FDA Warns of Lung Inflammation From CDK4/6 Inhibitor Use in Breast Cancers

The FDA has issued a warning for a rare, but severe, lung inflammation that could be caused by the use of CDK4/6 inhibition in patients with advanced breast cancers.¹The warning applies to treatment with palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) specifically, but warnings of the risk of lung inflammation have been approved to be added to the prescribing information for the entire class of CDK4/6 inhibitors.

The agency urged healthcare professionals to monitor patients with breast cancer being treated with these agents for signs of interstitial lung disease and/or pneumonitis. Symptoms could include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom other causes have been excluded.

For those who show new or worsening pulmonary symptoms, the FDA suggested interrupting treatment and permanently discontinuing CDK4/6 inhibition in those who have severe interstitial lung disease and/or pneumonitis.

Yet, the agency maintained that in the warning statement that “the overall benefit of CDK4/6 inhibitors is still greater than the risks when used as prescribed.”

CDK4/6 inhibitors have been approved for treatment in combination with hormone therapy to treat adult patients with hormone receptor (HR)—positive, HER2-negative advanced or metastatic breast cancer. The first CDK4/6 inhibitor, palbociclib, was approved for a breast cancer indication in February 2015.

Although cases of serious lung inflammation, including fatalities, were observed in clinical trials with all of the CDK4/6 inhibitors, each of the agents also demonstrated significant improvements in progression-free survival for patients.

Palbociclib first received an accelerated approval when used in combination with letrozole as initial endocrine therapy for postmenopausal women with estrogen receptor (ER)—positive, HER2-negative advanced or metastatic breast cancer. The approval has since been expanded to include men as well. Additionally, the CDK4/6 inhibitor is approved in combination with fulvestrant for the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have disease progression following endocrine therapy.

The incidence of interstitial lung disease and non-infectious pneumonitis were observed after the approval of palbociclib, according to the prescribing information for the agent.²

Abemaciclib was approved by the FDA in 2017 in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who have disease progression following endocrine therapy. The agent was also approved as a monotherapy for both men and women with HR-positive, HER2-negative advanced or metastatic breast cancer who have disease progression after endocrine therapy and who have received chemotherapy in the metastatic setting.

In the MONARCH 3 trial, which investigated the combination of abemaciclib plus an aromatase inhibitor or an aromatase inhibitor alone in postmenopausal women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer who were untreated in this setting, 1 patient who was treated with the combination died as a result of pneumonitis. Two patients also died due to pneumonitis in the MONARCH 2 trial, which looked at the CDK4/6 inhibitor plus fulvestrant versus fulvestrant alone in women with HR-positive, HER2-negative advanced or metastatic breast cancer who have disease progression following endocrine therapy.³Findings from the MONARCH 2 trial supported the approval for abemaciclib.

Post-approval cases of interstitial lung disease/pneumonitis were also seen, according to the prescribing information.³

Ribociclib was also approved in 2017 in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

The latest prescribing information for ribociclib, prior to the FDA warning, did not include mention of cases of interstitial lung disease/pneumonitis.⁴

Risk factors leading to the development of lung inflammation with CDK4/6 inhibition use have not yet been identified.

References

1. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. FDA website. Posted September 13, 2019. https://bit.ly/2lUvT1q. Accessed September 16, 2019.
2. Ibrance (palbociclib) [prescribing information]. Pfizer; April 2019. https://bit.ly/2kMcKPd.
3. Verzenio (abemaciclib) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; June 2019. https://bit.ly/2JIpYU6.
4. Kisqali (ribociclib) [prescribing information]. Novartis; February 2019. https://bit.ly/2EZPt5E.