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Cyclin-dependent kinase 4 and 6 (CDK4/6) are proteins that regulate the G1/S checkpoint in the cell cycle, which is a key point where cells decide whether to divide or enter a resting state. In breast cancer, CDK4/6 proteins can become overactive, causing cells to divide uncontrollably. This can occur due to a number of factors, including mutations in the genes encoding CDK4/6 or cyclin D proteins, which activate CDK4/6.

CDK4/6 inhibitors (CDK4/6i) are a class of drugs that block CDK4/6 proteins. This can help to slow or stop the growth of breast cancer cells. Three CDK4/6 inhibitors -- ribociclib, palbociclib, and abemaciclib -- are approved by the FDA for the treatment of hormone receptor-positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC). They are typically used in combination with endocrine therapy (ET), such as tamoxifen or aromatase inhibitors. Preclinical data suggest that the antiproliferative effect of a CDK4/6i can reverse quickly when it is stopped.

The combination of ribociclib with ET when compared with ET alone improved progression-free survival (PFS) and overall survival (OS) in patients without previous CDK4/6i therapy in three different randomized, placebo-controlled trials. Based upon these trials, CDK4/6i with ET has become standard of care for patients with HR+, HER2- MBC.

However, most patients eventually develop disease progression while on CDK4/6i with ET and require a change in therapy. A multicenter retrospective analysis showed that a subset of patients with HR+, HER2- MBC who had progression on palbociclib-based treatment benefited from abemaciclib. Notably, the duration of clinical benefit while on palbociclib was not associated with the subsequent duration of treatment with abemaciclib.

Although these data suggest that continuing a subsequent CDK4/6i and switching ET after progression on CDK4/6i with ET may be beneficial, there are no prospective randomized trials to support this approach. However, a recent randomized, placebo-controlled double-blind phase II trial () showed that among patients with HR+, HER2- MBC whose tumor progressed on previous CDK4/6i with ET, switching ET and continuing CDK4/6i with ribociclib resulted in a statistically significant improvement in progression-free survival (PFS) compared with switching to ET and placebo.

A total of 119 patients were enrolled in the trial and randomized in a 1:1 ratio to receive either ribociclib 600 mg orally once daily or placebo with fulvestrant (99 patients) or exemestane (20 patients). Despite efforts to add more patients with tumor progression on previous ribociclib, only 14 participants (12%) had previously received ribociclib, while the majority of participants (103, or 86.5%) had previously received palbociclib.

The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review. The median PFS was 5.29 months in the ribociclib arm and 2.76 months in the placebo arm. The PFS benefit with ribociclib was consistent across all subgroups, including patients who had received prior chemotherapy and patients who had progressed on more than one CDK4/6 inhibitor.

The MAINTAIN trial is the first randomized, placebo-controlled trial to show the benefit of switching ET and subsequent CDK4/6i after progression among patients with HR+, HER2- MBC on CDK4/6i with ET.

However, there are a few limitations worth mentioning. First, the trial was a relatively small phase II study, with only 119 patients enrolled, which may limit its generalizability. Second, the trial was not designed to assess overall survival (OS), so it is not yet known whether ribociclib improves OS in patients with HR+, HER2-negative MBC who progress on CDK4/6i therapy.

Importantly, the proportion of participants who received previous ribociclib or abemaciclib is under-represented. Subgroup analyses for these groups are exploratory and remain hypothesis-generating. In another randomized trial (PACE trial), patients with post-CDK4/6i progression did not benefit from switching ET to fulvestrant alone versus fulvestrant plus continuing palbociclib. This suggests that the benefit observed in the MAINTAIN trial could potentially be attributed to switching CDK4/6i from palbociclib to ribociclib.

Despite these limitations, the MAINTAIN trial is a significant study that provides evidence to support the use of ribociclib after CDK4/6i progression in patients with HR+, HER2- MBC.

There are ongoing larger phase III trials that will hopefully delineate which patients benefit from CDK4/6i post-CDK4/6i progression and address the ongoing need to clarify and optimize sequencing of combined endocrine and targeted therapies.

Arun Kumar, MD, is a hematology/oncology fellow PGY-5 at Medstar Georgetown University Hospital/Medstar Washington Hospital Center in Washington, D.C.; Amrita Devi, MBBS, is an Educational Commission for Foreign Medical Graduates-certified physician and an applicant for internal medicine residency training in the U.S.

Read the study here and an interview about it here.