CDK4/6 inhibitor-induced liver injury common in breast cancer

Liver injury occurs in around one in 20 patients treated with cyclin-dependent kinase 4/6 inhibitors for metastatic breast cancer, according to a multicentre retrospective study in Spain.

Of the 1,716 metastatic breast cancer patients who were initiated on CDK4/6 inhibitors (861 palbociclib, 504 ribociclib, and 351 abemaciclib) between 2018 and 2022, 85 had drug-induced liver injury (4.9 percent). Liver injury was grade 2 in 27 patients (31.8 percent), grade 3 in 46 (54.1 percent), and grade 4 in 12 (14.4 percent), reported first study author Dr Mar Riveiro-Barciela from the Vall d'Hebron University Hospital in Barcelona, Spain. [EASL 2025, abstract OS-033]

Furthermore, the frequency of CDK4/6 inhibitor-induced liver injury was higher with ribociclib (8.5 percent) and abemaciclib (8.0 percent) than with palbociclib (1.6 percent). Despite this, Riveiro-Barciela noted that the severity of liver injury was similar across the three drugs. For instance, severe cases (CTCAE* grade ≥3) occurred in 76.7 percent with ribociclib, 57.1 percent with palbociclib, and 60.7 percent with abemaciclib (p=0.227).

Similarly, the percentage of moderate or worse cases according to the DILI-IEWG** classification of severity showed no significant differences: 14.0 percent with ribociclib, 7.1 percent with palbociclib, and 14.3 percent with abemaciclib (p=0.778). These cases were significantly more common among patients with progressive disease at the time of drug-induced liver injury (p=0.015).

The pattern of drug-induced liver injury differed according to the specific CDK4/6 inhibitor used (p<0.001), the author said. Hepatocellular injury was most common in patients receiving ribociclib (65.1 percent) or palbociclib (61.5 percent), whereas a mixed pattern of injury was largely seen in those receiving abemaciclib (59.3 percent). Among the 20 patients tested for antinuclear antibodies, five (20 percent) presented with titres ≥1/80.

In terms of timing, drug-induced liver injury occurred within the first 3 months of therapy in 52.9 percent of patients, with no difference according to the type of CDK4/6 inhibitor (p=0.521) or severity (p=0.516), Riveiro-Barciela said.

Management of liver injury

Corticosteroids were used to manage drug-induced liver injury in 16 patients (18.8 percent), mostly those with grade 4 severity according to CTCAE (p<0.001) or moderate severity based on DILI-IEWG (p=0.005). Corticosteroid use tended to be higher for those on ribociclib (p=0.092). The median duration of corticosteroid treatment was 43 days.

Ten patients (11.8 percent) underwent liver biopsy. While biopsies were more frequently performed in those with grade 4 liver injury according to CTCAE (p<0.001), the rates did not significantly differ across the different CDK6/6 inhibitors (p=0.794), according to Riveiro-Barciela. The most common findings were the presence of eosinophils (90 percent), bridging necrosis (40 percent), cholestasis (40 percent), interphase hepatitis (30 percent), and lymphocytic/lymphoplasmacytic infiltrate (50 percent).

After a median of 36 days, 70 (82.4 percent) patients underwent CDK4/6 inhibitor treatment rechallenge. Rechallenge was less frequent for those who previously experienced moderate or worse liver injury as defined by DILI-IEWG (p=0.022). The initial CDK4/6 inhibitor used (p=0.287) and liver injury severity based on CTCAE (p=0.507) did not significantly influence the rechallenge rate.

Patients who initially took ribociclib were more likely to be switched to another CDK4/6 inhibitor (p=0.031). Drug switching during rechallenge was also more common among those whose initial injury showed a hepatocellular pattern (p=0.039) and was grade 3 or 4 according to CTCAE (p<0.001).

After rechallenge, liver injury recurred in 19 patients (27.1 percent), but all these recurrences were mild, according to Riveiro-Barciela.

These data have important clinical implications, given that CDK4/6 inhibitors are the first-line therapy for HER2-negative metastatic breast cancer, she continued.

“The [current] management of CDK4/6 inhibitor-induced liver injury is heterogeneous, and its standardization is a necessity in view of the recent approval of ribociclib and abemaciclib as adjuvant therapy,” Riveiro-Barciela said.