When to Use CDK4/6 Inhibitors in Early and Advanced Disease

  • The Food and Drug Administration (FDA) recently approved the drug Kisqali (ribociclib) in combination with an aromatase inhibitor (AI) for people with HR+/HER2- stage II and III early breast cancer (EBC) at high risk of recurrence.
  • Ribociclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. The recent approval of ribociclib in earlier-stage disease indicates that these drugs can be beneficial in both early and advanced disease.
  • SurvivorNet Connect spoke to several oncologists and specialists about the use of CDK4/6 inhibitors — and the consensus is that the benefit of adding these drugs to a treatment plan depends on the patient, their health history, and how they’re likely to tolerate potential side effects.
  • “I think it’s really going to come down to patient preference. We’re going to look at the side effect profile of those … drugs, the differences in the dose, the differences in the duration of therapy, and talk with our patients about what makes the most sense for them,” Dr. Stephanie Graff,  Director of the Breast Oncology at Brown University, tells SurvivorNet Connect.

The recent approval of the drug Kisqali (ribociclib) in combination with an aromatase inhibitor (AI) as treatment for people with HR+/HER2- stage II and III early breast cancer (EBC) at high risk of recurrence has many who work in the breast cancer space curious. Ribociclib, a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6), can significantly reduce the risk of disease recurrence in certain populations, but it has a side effect profile that may be too severe for some.

SurvivorNet Connect conducted formal interviews on this topic with several leading breast cancer specialists to get their view of the risks vs. benefits of these innovative drugs — and why different patients may want to consider different CDK4/6 inhibitors based on their health history.

“I think these are hard decisions … We ask a lot of our patients. Cancer treatment is intense. There’s so many modalities. There’s baby chemotherapy, there’s surgery, there’s radiation, there’s all of these things that all come with side effects,” Dr. Eleonora Teplinsky, Head of Breast Medical Oncology at Valley Health System, tells SurvivorNet Connect.

“Now we’re saying to patients: well, we’ve got yet another drug. It’s beneficial and it’s going to reduce your risk of recurrence. But it comes with side effects. The key is that this is not a one-time conversation. It’s saying, well, here are the benefits, here are potential side effects. Think about that.”

Expanded Eligibility

Breast cancer is one of the most common cancers worldwide, and hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer accounts for approximately 60-70% of all diagnosed cases — so these drugs have the potential to benefit a huge number of women.

CDK4/6 inhibitors have emerged as a critical advancement in targeted breast cancer therapy, particularly for HR+/HER2-negative (HER2-) breast cancer. These inhibitors work by disrupting the CDK4/6 pathway, which plays a vital role in cell cycle regulation and uncontrolled proliferation in breast cancer cells.

“More patients are actually eligible for receiving adjuvant CDK4/6 inhibitors. We know that patients with hormone receptor positive breast cancer are at risk of both early and late recurrences of disease. And this is an important targeted therapy option to try to address that,” Dr. Maryam Lustberg, Director of the Breast Center at Smilow Cancer Hospital and Chief of Breast Medical Oncology at Yale Cancer Center, tells SurvivorNet Connect.

Understanding CDK4/6 inhibitors

CDK4/6 inhibitors target cyclin-dependent kinases 4 and 6, which play a critical role in cell cycle regulation. By inhibiting these kinases, these drugs prevent cancer cells from progressing through the cell cycle, leading to cell cycle arrest and reduced tumor proliferation. This mechanism makes CDK4/6 inhibitors an essential addition to endocrine therapy, particularly for patients with HR+/HER2- advanced or metastatic breast cancer.

The three CDK4/6 inhibitors currently approved by regulatory agencies are:

  1. Palbociclib (brand name Ibrance): the first CDK4/6 inhibitor approved for HR+/HER2- advanced breast cancer. Ibrance is not approved for early-breast cancer.
  2. Ribociclib (brand name Kisqali): Approved for use in combination with endocrine therapy, for both early or metastatic breast cancer.
  3. Abemaciclib (brand name Verzenio): Notably has single-agent activity and can be used in early or advanced disease. Abemaciclib is noted for its higher selectivity for CDK4, leading to distinct toxicity profiles compared to other CDK4/6 inhibitors, including higher rates of gastrointestinal side effects but reduced bone marrow toxicity.

