LAUSR

In this issue of Targeted Oncology, the BI 853520 investigators present three complementary studies of BI 853520 that investigate this drug in both Western and Eastern patient populations, as well as investigating the effects of food and drug formulation on drug absorption [1–3]. It is the latest in the field of similar compounds against focal adhesion kinase (FAK), a pre-clinically promising target for cancer therapy. FAK is a multifunctional cytoplasmic tyrosine kinase that has been shown to play an important role in the regulation of proliferation, metastasis, angiogenesis and tumour microenvironment signalling [4]. Some of these effects are mediated through kinase-dependent signalling and others through kinase-independent signalling [1, 4]. Overexpression of FAK has been observed in multiple different malignancies and may contribute to tumour progression and aggressiveness [5]. Pre-clinically, inhibition of FAK has been shown to inhibit tumour growth [4, 5]. Anti-cancer drugs targeting FAK can broadly be divided into those that target kinase activity and those that target other functions such as the scaffolding functions provided by FAK [4, 5]. The most advanced of the drugs in testing have targeted the kinase activity of FAK, and include the drugs TAE226, VS4718, PF-00562271 (also known as a VS-6062) and defactinib (also known as VS-6063) [4]. Several phase 1 studies with these FAK inhibitors have been reported, namely PF-00562271 (IC50 1.5 nM), GSK2256098 (IC50 2–15 nM) and defactinib (IC50 0.6 nM) [6–8]. PF-00562271 and defactinib also inhibit Pyk2, whereas GSK2256098 does not [6–8]. All are potent ATPcompetitive inhibitors with good clinical safety, tolerability and pharmacokinetic (PK) profiles. However, efficacy has been limited to stable disease [6–8]. Defactinib progressed to phase 2 trials in KRAS-mutant lung cancer and mesothelioma (COMMAND trial), but again without evidence of objective responses [9, 10]. The development of defactinib for mesothelioma was subsequently terminated [10]. Similarly, TAE266 and VS4718 are also no longer in active clinical development [11]. The current studies on BI 853520 extend the information about this class of FAK kinase inhibitors [1–3]. BI 853520 is a highly potent and specific FAK inhibitor, with an IC50 of 1 nM and no meaningful activity against Pyk2 [1]. No obvious significant differences in safety and PK profiles across racial groups were observed [1, 2]. PK parameters were supportive of a once-daily dosing schedule with an MTD of 200 mg once daily, which is advantageous, although significant inter-patient variability was seen. Neither food nor liquid formulation appeared to have a substantial impact on the measured PK parameters of BI 853520 [3]. The dose-limiting toxicities were grade 3 proteinuria and fatigue, requiring dose reduction. The frequency of grade 3 proteinuria seen with BI 853520 (21%) [1] appeared more common than with other FAK inhibitors; proteinuria was not a major toxicity with PF-00562271 (1%) [6] or defactinib (0%) [8], while GSK2256098 reported grade 1–2 proteinuria (26%) [7]. Interestingly, the BI 853520 investigators were able to obtain kidney biopsies in two of their patients with grade 3 proteinuria and showed that this was associated with disjunction of the podocytes from the glomerular basement membrane and moderate-marked podocyte effacement. In the study, proteinuria was reversible and further dosing was possible with dose reductions. However, BI 853520 was not associated with headache and unconjugated hyperbilirubinemia as seen with other FAK inhibitors. From an efficacy viewpoint BI 853520 predominantly showed disease stabilisation, but interestingly, a confirmed partial response was seen in an Asian patient with gastric cancer. However, the modest monotherapy activity of FAK kinase inhibitors as a class makes their further development less attractive. Biomarkers are one potential avenue to improve their monotherapy efficacy. The inactivating mutation of the NF2 gene causes loss of Merlin expression and an increase in FAK activity. In Merlin-negative cancer cells, adhesion and proliferation signals are * Hui K. Gan [email protected]