Cardiac safety of afatinib: a review of data from clinical trials

Abstract

Background: Afatinib is an oral irreversible ErbB family blocker that targets epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and HER4 (ErbB4) and is approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) with certain sensitizing EGFR mutations. As anti-HER2 therapies have been associated with cardiac dysfunction, we report cardiac safety data for afatinib.

Methods: Cardiac data were analyzed from phase III trials of afatinib 40 mg in treatment-naive patients with EGFR mutation-positive NSCLC (LUX-Lung 3 [LL3]; n = 229 afatinib, n = 111 chemotherapy) and afatinib 50 mg in EGFR tyrosine kinase inhibitor-pretreated NSCLC patients (LUX-Lung 1 [LL1]; n = 390 afatinib, n = 195 placebo). Additional pooled data from 49 trials (n = 3865 afatinib-treated patients) is reported. Cardiac failure adverse events (CF-AEs), including symptomatic cardiac failure and depressed left ventricular ejection fraction (LVEF), were analyzed.

Results: Time at risk-adjusted CF-AE rates (events/100 patient-years) were similar for afatinib versus placebo in LL1 (2.40 vs 2.23) and versus chemotherapy in LL3 (2.28 vs 2.92); the pooled afatinib CF-AE rate (2.88) was consistent with that for both trials. The frequency of clinically significant LVEF reductions was higher for chemotherapy in LL3 (2/15 [13.3 %], afatinib 13/208 [6.3 %]; p = 0.267) and similar to placebo in LL1 (5/122 [4.1 %], afatinib 14/304 [4.6 %]; p = 1.000).

Conclusion: Afatinib was not associated with cardiac failure or LVEF reductions in the afatinib clinical trial program.

Keywords: Afatinib; Cardiac safety; Non–small cell lung cancer; Tyrosine kinase inhibitor.

Fig. 1

a Relative LVEF change from baseline in LL3. Although there was no global tendency to decline, there were 3 LVEF measurements in LL3 that were reduced from baseline, and there were no increases beyond the 700-day mark; these represent 3 distinct patients whose LVEF reductions were not clinically significant (<10 % change from baseline) and were >50 % (the lowest LVEF was 61 %). b Relative LVEF change from baseline in LL1. Although there was no global tendency to decline beyond the 700-day mark, 7 LVEF measurements were reduced or at neutral; these 7 LVEF measurements were from 2 patients, and 1 patient had 3 measurements beyond day 700 (76.1 % on day 726, 76.9 % on day 810, and 74.4 % on day 894) that were close to his baseline LVEF of 76.80 %. Another patient had 4 LVEF measurements beyond day 700 (76.3 % on day 735, 65.3 % on day 819, 56.5 % on day 903, and 55.0 % on day 945); disease progression was diagnosed around the time of the final LVEF measurement. Abbreviations: LVEF, left ventricular ejection fraction; LL3, LUX-Lung 3; LL1, LUX-Lung 1

Fig. 2

Adjudicated LVEF reductions in the afatinib treatment arms of LL3 and LL1. Six of the 13 patients in the afatinib group for LL3 achieved a full recovery, and 2 patients had a partial recovery. Follow-up ECHOs were not available for 5 patients, 4 of whom had a final LVEF measurement of >50 %. The remaining patient had a final LVEF measurement of 47 %. Three of the 14 patients in the afatinib group for LL1 achieved a full recovery, and 2 patients had a partial recovery. Follow-up ECHOs were not available for 9 patients, 7 of whom had a final LVEF measurement of >50 %. One patient had disease progression and another patient experienced a final LVEF measurement of 46 %. Clinically significant LVEF reductions were examined using established criteria: LVEF <50 and ≥10 % decrease from baseline or LVEF ≥50 and ≥15 % decrease from baseline. Abbreviations: LVEF, left ventricular ejection fraction; LL3, LUX-Lung 3; LL1, LUX-Lung 1; ECHO, echocardiogram; SD, standard deviation. ^*Mean (SD) percent change from baseline to minimum LVEF during treatment: −24.90 (4.86) for afatinib and −29.30 (0.99) for chemotherapy; mean (SD) percent change from baseline to last LVEF during treatment: −13.95 (10.83) for afatinib and −29.30 (0.99) for chemotherapy. ^†Mean (SD) percent change from baseline to minimum LVEF during treatment: −22.71 (3.33) for afatinib and −31.24 (7.94) for placebo; mean (SD) percent change from baseline to last LVEF during treatment: −16.88 (8.45) for afatinib and −29.38 (11.52) for placebo. ^‡Last reported LVEF measurement at database lock