Indications and Timing for CDK4/6 Inhibitors

CDK4/6 inhibitors are approved for use in combination with endocrine therapies, such as aromatase inhibitors or fulvestrant, in various settings of HR+/HER2- breast cancer:

  1. First-Line Treatment in Postmenopausal Women: Palbociclib, ribociclib, and abemaciclib are all approved for first-line treatment in combination with an aromatase inhibitor (AI) in postmenopausal women with HR+/HER2- advanced breast cancer.
  2. Pre- and Perimenopausal Women: Ribociclib, combined with an aromatase inhibitor and ovarian suppression, is specifically approved for pre- and perimenopausal women, providing a valuable option for younger patients.
  3. Second-Line Treatment: For patients whose cancer has progressed on initial endocrine therapy, CDK4/6 inhibitors are recommended in combination with fulvestrant.
  4. High-Risk Early Breast Cancer: Both Abemaciclib and Ribociclib are approved for use in high-risk early breast cancer, combined with endocrine therapy, due to its efficacy in reducing recurrence in this subset of patients.

Clinical Trial Evidence Supporting CDK4/6 Inhibitors

Each CDK4/6 inhibitor has been studied extensively in clinical trials, demonstrating significant improvements in progression-free survival (PFS) and, in some cases, overall survival (OS) compared to endocrine therapy alone.

Palbociclib (Ibrance)

The PALOMA trials have been pivotal in establishing palbociclib’s role. PALOMA-2 demonstrated a significant improvement in PFS when palbociclib was combined with letrozole compared to letrozole alone as a first-line therapy for advanced breast cancer. However, PALOMA-3, which studied palbociclib with fulvestrant in a second-line setting, showed a significant PFS benefit but did not reach a statistically significant improvement in OS.

After a median follow-up of 90.1 months, 405 deaths were observed and 155 patients were known to be alive. The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus letrozole (hazard ratio [HR], 0.96 [95% CI, 0.78 to 1.18]; stratified one-sided P = .34).

An imbalance in the number of patients with unknown survival outcome between the treatment arms (13.3% v 21.2%, respectively) limited interpretation of OS results. With recovered survival data, the median OS was 53.8 (95% CI, 49.8 to 59.2) versus 49.8 months (95% CI, 42.3 to 56.4), respectively (HR, 0.92 [95% CI, 0.76 to 1.12]; one-sided P = .21). OS was not significantly improved with palbociclib plus letrozole compared with placebo plus letrozole.

Ribociclib (Kisqali)

The MONALEESA trials have highlighted ribociclib’s efficacy across different patient populations. MONALEESA-2, -3, and -7 all reported significant PFS improvements with ribociclib combined with either an aromatase inhibitor or fulvestrant. Notably, MONALEESA-3 showed a significant OS benefit, making ribociclib a strong contender, particularly in patients requiring demonstrated survival benefits. More recently, the FDA approved Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer.

This new approval is based on results from the pivotal Phase III NATALEE trial, which showed a significant and clinically meaningful 25.1% (HR=0.749; 95% CI: 0.628, 0.892; P=0.0006) reduction in risk of disease recurrence in a broad population of patients with HR+/HER2- stage II and III EBC treated with adjuvant Kisqali plus endocrine therapy (ET) compared to ET alone, including those with high-risk N0 disease.

Kisqali significantly reduced the risk of recurrence by 25% vs. endocrine therapy alone.

Abemaciclib (Verzenio)

Abemaciclib differs slightly from palbociclib and ribociclib due to its ability to be administered continuously without breaks, which can be advantageous in certain patients. The MONARCH trials, particularly MONARCH 2 and 3, demonstrated substantial PFS benefits in combination with endocrine therapy. MONARCH 3, an ongoing study, is also evaluating OS benefits.

