#Ribociclib liver toxicity update#
#Ribociclib liver toxicity trial#

Also, ribociclib may prolong the QTc interval in a small proportion of patients (<5%), necessitating ECG monitoring during the first 2 cycles 2, 12.ĭuring the last decade, 7 pivotal prospective randomized controlled trials have established the roles of palbociclib, ribociclib and abemaciclib combined with an endocrine partner in the treatment of first-line (Table 1) and pre-treated patients with HR + MBC. In contrast to palbociclib, both abemaciclib and ribociclib require liver function monitoring. Abemaciclib causes predominantly gastrointestinal toxicity, whereas palbociclib and ribociclib are characterized by hematologic toxicity, notably asymptomatic neutropenia. Toxicity profiles differ among these three agents.

#Ribociclib liver toxicity trial#

The NATALEE trial (NCT03701334) of adjuvant ribociclib has completed accrual however, the results are pending. Evaluation of the addition of palbociclib to endocrine therapy in the adjuvant setting has been explored in the PALLAS and PENELOPE-B trials but did not demonstrate benefit beyond endocrine therapy alone 10, 11.

#Ribociclib liver toxicity update#

An update at 4 years of follow-up has demonstrated continued and further improvement in invasive disease-free survival between the treatment and control groups, implying a carry-over effect beyond the active treatment period 9. In the adjuvant setting, as supported by the MONARCH-E study, the addition of 2 years of abemaciclib to adjuvant endocrine therapy improves disease-free survival, a finding which led to FDA approval for high-risk node positive HR + disease in October 2021 5, 8. Despite substantial translational work across the large pivotal metastatic trials, currently the only predictive biomarker for CDK4/6 benefit is estrogen receptor positivity (ER+).

Clinically, abemaciclib is given continuously, has proven blood-brain barrier penetration and is approved as monotherapy in pre-treated patients 7. Moreover, the agents exhibit different acquired resistance mechanisms, demonstrated in a recent high-resolution analysis of pre-clinical models, providing further support for their disparate nature 6. Abemaciclib has a different chemical structure and exhibits the highest inhibitory effect on CDK4/6 with a CDK4:CDK6 inhibition ratio of 5, and additional activity on multiple kinases 5. Palbociclib and ribociclib are given in an intermittent fashion and, while both have high selectivity for CDK4 and CDK6, ribociclib has a higher CDK4:CDK6 inhibition ratio (~4) given its weaker potency for inhibition of CDK6 5. All three CDK4/6i are orally bioavailable but have some differences in their chemical, biologic and pharmacologic features 2, 4. Overall, these drugs form the backbone of contemporary therapy, used in combination with endocrine therapy typically in the first-line setting for metastatic HR + disease 4. market, with ribociclib and abemaciclib comprising a smaller market share 3.

Palbociclib was the first agent to be approved and has been the leading drug in the U.S.

The three FDA approved agents in the metastatic setting are palbociclib, ribociclib and abemaciclib.