Afatinib is an oral, irreversible ErbB family blocker that targets the epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and HER4 (ErbB4) [1, 2], which results in the inhibition of ErbB3/HER3 phosphorylation . This agent was approved by the US Food and Drug Administration (FDA) in July 2013 for the first-line treatment of metastatic non–small cell lung cancer (NSCLC) in patients whose disease harbors common EGFR mutations, namely exon 19 deletions (Del19) or exon 21 (L858R) substitutions, as identified by an FDA-approved test . The first-line, phase III LUX-Lung 3 (LL3) trial in metastatic EGFR mutation–positive NSCLC had documented a significant improvement in the primary endpoint of progression-free survival (PFS) with afatinib 40 mg/day versus pemetrexed/cisplatin (11.1 vs 6.9 months; hazard ratio [HR], 0.58; p = 0.001) for all patients with EGFR mutations . A larger median PFS difference was noted for patients with common mutations (13.6 months for afatinib vs 6.9 months for chemotherapy; HR, 0.47; p <0.001) [5, 6]. The LUX-Lung 1 (LL1) trial was a phase IIb/III study in patients with chemotherapy- and EGFR tyrosine kinase inhibitor (TKI)–progressive NSCLC, in which afatinib 50 mg/day prolonged PFS versus placebo (3.3 vs 1.1 months; HR, 0.38; p <0.0001), but there was no corresponding improvement in the primary endpoint of overall survival (OS; 10.8 vs 12.0 months; HR, 1.08; p = 0.74) . First-line afatinib significantly prolonged OS for patients with Del19 mutations compared with chemotherapy in LL3 and LUX-Lung 6 (HR, 0.54; p = 0.0015 and HR, 0.64; p = 0.023, respectively) . The approved administration of afatinib is at the 40-mg dose level, to be given orally once daily .
The HER2 pathway is known to play a role in normal cardiac function . HER2 is expressed in the heart, and preclinical studies suggest that HER2 downstream pathways are important for cardiomyocyte survival . Therefore, cardiotoxicity is an established safety concern with the use of anticancer agents designed to target this particular pathway, including the anti-HER2 monoclonal antibody trastuzumab [11, 12] and the anti-HER2/EGFR TKI lapatinib . The cardiac adverse event (AE) profile of molecularly targeted agents, including the aforementioned anti-HER2 therapies and multitargeted small-molecule TKIs, such as sunitinib, primarily consists of symptomatic or asymptomatic declines in left ventricular ejection fraction (LVEF) or alterations in blood pressure, with prolongation of the corrected QT interval and cardiac dysrhythmias as additional risks [14–17]. Cardiac AEs reported with these newer agents are typically low-grade and reversible, including LVEF reductions [18, 19] and blood pressure elevations with or without secondary or end-organ involvement [17, 20]. Although trastuzumab- and TKI-attributable high-grade cardiac AEs and cardiovascular mortality are rare, concerns regarding the inherent propensity for cardiovascular AEs have resulted in widespread monitoring and assessment of multiple cardiac parameters in patients receiving these agents. At the same time, however, assessing their true clinical impact has been problematic. Unlike the anthracyclines, for which cardiotoxicity is cumulative and dose related , cardiac AEs associated with targeted therapies have been far less predictable, have generally been reversible, and have not precluded reintroduction of these agents once the initial cardiac event has been controlled [18–20]. Given the potential for cardiotoxicity with HER2 inhibitors and the known activity of afatinib against several ErbB family members, including HER2, it is important to establish the cardiovascular AE profile for afatinib as part of the clinical development process.
A phase II trial of afatinib utilized electrocardiograms (ECGs) to assess possible QTcF (QT interval corrected by the Fridericia formula) effects and found no afatinib effect on cardiac repolarization . The analyses reported herein were conducted to further characterize the cardiac safety of afatinib, based on cardiac failure AEs (CF-AEs), including symptomatic cardiac failure and LVEF reductions, reported from LL1 and LL3, as well as patient information available from a large number of additional trials that was derived from the broader clinical databases.
Patients and methods
Study design, patients, and treatment
The study designs of LL1 (phase IIb/III) and LL3 (phase III), both conducted in patients with stage IIIB/IV adenocarcinoma of the lung, are described in detail in their primary publications [5, 7]. In brief, in LL3, EGFR TKI–naive patients with NSCLC and a documented EGFR mutation were randomly assigned in a 2:1 ratio to receive either afatinib 40 mg (229 patients) or chemotherapy with pemetrexed/cisplatin (111 patients) . LL1 was conducted in EGFR TKI– and chemotherapy-pretreated (up to 2 lines of chemotherapy) patients, who were randomly assigned 2:1 to receive afatinib 50 mg/day (390 patients) or placebo (195 patients) . In addition to the afatinib-treated patients from LL3 and LL1 (n = 619), 3246 additional patients from all 47 completed, Boehringer Ingelheim–sponsored, phase I-III clinical trials of afatinib, as well as from reported clinical experience, were included in the pooled analysis. No trials were excluded except for 1 blinded clinical trial of afatinib in head and neck cancer that included only 3 patients at the time of the data cut. Overall, these trials provided a combined cohort of 3865 patients treated with afatinib, as monotherapy or as a component of a combination regimen. This pooled data analysis set is a heterogeneous population in terms of tumor type, prior therapy, and afatinib dose and treatment.
When feasible, LVEF was assessed at baseline, every 12 weeks, and at the end of treatment. In all trials, AEs were categorized and graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 [5, 7].
All studies were conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice, and the protocols were approved by local ethics committees at each participating center.
The endpoints of interest for this secondary analysis were cardiac failure–related AEs and clinically significant LVEF reductions, per multigated acquisition (MUGA) scan or echocardiogram (ECHO). The Standardized MedDRA Query (SMQ) of “Cardiac Failure” was utilized to identify CF-AEs (eg, acute left ventricular failure, high-output cardiac failure, left ventricular failure) that were reported during the routine AE surveillance of the trials. The SMQ was modified by removing preferred terms considered non-specific (eg, edema) that are common in the target population. Time at risk (TAR)–adjusted CF-AE rates were used to compare treatment arms in LL1 and LL3 due to large differences in treatment exposures. TAR-adjusted CF-AE rates were calculated as events per 100 patient-years, with the treatment groups being compared using proportional hazards regression. Clinically significant LVEF reductions were examined using the following criteria: LVEF <50 and ≥10 % decrease from baseline or LVEF ≥50 and ≥15 % decrease from baseline, with partial recovery defined as an increase in ejection fraction of ≥10 percentage points from the nadir to a level ≤5 percentage points below baseline, and full recovery defined as recovery to within 5 percentage points of baseline. The frequency of clinically significant LVEF reductions in the 2 treatment arms of LL3 and LL1 were compared using 2 × 2 contingency tables and Fisher exact test to determine 2-tailed p-values.