Abemaciclib’s approval in the early setting is specifically for patients with high-risk, node-positive disease, based on the monarchE trial data.

“Right now in the hormone receptor positive early stage breast cancer, we have had adjuvant abemaciclib approved for patients with high-risk lymph node positive breast cancer and as of this weekend, we’ve gotten an update looking at the adjuvant ribociclib data and immediately followed with an approval for ribociclib,” Dr. Stephanie Graff,  Director of the Breast Oncology at Brown University, tells SurvivorNet Connect.

The inclusion of patients with node-negative disease in a new trial shed new light for early-breast cancer patients, broadening CDK4/6 inhibitors potential impact on clinical practice.

“The NATALEE trial, included a broader population than what was used in the MONARCHE (abemaciclib data). So now there’s a group of patients that even have lymph node-negative disease, smaller tumors that are eligible for adjuvant CDK4/6 inhibitors,” Dr. Graff adds.

When to Choose CDK4/6 inhibitors?

Dr. Teplinsky stresses that deciding which CDK4/6 inhibitor to choose for a patient (if any at all) will depend a lot on the patient’s input.

“Shared decision making, what is that?” she asks. “These are conversations between patients and their healthcare teams about their individual risk, their individual medical histories. As we know, all cancers are different and have different prognostic features.”

The decision to use palbociclib, ribociclib, or abemaciclib often hinges on patient-specific factors, including tolerability, comorbid conditions, and personal preferences.

“I think it’s really going to come down to patient preference. We’re going to look at the side effect profile of those … drugs, the differences in the dose, the differences in the duration of therapy, and talk with our patients about what makes the most sense for them,” Dr. Graff adds. Because there’s going to be patients that may prefer one set of side effects or one duration of therapy based on their lifestyle or their particular concerns over another.”

The experts we consulted suggested considering the following factors:

  1. Tolerability: Each inhibitor has a distinct side effect profile. Palbociclib is generally well-tolerated but may cause neutropenia. Ribociclib can affect liver function and prolong QT intervals, requiring careful monitoring. Abemaciclib, with a higher incidence of gastrointestinal side effects, may not be suitable for patients with existing GI concerns.
  2. Comorbidities: Ribociclib might be less suitable for patients with cardiac issues due to its impact on QT intervals, while abemaciclib may be avoided in patients with significant GI comorbidities.
  3. Patient Preferences and Lifestyle: Abemaciclib’s continuous dosing schedule might appeal to patients seeking a more consistent treatment approach without breaks.

Side Effects

While CDK4/6 inhibitors are generally well-tolerated, they are associated with specific adverse effects, including:

  • Neutropenia: Particularly common with palbociclib and ribociclib, but often manageable and rarely leads to febrile neutropenia.
  • Gastrointestinal Toxicity: Abemaciclib is associated with higher rates of diarrhea.
  • Hepatotoxicity: Elevated liver enzymes have been observed, especially with ribociclib.
  • QT Interval Prolongation: Ribociclib requires monitoring due to its potential to prolong the QT interval.
  • Venous Thromboembolism: There is a slight increased risk, necessitating vigilance. Abemaciclib has been associated with a higher risk of VTE compared to other CDK4/6 inhibitors.

“I think different patients do indeed choose differently. Verzenio is associated with a higher chance of diarrhea but also tends to have less cytopenias or low count issues associated with it. It tends to have less risk of cardiac EKG changes and less risk of liver function test changes,” Dr. Lustberg explains.

“Whereas Kisqali does not have nearly as much diarrhea. But we do need to do careful EKG monitoring early on to make sure that the QTC interval is not getting prolonged and we do careful monitoring of liver function tests. There is also a higher chance of white count or platelets dropping, which we can always adjust for and it’s not a problem.

“There are patients who maybe have more sensitive guts and have had issues with diarrhea. For them Kisqali may be a better choice. Others may have existing cardiac issues or existing liver problems, in which case Verzenio may be a good choice. So I think it goes beyond simply patient preference but also taking into account preexisting health conditions that a patient may have and kind of making a decision that way,” she adds.