Data and Decisions for the Three Different CDK4/6 Inhibitors

Hormone receptor-positive and HER2 receptor-negative (HR+/HER2-) breast cancer can be treated with CDK4/6 inhibitors. When cyclin-dependent kinase (CDK) cellular biology becomes dysregulated, cell proliferation occurs, and this has led to the discovery of three current CDK4/6 inhibitor drugs to treat HR-positive HER2-negative breast cancer: palbociclib, ribociclib and abemaciclib (1).

All CDK4/6 inhibitors (CDK4/6i) used for HR+/HER2- breast cancer should be used in combination with an endocrine inhibitor such as an aromatase inhibitor or Fulvestrant. (2) If using palbociclib in endocrine pre-treated patients, then fulvestrant would be the recommended endocrine inhibitor of choice (2).

Seven pivotal trials have determined the efficacy of all three current CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer. Although one should be prudent when directly translating across three different trials, the progression-free survival (PFS) hazard ratios are similar between the three molecules (3).

It should also be noted that in pre-treated patients, the combination of ribociclib or abemaciclib with fulvestrant produced greater overall survival (OS) than with fulvestrant alone. Although statistical significance wasn’t seen with palbociclib in combination with fulvestrant for OS in pre-treated patients, the population studied received significantly more pre-therapy than trials with ribociclib or abemaciclib (3).

Overall survival was a secondary endpoint in the first-line metastatic trials. Abemaciclib did not reach statistical significance for OS after 70.2 months of follow-up. A recent presentation of 8 years of follow-up in the abemaciclib MONARCH-3 study showed an increase in overall survival of 13 months (66.8 months vs 53.7 months). Although this effect unfortunately did not quite reach statistical significance, it is worth noting (4). Ribociclib reached statistical significance for OS in several trials compared to endocrine therapy alone for first-line metastatic HR+/HER2- breast cancer. Palbociclib did not reach statistical significance. However, there is controversy in regard to the veracity of this finding for palbociclib. Survival data was missing, and post-progression therapy in the control arm was higher in the palbociclib trial (3). After 7.5 years, 10% of patients are still on palbociclib, and real-world data outside of a trial setting showed an OS benefit (3).

The disparate results in OS and the very similar results in PFS between the three molecules have caused some debate as to the reasons behind this. Overall survival was a secondary endpoint in each of the studies, and this highlights the importance of primary and secondary endpoints when analysing the results of trials. In fact, it has been suggested both the MONALEESA trial and PALOMA-2 trial were only powered to <70% for OS and the differences could very well be attributed to chance. As discussed previously, the post-progression treatment rates were different and, as palbociclib underwent regulatory approval, those on ribociclib in the MONALEESA trials who progressed received palbociclib, a different drug to the treatment arm. In the palbociclib (PALOMA-2 trial) trial, those who progressed received the same drug palbociclib post-progression. There were also differences in disease-free intervals in the exclusion criteria for the trial designs that may possibly imply differences in endocrine sensitivities. Other differences existed in patient recruitment across trials and there is debate if they were a potential cause of difference. This is always a factor to consider with no head-to-head trials to draw from (3).

The Monarch-E trial combined abemaciclib with endocrine therapy for HR-positive, HER2-negative early breast cancer that was node-positive and at high risk of recurrence (5). This phase III open-label trial assigned patients to receive either abemaciclib for two years combined with anti-estrogen therapy for five years or anti-estrogen therapy alone for five years. At the initial follow-up of 27 months, the results were statistically significant in favour of the treatment arm (2). At an additional follow-up of 42 months, this statistically significant result was maintained, and data presented at the ASCO conference showed a statistically significant five-year invasive disease-free survival (IDFS) benefit (6).

The NATALEE trial is investigating ribociclib 400mg daily using the 21-day treatment and seven-day rest protocol for three years for early breast cancer. Patients were included who had stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer and were at risk of recurrence. The final analysis has been done, and the results are positive for ribociclib for this new indication and even for patients with node-negative disease. (7) Upon publication, there is anticipated much discussion about the pros and cons of abemaciclib vs ribociclib for the treatment of high-risk HR+/HER2- early breast cancer.

One of the most important aspects for pharmacists managing CDK4/6 inhibitors is interpreting the adverse effect profile of the three current agents in use for individual patients. This will be even more important with TGA approval and PBS approval for early breast cancer. It is easier to be less cautious in the metastatic setting than in those with quite likely curable early breast cancer.

The differing adverse effect profiles are due to the difference in affinity for each of the two receptors amongst the three molecules. Neutropenia and other haematological adverse effects are more common with ribociclib and palbociclib. The neutropenia seen with CDK4/6 inhibitors is distinct from that seen with other cytotoxic agents in that it is easily reversible, reflecting a cytostatic effect on the bone marrow and rarely associated with febrile neutropenia. Ribociclib is associated with QT prolongation, and baseline ECG should be done and monitored during treatment. Diarrhoea is mostly associated with abemaciclib and it is important to discuss this with patients at the start of treatment to come up with a plan as to how to treat with loperamide and electrolytes and when to seek medical or emergency help. (7) Liver toxicities are associated with the CDK4/6 inhibitors abemaciclib and ribociclib, and liver enzymes should be monitored (3).

Patient counselling on the rare but serious side effect of interstitial lung disease should occur, and patients should be cognizant of cough or shortness of breath. Blood clots are also rare but serious potential side effects, and although rare, one has to consider this in particular in the early breast cancer setting as to whether the risk outweighs the potential reward for those at particular risk of VTE and potential prophylactic anticoagulation. (7) There is also an increase in hypertension and other cardiovascular events amongst patients treated with CDK4/6 inhibitors (8).

There are potential drug interactions associated with all three molecules, both metabolic in terms of CYP3A4 inhibition or induction. P-gp drug interactions and pharmacodynamic drug interactions, particularly with QT prolongation for ribociclib are also possible.

The CDK4/6 inhibition and the resulting choice of drugs are an exciting development in the treatment of both metastatic and now early breast cancer. Pharmacists must strive to play a pivotal role in the management of these medications to ensure to get the most out of these exciting new treatment protocols.