Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies

Cellular interactions with the extracellular matrix play a pivotal role in tumor initiation, progression, and metastasis [1]. Focal adhesion kinase [FAK; also known as protein tyrosine kinase 2 (PTK2)] is a widely expressed, nonreceptor, cytoplasmic tyrosine kinase [1‐3] that is a key component of the focal adhesion complex, which plays an important role in integrating signals from integrins and growth factor receptors in both normal and cancer cells [1, 4], among other functions. A role for FAK in cancer development is suggested by its amplification, overexpression, and/or activation in a variety of human malignancies [1, 3, 5], including breast [6, 7], colorectal [7, 8], ovarian [9], prostate [10], and sarcoma [7, 11]. Research suggests that FAK signaling is involved in cellular proliferation, migration, angiogenesis, invasion, survival, and epithelial-mesenchymal transition, via a variety of different pathways [4]. In addition, FAK appears to play a role in tumor metabolism, and can promote glucose consumption, lipogenesis, and glutamine dependency to promote cancer cell proliferation, motility and survival [12]. FAK has been shown to be a central driver of the fibrotic and immunosuppressive tumor microenvironment that protects pancreatic ductal adenocarcinomas from immune surveillance [13]. Furthermore, through its effects on chemokine transcription in the cell nucleus, FAK can promote antitumor immune evasion [14].

Given its putative role in tumor development and progression, FAK has become a logical therapeutic target, and numerous attempts have been made to inhibit the oncogenic activity of FAK [4]. Preclinical studies have demonstrated antitumor activity with FAK blockade [15‐20], and several orally bioavailable, adenosine triphosphate (ATP)-competitive, small-molecule inhibitors of FAK are undergoing evaluation in early-phase clinical trials in patients with cancer, including VS-6063, GSK2256098, and PF-00562271 [21‐24].

BI 853520 is a novel, potent, highly selective, ATP-competitive inhibitor of FAK that has demonstrated activity in a variety of preclinical human tumor xenograft models [25]. In vitro, BI 853520 inhibited recombinant FAK with a half maximal (50%) inhibitory concentration (IC₅₀) of 1 nM [26], which is largely comparable to the IC₅₀ values reported for VS-6063 (0.6 nM) [23], PF-00562271 (1.5 nM) [18], and GSK2256098 (2–15 nM) [27]. BI 853520 has also demonstrated high selectivity; IC₅₀ for the related kinase proline-rich tyrosine kinase 2, PYK2, was > 50,000 nmol/L [26]. The antitumor activity of BI 853520 was found to vary widely across a diverse panel of 16 murine subcutaneous adenocarcinoma xenograft models, from complete tumor inhibition to an absolute lack of sensitivity [26]. Biomarker analysis suggests that the in vivo efficacy of BI 853520 in these models is linked to a mesenchymal tumor phenotype characterized by low E-cadherin messenger RNA (mRNA) and protein levels, and by low expression of the microRNA hsa-miR-200c-3p, an epithelial-specific microRNA that promotes E-cadherin expression [26]. All xenograft models that were highly sensitive to BI 853520, including kidney, lung, ovary, pancreas and prostate adenocarcinomas, were found to lack E-cadherin expression or to express low levels of E-cadherin [26]. Conversely, of five BI 853520-resistant models, three were E-cadherin positive. In murine breast cancer models, BI 853520 most effectively prevented the establishment of metastases in tumors in which E-cadherin was either deficient or downregulated [28].

We report here the first-in-human phase I study of BI 853520, which comprised a dose-escalation phase followed by an expansion phase in patients with advanced nonhematologic cancers.

This phase I trial demonstrated that continuous monotherapy with BI 853520 is feasible in heavily pretreated patients with advanced or metastatic nonhematologic malignancies; the MTD is determined at 200 mg QD.

