Frontline Palbociclib Opens the Door to Subsequent CDK4/6 Inhibition in Metastatic Breast Cancer

Jairam Krishnamurthy, MD, FACP

Biomarker testing results and treatment history are among the most important factors to determine optimal next steps for patients with metastatic breast cancer who have progressed on a frontline CDK4/6 inhibitor, according to Jairam Krishnamurthy, MD, FACP.

“If patients [received] palbociclib [Ibrance] previously, had progression, and don’t have a mutation, [it would be] reasonable to use abemaciclib [Verzenio],” Krishnamurthy said in an interview with OncLive^®. "However, if they were started on ribociclib [Kisqali] or abemaciclib, we still don’t know what to do [in the second-line setting].”

In the interview, Krishnamurthy discussed the use of next-generation sequencing (NGS) to inform potential targeted treatment approaches for patients with breast cancer, data that support the selective use of CDK4/6 inhibitors after prior progression on these agents in patients with no targetable mutations, and ongoing research with palbociclib in the neoadjuvant setting. Krishnamurthy is an associate professor in the Division of Oncology & Hematology and the codirector of the Breast Cancer Program at the University of Nebraska Medical Center in Omaha.

He also highlighted the significance of the FDA approval of ribociclib for patients with hormone receptor (HR)–positive, HER2-negative, high-risk early-stage breast cancer and how this agent fits into the adjuvant treatment paradigm in another article.

OncLive: How does mutation status help determine optimal treatment sequencing approaches for patients with HR-positive, HER2-negative metastatic breast cancer following progression on a first-line CDK4/6 inhibitor?

Krishnamurthy: The adverse effect profile of capivasertib [Truqap] seems to be better than that of alpelisib [Piqray], at least on paper at this time. Elacestrant [Orserdu] is being used in patients with ESR1 mutations. [We also have evaluated] switching CDK4/6 inhibitors from [first line] palbociclib to [second line] ribociclib or abemaciclib) in patients with no targetable mutations] based on the phase 2 MAINTAIN [NCT02632045] and phase 3 postMONARCH [NCT05169567] studies, respectively. We have various treatment options in this setting to choose from regardless of whether patients have a mutation.

NGS through whichever platform you want to use is vital whether it be [through] Tempus, FoundationOne, Caris, Guardant, or your in-house test. Without it, you won’t know whether [a patient] carries a PIK3CA, PTEN, AKT, or ESR1 alteration, and that’s vital to determine the next step. Even if the patient does not have such a mutation, there is evidence that you could switch between CDK4/6 inhibitors. In those trials, most patients had [received prior] palbociclib, but [these trials] tell us those patients could go on to receive [second line] ribociclib or abemaciclib.

In the MAINTAIN trial, 86.5% of the patients [initially received] palbociclib [and switched to ribociclib plus endocrine therapy or placebo plus endocrine therapy].¹ In the postMONARCH trial, 59% of patients [initially received] palbociclib [and switched to] abemaciclib [plus fulvestrant (Faslodex) vs placebo plus fulvestrant].² These 2 trials teach us that if a patient received palbociclib in the first line, progressed, and doesn’t have a mutation that can be targeted, switching them to either ribociclib or abemaciclib would be reasonable, [as well as] switching the endocrine therapy partner.

Based on the findings from postMONARCH, what questions remain regarding the second-line treatment of patients with HR-positive, HER2-negative metastatic breast cancer after progression on CDK4/6 inhibition?

[The postMONARCH data] tell us that post-palbociclib it’s reasonable to switch to abemaciclib. There were no new safety signals; [second-line abemaciclib] seemed to be well tolerated and had good efficacy. However, what postMONARCH doesn’t tell us is what to do with patients who were receiving ribociclib or abemaciclib to begin with. In that trial, 33% of the patients [initially received] ribociclib. These are small numbers because the overall sample size was only 182 patients in the abemaciclib arm and 186 patients in the placebo arm.

We still don’t know about that aspect, and given the overall survival benefit that ribociclib [has generated] in the first-line setting, most new patients who are starting on a CDK4/6 inhibitor in the first-line setting are being treated with ribociclib. If they progress and don’t have a mutation to target, I don’t think we can switch to a different CDK4/6 inhibitor at this time because we don’t have evidence in that setting.

What ongoing breast cancer research with CDK4/6 inhibitors are you involved in?

At the University of Nebraska Medical Center, I am the principal investigator for an investigator-initiated neoadjuvant palbociclib phase 2 trial [NCT05069038]. It’s a trial for patients with localized HR-positive HER2-negative breast cancer who have a primary tumor at least 2 centimeters in size or lymph node–positive disease. This is a single-arm study where patients receive palbociclib with an aromatase inhibitor with or without ovarian suppression depending on whether they are menopausal or not.

[Patients receive] this treatment for potentially 6 months. At the end of the first month, we do a repeat biopsy to see the Ki-67 index. If it’s less than 10%, [the patients] continue treatment for another 5 months. We are also conducting genomic analyses of the tumors with a test called MammaPrint, both initially and subsequently at the 4-week mark to understand genomic changes in tumors [being treated] with endocrine therapy and targeted agents. This trial is actively accruing, and there are still patients to be enrolled.

References

1. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392
2. Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. J Clin Oncol. 2024;42(suppl 17). doi:10.1200/JCO.2024.42.17_suppl.LBA1001