciclib/endocrine therapy (HR, 0.713; 95% CI, 0.583-0.871; P = .0009).⁷ The 2-year IDFS rates were 92.3% in the abemaciclib/endocrine therapy arm vs 89.3% in the endocrine-alone arm. Moreover, the risk of distant recurrence was reduced by 31.3% with abemaciclib/endocrine therapy (HR, 0.687; 95% CI, 0.551-0.858; P = .0009). The 2-year DRFS rates were 93.8% with abemaciclib/endocrine therapy vs 90.8% with endocrine therapy alone.

Moreover, in a prespecified subgroup analysis that was presented at the 2021 ASCO Annual Meeting, patients who had received neoadjuvant chemotherapy experienced an absolute improvement in 2-year IDFS and 2-year DRFS of approximately 6% with abemaciclib.⁸

“The curves are clearly pulling apart. We hope they’ll continue to pull apart, but it’s too soon to tell,” said O’Shaughnessy.

The final phase 3 trial, PENELOPE-B (NCT01864746), randomized patients with HR-positive, HER2-negative disease who did not achieve a pathologic complete response to neoadjuvant chemotherapy to 1 year of palbociclib or placebo.

Results showed that at a median follow-up of 42.8 months, the number of IDFS events in the palbociclib/endocrine therapy arm was 152 vs 156 in the placebo/endocrine therapy arm (stratified HR, 0.93; 95% CI, 0.74-1.17; P = .525).⁹ At 2 years, the estimated IDFS rates were 88.3% and 84.0%, respectively. Moreover, the estimated 3-year IDFS rates were 81.2% with palbociclib vs 77.7% with placebo, while the 4-year IDFS rates were 73.0% vs 72.4%, respectively.

“We need to see additional data at 3 and 4 years in order to really know whether those curves can continue to pull apart,” said O’Shaughnessy.

Ongoing trials to keep an eye on include the phase 2 CARABELA (NCT04293393) and phase 3 ADAPTlate (NCT04565054), eMonarcHER (NCT04752332), NATALEE (NCT03701334), and POETIC-A (NCT04584853) trials, concluded O’Shaughnessy.

References

1. Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 Inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017;23(15):4055-4065. doi:10.1158/1078-0432.CCR-16-3206
2. Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). J Clin Oncol. 2020;38(suppl 15):505. doi:10.1200/JCO.2020.38.15_suppl.505
3. 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
4. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):33-43. doi:10.1016/S1470-2045(19)30786-7
5. 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
6. 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). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514
7. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Cancer Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS1-01
8. Martin M, Hegg R, Kim SB, et al. Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC). J Clin Oncol. 2021;39(suppl 15):517. doi:10.1200/JCO.2021.39.15_suppl.517
9. 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