The arrival of the CDK 4/6 inhibitors offered new hope for patients with advanced hormone-receptor–positive (HR+)/human epidermal growth factor receptor (HER)-2–negative breast cancer (BC). However, clinical regulatory trials designed to secure drug approval demonstrated the occurrence of a few severe and fatal cases of interstitial lung disease (ILD)/pneumonitis that were attributed to the use of these agents.

This prompted the FDA to include the occurrence of ILD/pneumonitis in the "Warning and Precautions" section of the product labeling for these compounds. The incidence of ILD/pneumonitis reported from clinical trials ranges from 3.3% for abemaciclib, to 1.1% for ribociclib, to 1.00% for palbociclib, and to 0.4% for trilaciclib; however, clinical regulatory trials often underestimate the true incidence of adverse events as this is not seen unless the drugs are available for use in the general population.

The purpose of this systematic review and meta-analysis (SR/MA) was to evaluate the overall incidence and risk of ILD/pneumonitis related to CDK 4/6 inhibitors in randomized clinical trials (RCTs). Investigators searched multiple databases, including PubMed, the Cochrane Central Registry of Controlled Trials, Embase, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang,, oncological meeting proceedings, FDA drug labeling, and reference lists of trials and reviews for RCTs to assess the risk of ILD/pneumonitis from CKD 4/6 inhibitors. Data were collected from the inception of the databases until October 1, 2021.

Studies were included in this SR/MA if they were phase II or III RCTs with participants assigned to either CDK 4/6 inhibitors or a control group; reported on ILD/pneumonitis; and were published in English or Chinese. Exclusion criteria included case reports, reviews, case-control studies, cohort studies, phase I studies, single-arm phase II studies, randomized, controlled trials without available outcomes, and RCTs with CKD 4/6 inhibitors in all arms.

The primary outcomes were the incidence and risk of all-grade ILD/pneumonitis in patients treated with CDK 4/6 inhibitors compared with controls. Secondary outcomes were the incidence and risk of grade 3 or higher ILD/pneumonitis.

Twelve studies were included in this SR/MA (three phase II and nine phase III clinical trials) that represented 16,060 patients. Nine of these studies were conducted in patients with BC. The rest were in patients with non-small cell lung cancer and head and neck cancer. Abemaciclib was studied in seven trials, three trials examined the use of palbociclib, and two trials involved the use of ribociclib. Seven of the studies were double-blinded.

Investigators found that the incidence of all-grade ILD/pneumonitis in patients treated with CDK 4/6 inhibitors was 1.6% compared with 0.7% in the control group. Due to the rare incidence of ILD/pneumonitis and the need to pool the data, researchers utilized the Peto odds ratio (Peto OR).
The use of CDK 4/6 inhibitors was associated with a 2.12 times greater risk of developing all-grade ILD/pneumonitis compared with the control group (Petro OR 2.12, 95% CI 1.57-2.86, P <.00001). Use of CKD 4/6 inhibitors was also associated with a 2.23-fold greater risk of developing all-grade ILD and a 1.86-fold greater risk of developing all-grade pneumonitis compared with controls (Peto OR 2.23, 95% CI 1.55-3.21, P <.0001 and Peto OR 1.86, 95% CI 1.07-3.25, P = .03, respectively). There was also a 3.22-fold greater risk of developing grade 3 or higher ILD/pneumonitis compared with controls (Peto OR 3.22, 95% CI 1.28-8.09, P = .01). Event rates ranged from 0.2% in the treatment group to a low of 0.05% in the control group.

Greater risk of developing ILD/pneumonitis was seen in trials involving BC patients, combination therapy, phase III trials, when endocrine therapy was used as a control, and when CDK 4/6 inhibitors were utilized as adjuvant therapy.

The incidence of all-grade ILD/pneumonitis in patients treated with palbociclib, abemaciclib, and ribociclib was 0.5%, 2.5%, and 1.1%, respectively. Both palbociclib (Peto OR 2.41, 95% CI 1.04-5.59, P = .04) and abemaciclib (Peto OR 2.10, 95% CI 1.51-2.92, P = .0000) significantly increased the risk of ILD/pneumonitis compared with controls.

Pharmacists should be aware of the results from this latest and most comprehensive meta-analysis that evaluated the incidence and risk of all-grade and grade 3 or higher ILD/pneumonitis in cancer patients treated with CDK 4/6 inhibitors and should target patients on these medications for closer monitoring.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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