CDK 4/6 inhibitor successful rechallenge after limiting hepatic toxicity

Lucie Meynard MBBS1,2 | Thomas Grellety MD, PhD1,2

1Department of Medical Oncology, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France
2University of Bordeaux, Bordeaux, France


The standard first‐line treatment for metastatic luminal breast can‐ cer is endocrine therapy combined with a CDK 4/6 inhibitor (except for patients with visceral crisis).1 Currently, three CDK 4/6 inhibitors are approved: abemaciclib, palbociclib, and ribociclib. Here, we re‐ port the case of a patient presenting a persistent Grade 3 hepatic toxicity while receiving letrozole and ribociclib that was successfully rechallenged by switching to palbociclib.


A 59‐year‐old woman was treated in 2000 for a localized Grade II invasive lobular breast cancer, estrogen (ER) and/or progesterone receptor (PR) positive, ERBB2 negative. Lumpectomy and external beam radiation were performed. In 2007, she presented with an ipsi‐ lateral relapse treated by radical mastectomy and endocrine therapy. In 2017, she relapsed with diffuse bone lesions. A biopsy confirmed luminal breast cancer metastasis. There was no visceral involvement. The patient initiated letrozole 2.5 mg per day and ribociclib at full dose of 600 mg per day. After 16 weeks, she presented an increase of liver transaminases initially Grade 1 for aspartate aminotransferase (ASAT) and Grade 2 for alanine aminotransferase (ALAT), then rising rapidly to Grade 3 (Figure 1). There was no other toxicity. Ribociclib was immediately discontinued. Viral serology for hepatitis A, B, and C was negative. There was no iron overload, and a CT scan did not identify any hepatic‐specific involvement. Grade 3 increased trans‐ aminases lasted for 14 weeks.

Once the liver function normalized, palbociclib was introduced at 75 mg per day, and then increased to 100 mg per day. One year on, the patient remains free of any clinical or biological toxicities. The CA15‐3 marker remains stable, and a CT scan has shown ongoing stable disease.


Here, for the first time, we report the case of a rechallenge of a CDK 4/6 inhibitor after serious liver toxicity. Endocrine therapy and CDK 4/6 inhibitor combinations have substantially prolonged progression‐free survival making them a standard of care for ad‐ vanced luminal breast cancer.2‐8 Increased transaminases have been described as adverse events in previous phase 3 trials (Table 1). Elevated ALAT (all grades) occurred in 6%‐15% of patients, includ‐ ing Grade 3 in 2%‐7.5% of patients.2‐8 A pooled analysis of ribociclib studies revealed 7% Grade 3 ALAT increases, leading to permanent discontinuation of the treatment for the majority of patients.9 Two cases of liver failure were also reported for the letrozole/palbociclib combination.

F I G U R E 1 Changes of ASAT/ALAT and CA 15‐3 between September 2017 and April 2019. ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase.

In the present case, toxicity was attributed to ribociclib after ex‐ cluding standard causes of hepatic transaminases perturbation. The Naranjo algorithm classified the imputability of ribociclib as probable adverse drug reaction.11
We believe that this case shows that it is feasible to rechallenge a CDK 4/6 inhibitor by switching to a different drug of the three available. However, reintroduction of the CDK 4/6 inhibitor should be considered with progressive dose escalation and close biological monitoring to avoid reappearance of hepatic injury.


We thank Pippa McKelvie‐Sebileau for the medical writing service.


Written informed consent was obtained from the patient for publi‐ cation of this case report. Thomas Grellety declared consulting and advisory role for Novartis.


Thomas Grellety‐0001‐5316‐1420


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