CDK4/6 Inhibitors Improve OS, but Sequencing Strategies Continue to Form in HR+/HER2- Breast Cancer

As first- or second-line treatments, the CDK4/6 inhibitors ribociclib (Kisqali), palbociclib (Ibrance), and abemaciclib (Verzenio) in combination with aromatase inhibitors (AI) or fulvestrant (Faslodex) have demonstrated similar hazard ratios in terms of progression-free survival (PFS) for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, explained Sara A. Hurvitz, MD, who added that although differences in overall survival (OS) and toxicity profile could inform treatment selection, optimal sequencing with these agents remains uncertain.¹

“There is still a bit of controversy about whether these [agents] are all 3 different flavors of the same drug,” said Hurvitz, director of the Breast Cancer Clinical Trials Program and co-director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Oncology Practices, in a presentation during the 20th Annual International Congress on the Future of Breast Cancer® West, a virtual program hosted by Physicians’ Education Resource^®, LLC. “Of course, we could talk all day about the preclinical data with these agents and how they’re different, but what really matters is how they differ in the clinic.”

CDK4/6 Inhibitors Induce OS Improvement in Advanced HR+/HER2- Breast Cancer

Findings from the phase 3 MONALEESA-7 trial (NCT02278120) demonstrated a 29% reduction in the risk of death with ribociclib plus endocrine therapy vs placebo plus endocrine therapy in pre- or perimenopausal women with advanced HR-positive, HER2-negative breast cancer (hazard ratio, 0.71; 95% CI, 0.54-0.95; P = .00973).²

Updated data from MONALEESA-7 showed that at a median follow-up of 53.5 months, the median OS was 58.7 months with ribociclib compared with 48 months with placebo (hazard ratio, 0.763; 95% CI, 0.608-0.956).³ Additionally, time to chemotherapy, chemotherapy-free survival, and PFS through the next line of treatment (PFS2) were improved with ribociclib vs placebo.

“[These end points] are arguably very important in patients who are being treated in a palliative manner. [PFS2] underscores the benefit of this agent even after patients have progressed and come off ribociclib,” said Hurvitz, who is also an associate professor of medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA.

Another phase 3 study of ribociclib, MONALEESA-3 (NCT02422615), demonstrated that at a median follow-up of 39.4 months, ribociclib plus fulvestrant induced a 28% reduction in the risk of death vs placebo in postmenopausal patients with advanced HR-positive, HER2-negative breast cancer (hazard ratio, 0.72; 95% CI, 0.57-0.92; P = .00455).⁴

During the 2021 ASCO Annual Meeting, updated findings from MONALEESA-3 were presented virtually, revealing that at a median follow-up of 56.3 months, the median OS was 53.7 months with ribociclib plus fulvestrant vs 41.5 months with placebo plus fulvestrant (hazard ratio, 0.73; 95% CI, 0.59-0.90).⁵ Moreover, time to chemotherapy, chemotherapy-free survival, and PFS2 were improved with ribociclib vs placebo.

Notably, the improved OS benefit was observed across all relevant patient subgroups, including harder-to-treat patients, such as those with lung or liver metastases, 3 or more metastatic sites, and endocrine resistance.

The results of MONALEESA-3 were important as they were the only data to demonstrate an improvement in OS with a CDK4/6 inhibitor in postmenopausal patients exclusively, Hurvitz explained.

Regarding abemaciclib, the results of the phase 3 MONARCH 2 trial (NCT02107703) demonstrated a median OS of 46.7 months with abemaciclib plus fulvestrant vs 37.3 months with placebo plus fulvestrant in patients with advanced HR-positive, ERBB2-negative breast cancer who progressed on prior endocrine therapy (hazard ratio, 0.757; 95% CI, 0.606-0.945; P = .01).⁶

Despite the improved OS demonstrated in the prior 3 studies, the findings of the phase 3 PALOMA-3 trial (NCT01942135) failed to demonstrate a statistically significant improvement in OS with palbociclib plus fulvestrant vs placebo plus fulvestrant in patients with advanced HR-positive, HER2-negative breast cancer who had sensitivity to prior endocrine therapy (hazard ratio, 0.81; 95% CI, 0.64-1.03; P = 0.09).⁷

Updated findings, which were presented during the 2021 ASCO Annual Meeting, demonstrated that the numeric improvement in OS with palbociclib vs placebo was maintained with more than 6 years of median follow-up in this patient population (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99; P = .0221).8 Moreover, patients with endocrine-sensitive disease and those without prior chemotherapy exposure in the metastatic setting appeared to derive additional OS benefit with palbociclib.

