The FDA is updating the prescribing information and Patient Package Insert for CDK4/6 inhibitors to include a warning that the treatments in rare cases may cause severe inflammation of the lungs.
The FDA is updating the prescribing information and Patient Package Insert for the CDK4/6 inhibitors palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) to include a warning that the treatments in rare cases may cause severe inflammation of the lungs.1
The inflammation can be life-threatening, so the FDA recommends that patients receiving CDK4/6 inhibitors should immediately contact their healthcare professional if they experience shortness of breath with low activity or while at rest, or discomfort or difficulty breathing. The warning also stipulates that patients should not stop taking a CDK4/6 inhibitor without first consulting with their healthcare professional.
The agency noted in its statement, however, that, “The overall benefit of CDK4/6 inhibitors is still greater than the risks when used as prescribed.”
Palbociclib is approved for use in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men with HR-positive/HER2-negative breast cancer. It is also approved as a second-line therapy for these patients in combination with fulvestrant after disease progression on endocrine therapy.
The full approval for palbociclib in the frontline setting was based on data from the phase III PALOMA-2 trial.2 Results available at the time of approval showed that adding palbociclib to letrozole reduced the risk of disease progression by 42% compared with letrozole alone. The median progression-free survival (PFS) was improved by more than 10 months with the addition of palbociclib.
Ninety-nine percent of patients in the palbociclib arm experienced a hematologic adverse event (AE) of any grade, including neutropenia (80%), leukopenia (39%), anemia (24%), and thrombocytopenia (16%). The grade 3 rates of these AEs in the palbociclib arm were 56%, 24%, 5%, and 1%, respectively and the grade 4 rates were 10%, 1%, <1%, and <1%, respectively. Overall, 62% and 14% of patients in the palbociclib arm experienced a grade 3 and grade 4 hematologic AE, respectively.
In the combination arm, the most common nonhematologic all-grade AEs included fatigue (37%), nausea (35%), arthralgia, (33%) alopecia (33%), diarrhea (26%), cough (25%), back pain (22%), headache (21%), and hot flush (21%). Sixty-two percent of patients in the palbociclib arm had a grade 3 nonhematologic AE, with the most frequent being fatigue (2%) and asthenia (2%). Grade 4 nonhematologic AEs occurred in 14% of patients in the palbociclib arm.
Serious AEs occurred in 19.6% of the palbociclib arm compared with 12.6% of the control arm. The most common serious AEs with the palbociclib combination versus letrozole alone were neutropenia (1.6% vs 0) and pulmonary embolism (0.9% vs 1.4%).
Ribociclib is approved for use in combination with an aromatase inhibitor for the first-line treatment of pre/perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. The agent is also approved in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as a frontline therapy or after disease progression on endocrine therapy.
The frontline indication for ribociclib plus an aromatase inhibitor was based on the phase III MONALEESA-7 trial, in which combining ribociclib with an AI resulted in a 14-month improvement in median PFS compared with an AI alone (27.5 vs 13.8 months; HR, 0.569; 95% CI, 0.436-0.743).3
Other AEs included hot flashes, nausea, leukopenia, and joint pain/stiffness. The most common (≥5%) grade 3/4 AEs in patients receiving ribociclib combination therapy compared to endocrine therapy alone were neutropenia (60.6% vs 3.6%) and leukopenia (14.3% vs 1.2%).
Abemaciclib is approved for use in combination was an aromatase inhibitor as a frontline therapy for patients with HR-positive/HER2-negative advanced or metastatic breast cancer. In the second-line setting, the agent is approved for use with fulvestrant after disease progression on endocrine therapy. The CDK4/6 inhibitor also has a third indication as a monotherapy for patients who progress after endocrine therapy and prior chemotherapy in the metastatic setting.
The frontline indication for abemaciclib was based on data from the phase III MONARCH 3 trial, in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the nonsteroidal aromatase inhibitor alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer.4
The most common AE associated with abemaciclib was diarrhea, which occurred in 81.3% of patients treated with the CDK4/6 inhibitor versus 29.8% of those in the control arm. These events were primarily grade 1/2 in both arms. With abemaciclib there was no grade 4 diarrhea and grade 3 diarrhea occurred in 9.5% of patients.
In addition to diarrhea, neutropenia was also common, which is a known AE associated with CDK4/6 inhibition. This AE was seen in 41.3% of those treated with abemaciclib versus 1.9% in the control arm. Only 1 patient developed febrile neutropenia in the abemaciclib arm.
Other common AEs with abemaciclib versus placebo, respectively, included fatigue (40.1% vs 31.7%), nausea (38.5% vs 19.9%), abdominal pain (29.1% vs 11.8%), anemia (28.4% vs 5.0%), vomiting (28.4% vs 11.8%), alopecia (26.6% vs 10.6%), decreased appetite (24.5% vs 9.3%), and leukopenia (20.8% vs 2.5%). Additionally, grade 2 creatinine increase was experienced by 52.9% of those in the abemaciclib arm versus 4.5% with placebo.
Overall, 27.5% of patients in the abemaciclib arm experienced a serious AE versus 14.9% of those in the control arm. There were significantly more deaths from AEs in the abemaciclib arm (2.4%) versus placebo group (1.2%). Deaths in the investigational arm were attributed to lung infection (n = 3), embolism (n = 2), cerebral ischemia (n = 1), pneumonitis (n =1), and respiratory failure (n = 1). Additionally, venous thromboembolic events occurred in 4.9% of patients treated with abemaciclib versus 0.6% with placebo.hr />
Neutropenia was the most frequently reported AE for both the experimental arm (76%) and the placebo arm (8%) in updated safety results. Six in 10 patients in the ribociclib arm experienced grade 3/4 neutropenia compared with 4% in the placebo arm, but the condition was asymptomatic in most patients. Two percent of patients in the experimental arm and 1% in the placebo arm experienced neutropenia associated with fever and infection.