The tolerability profile for BI 853520 is acceptable and is similar to that observed with other FAK inhibitors [e.g. VS-6063 (defactinib) and GSK2256098] [21, 22, 24]. The most common drug-related AEs included gastrointestinal events (nausea, diarrhea, vomiting), proteinuria, and fatigue, and were predominantly mild to moderate in severity.

No grade 4 or 5 drug-related AEs were reported; drug-related grade 3 AEs occurred in 35% of patients. Thirteen (21%) patients experienced grade 3 proteinuria, which was unexpected as preclinical toxicology studies did not identify any kidney abnormalities [31]. After the first occurrence of grade 3 proteinuria in a patient treated at the 300-mg dose, frequent monitoring of urine protein levels was implemented to facilitate early detection. Importantly, proteinuria was generally improved to grade 1 upon treatment interruption and subsequent dose reduction, suggesting a dose-dependent effect. To date, no predisposing or risk factors for the development of BI 853520-associated proteinuria have been identified, and no clear correlation was identified with prior nephrotoxic therapy. In kidney biopsies from two patients with grade 3 proteinuria, dysjunction of podocytes from the glomerular basement membrane and podocyte effacement was observed. FAK has been localized to the cytoplasm and nuclei of glomerular podocytes, and studies suggest that proteinuria may be related to activation of FAK in the glomerulus [32, 33]. However, the underlying mechanism of proteinuria following FAK inhibition remains unclear and requires further investigation. Proteinuria has also been reported as an AE following treatment with GSK2256098 [24] and PF-00562271 [21].

PK analysis demonstrated that BI 853520 was rapidly absorbed and exhibited at least biphasic disposition kinetics. A trend was observed toward an overproportional increase in mean exposure within the entire dose range investigated; however, interpatient variability of PK parameters was moderate to high. While this variability cannot yet be fully explained, it was within the expected range for an orally administered anticancer drug in the first dose-finding study. The PK data demonstrate oral bioavailability of BI 853520 and support a QD dosing schedule.

In five of eight cases, including three patients with soft tissue sarcoma, the ratio of active pFAK/total FAK was substantially reduced at the end of the first cycle, thus providing clinical evidence supporting target engagement with BI 853520 in patients treated with the 200 mg QD dose.

Disease control was observed in 27% of patients with a median duration of 99 days, and four patients achieved disease control for ≥ 150 days. No objective tumor responses were observed. In order to identify patients most likely to derive benefit from FAK inhibitors, we undertook an exploratory analysis of E-cadherin expression as a potential predictive biomarker [34]. There were no clear differences in disease control rate with respect to E-cadherin levels. However, it should be noted that the majority of patients with E-cadherin-negative tumors had soft tissue sarcomas, which are of mesenchymal origin and would not be expected to express E-cadherin at all. Based on this study, the potential predictive value of E-cadherin could not be determined, and further studies are warranted to identify other potential biomarkers to guide patient selection for FAK inhibitor treatment.

Given the cytostatic activity of BI 853520, the combination with other compounds such as immunotherapy [13, 19] should be considered for further development. In vitro and clinical studies suggest that combining FAK inhibitors with other biologic or chemotherapeutic agents such as MEK inhibitors, vascular endothelial growth factor (VEGF) inhibitors, immune checkpoint inhibitors, gemcitabine, paclitaxel, or cisplatin may overcome resistance, reduce metastasis and/or improve antitumor efficacy [13, 35‐39]. A separate phase I study of BI 853520 has been conducted in 21 Japanese and Taiwanese patients with advanced or metastatic solid tumors [40]. In this study, a similar safety and PK profile was observed, with an equivalent MTD of 200 mg QD. The most common drug-related AEs were proteinuria and gastrointestinal events. One patient with gastric cancer who received BI 853520 100 mg QD achieved a confirmed partial response, with disease control seen in 29% of patients.

These data demonstrate that BI 853520 has a manageable and acceptable safety profile, favorable PK, and preliminary antitumor activity, including, for some patients, SD lasting ≥ 150 days, and PD modulation at the MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. As single-agent activity is modest, future development should focus on BI 853520 in combination with other agents.