Data Driving Sequencing and Combinations Strategies With CDK4/6 Inhibitors

Although additional data are needed, treatment decisions with available data are required when selecting between available CDK4/6 inhibitors for patients with HR-positive, HER2-negative breast cancer, as well as for determining the optimal partner for CDK4/6 inhibitor therapy in this setting, explained Hurvitz.

For example, findings from the phase 2 PARSIFAL trial (NCT02491983) demonstrated a median PFS of 32.8 months with the combination of palbociclib and letrozole vs 27.9 months with palbociclib plus fulvestrant (hazard ratio, 1.13; 95% CI, 0.89-1.45; two-sided P = .321) in patients with endocrine-sensitive, HR-positive, HER2-negative metastatic breast cancer who were at least 12 months post–adjuvant endocrine therapy or were endocrine therapy–naïve.⁹

“There really is no benefit with the use of fulvestrant; the outcomes appear quite similar. [This] gives you the freedom to choose among [fulvestrant or chemotherapy] freely,” said Hurvitz.

Without comparative data, differences in safety profiles between the CDK4/6 inhibitors could inform treatment decisions, Hurvitz explained. For example, palbociclib, ribociclib, and abemaciclib are all associated with neutropenia, anemia, fatigue, and interstitial lung disease. However, thrombocytopenia is reported with palbociclib, nausea is reported with abemaciclib, and QTc prolongation is reported with ribociclib relatively exclusively, Hurvitz explained. Moreover, liver transaminases should be monitored with ribociclib and abemaciclib, whereas patients receiving abemaciclib should be monitored for venous thromboembolic events.

“There are differences that are emerging from a clinical standpoint as it relates to toxicity and the way that we dose the agents,” Hurvitz said. “[Patient-reported outcome (PRO) data] have shown consistently that patients feel better on the doublet therapy with a CDK4/6 inhibitor, which is reassuring that we are not just improving PFS, but we are allowing patients to feel better.”

However, whether to dose CDK4/6 inhibitors in the frontline setting vs holding them until after symptomatic disease is mitigated with chemotherapy remains an open-ended question, Hurvitz explained.

The results of the phase 3 PEARL trial (NCT02028507) showed that at a median follow-up of 13.47 months, the median PFS was 7.5 months with palbociclib plus fulvestrant vs 10 months with capecitabine in patients with HR-positive, HER2-negative, AI-resistant advanced breast cancer (adjusted hazard ratio, 1.09; 95% CI, 0.83-1.44; P = .537).10 In patients with ESR1 wild-type disease, the median PFS was 8 months vs 10.6 months, respectively, at a median follow-up of 18.89 months (adjusted hazard ratio, 1.08; 95% CI, 0.85-1.36; P = .526).

“Although this isn’t in the frontline setting, the PFS was not improved with a CDK4/6 inhibitor, but it certainly doesn’t look like the chemotherapy is winning in the overall cohort or ESR1 wild-type cohort,” Hurvitz stated.

In the phase 2 Young Pearl trial (NCT02592746), premenopausal patients with HR-positive, HER2-negative breast cancer had a median PFS of 20.1 months with palbociclib plus exemestane and leuprolide vs 14.4 months with capecitabine (hazard ratio, 0.659; 95% CI, 0.437-0.994; P = .0235).¹¹

“[The data from PEARL and Young Pearl] indicate and reassure us that chemotherapy doesn’t appear to be getting us better outcomes in patients than CDK4/6 inhibitor–based therapy, at least in the second-line setting. It does validate early use of these agents, especially when keeping in mind the time-to-chemotherapy and PRO benefits,” concluded Hurvitz.

References

1. Hurvitz SA. New algorithms for treating HR+ metastatic breast cancer. Presented at: 20th Annual International Congress on the Future of Breast Cancer^® West; July 30-31, 2021; virtual.
2. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765
3. Tripathy D, Im SA, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD2-04.
4. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149
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8. Cristofanilli M, Rugo HS, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): updated analyses from PALOMA-3. J Clin Oncol. 2021;39(suppl 15):1000. doi:10.1200/JCO.2021.39.15_suppl.1000
9. Llombart-Cussac A, Pérez-García JM, Bellet M, et al. PARSIFAL: a randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer. J Clin Oncol. 2020;38(suppl 15):1007. doi:10.1200/JCO.2020.38.15_suppl.1007
10. Martin M, Zielinski C, Ruiz-Borrego M, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial–PEARL. Ann Oncol. 2021;32(4):488-499. doi:10.1016/j.annonc.2020.12.013
11. Park YH, Kim TY, Kim GM, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. doi:10.1016/S1470-2045(19)30565-0