Afatinib (BIBW‐2992): a novel dual EGFR/HER2neu inhibitor with promising activity in non‐small‐cell lung cancer

Lung cancer is the leading cause of cancer death in the USA. Approximately 215,020 new cases (114,690 men and 100,330 women) were diag‐ nosed and 161,840 died of lung cancer in 2008 (National Cancer Institute [NCI] 2009). The extremely high lung cancer‐related mortality, demonstrates the limited efficacy of traditional cytotoxic chemotherapy in patients with this disease [1,2]. In the past few years, a number of new agents have been demonstrated to have significant activity in non‐small‐cell lung can‐ cer (NSCLC). These include some new chemo‐ therapy agents and mainly targeted agents, including antiangiogenic drugs and agents blocking the EGF receptor (EGFR) pathway. EGFR is a member of the ErbB receptor tyrosine kinase family, which includes HER2, HER3 and HER4. Recently observed patterns of oncogenic mutation of EGFR and HER2 present an attrac‐ tive option for targeted therapy in patients with NSCLC [3–5]. Erlotinib and gefitinib are part of a first‐generation of small molecules with com‐ petitive reversible EGFR tyrosine kinase inhibi‐ tory (TKI) activity. Erlotinib and gefitinib have cytotoxic activity against lung cancer cells har‐ boring somatic gain‐of‐function mutations in the intracellular kinase domain of EGFR; most commonly, small in‐frame deletions in exon 19 or the L858R missense mutation in exon 21 [6]. Even when dramatic clinical responses are observed in this patient population (70–80%) [7–10], caused by alterations in the ATP cleft associated with these mutations, and biological dependence of the cancer cells on the increased survival signals transduced by the mutant receptors or ‘oncogene addiction’ [11,12], the average response has been demonstrated to last between 6 and 8 months (Kris et al.) [13] and 9.2 and 10.8 months (Mitsudomi et al. and Maemondo et al.) [14,15], before the cells develop acquired drug resistance to these reversible TKIs and relapse [16]. A spe‐ cific secondary mutation in the kinase domain of the EGFR, located in exon 20, leads to a sub‐ stitution of Met for Thr at position 790 (T790M) and was found responsible for rendering the cells insensitive to the TKIs [17]. Although the T790M mutation was not initially detected in untreated tumor samples, more recently, the same mutation has been reported to be coexpressed with sensitive mutations in patients never treated with EGFR TKIs, accounting for the primary resistance of the harboring cells to erlotinib and gefitinib [18]. Additional mechanisms of resistance to gefitinib and erlotinib have been reported, including focal amplification of the MET proto‐oncogene, by driving ErbB3 (HER3)‐dependent activation of PI3K, a pathway believed to be specific to the EGFR/ErbB family of receptors, which is detected in 22% of lung cancer specimens [19], and primary resistance caused small in‐frame Lung cancer is not one disease but many diseases with specific molecular profiles and treatment alternatives. EGF receptor-activating mutations predict a high, albeit short-lived, response to reversible tyrosine kinase inhibitors (e.g., gefitinib and erlotinib). Acquired resistance mutations can result in tumor progression. Dual EGFR/HER2 irreversible inhibitors are small novel molecules that can overcome gefitinib/erlotinib resistance by potentially circumventing multiple mechanisms of acquired resistance, as shown in vitro. Afatinib is an irreversible inhibitor with potent phosphorylation inhibitory activity of both EGF receptor and HER2. Durable responses were observed in Phase I trials in advanced non-small-cell lung cancer at 50 mg once daily. In Phase II trials, reduction in tumor size was observed in 90% of patients. The objective response and disease control rate were 62 and 94%, respectively. Median progression-free survival was estimated at 12 months (95% CI: 10.0–19.2). The most common drug-related adverse events were diarrhea and rash/acne, 18% were grade 3 and none grade 4. LUX-Lung 1, one of two global Phase III studies, was presented in October 2010. At primary ana lysis (358 events), the study did not meet its primary end point to improve overall survival compared with placebo.