As molecular targeted therapies have been developed and are being integrated into clinical practice with increasing frequency, personalized medicine approaches have evolved. A recent report identified important clinical considerations that may pertain to treatment choices, focusing on similarities in efficacy and indications of abemaciclib, palbociclib, and ribociclib, and the salient differences among these agents based on specific attributes of their toxicity profiles.
A systematic review and meta-analysis were conducted to evaluate the toxicity profiles of the 3 currently available medications for hormone-responsive breast tumors. The approval of cyclin-dependent kinase (CDK)4/6 inhibitors has significantly changed the treatment landscape, modifying current therapeutic algorithms. While abemaciclib has been approved by the US Food and Drug Administration (FDA) as a monotherapy, currently there are 3 CDK4/6 inhibitors approved in combination with aromatase inhibitors or fulvestrant for treating metastatic hormone receptor–positive/HER2-negative breast cancer, having received both FDA and European Medicines Agency approval.
Included in the investigation were retrospective, phase 1, phase 2, and phase 3 trials, as well as expanded access program and compassionate use program studies. From a MEDLINE search that originally retrieved 1024 articles, 27 studies were included in the final meta-analysis.
A high risk of respiratory and hepatic toxicity and QTc prolongation was associated with ribociclib treatment, and these risks for toxicity were higher in metastatic patients than nonmetastatic patients.
A high risk of hematologic toxicity that clinically manifested as neutropenia and a low risk of severe infections were found with palbociclib and ribociclib treatment. It should be noted that according to the analysis in patients treated with palbociclib and ribociclib, the high rate of neutropenia was rapidly reversible.
A high risk of gastrointestinal toxicities of grade 1/2 in most cases was the primary issue with abemaciclib treatment. The investigators noted that in patients treated with abemaciclib, this high risk of gastrointestinal side effects was specifically detected as abdominal pain and diarrhea; although these are considered low grade, they can greatly impact patient quality of life.
Notably, while ribociclib and palbociclib did not appear to be more toxic in pretreated patients than in previously untreated patients, abemaciclib appeared to be associated with a higher risk of any grade neutropenia and grade 3/4 diarrhea. Therefore, the investigators concluded that pretreatment did not impact patients who exhibit higher toxicity rates for palbociclib or ribociclib than previously untreated patients. However, they underscored that with the abemaciclib treatment, both a 26% higher risk of any grade neutropenia and a 6% higher risk of grade 3/4 diarrhea were observed.
Menopausal status was a factor in some cases. Palbociclib and ribociclib had similar toxicity profiles in pre- and postmenopausal patients; however, a slight increase in the risk of diarrhea in postmenopausal patients was detected.
The authors noted that although CDK4/6 inhibitors are generally safe and manageable treatment options, clinical choices should be based on criteria minimizing the risk of severe complications as well as specific toxicity profile attributes. When clinicians evaluate treatment options, they should consider the most common toxicities, including those with hematologic ramifications for palbociclib and ribociclib, associated with potential gastrointestinal effects of abemaciclib, and with less frequent adverse events.
Remarkably, in early-stage cancer cases the CDK4/6 inhibitors appear to be better tolerated, likely due in part to the better or healthier baseline clinical status or to the limited number of treatment cycles compared to metastatic patients. While this class of medication is currently not approved for this indication, several ongoing clinical trials have begun to be published. In the future, findings from these studies may support their use as therapeutic alternatives in the early treatment paradigm, profoundly impacting quality of life, and possibly delaying the initiation of toxic therapeutic options.
Onesti CE, Jerusalem G. CDK4/6 inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis. Expert Rev Anticancer Ther. 2021;21:283-298.