A. Douglas Laird

Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth

The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. Mol Cancer Ther; 10(12); 2298–308. ©2011 AACR.

Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents

Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa™ and Tarceva™), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec™). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance.

SU6668 inhibits Flk-1/KDR and PDGFRβ in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice

SU6668 is a small molecule inhibitor of the angiogenic receptor tyrosine kinases Flk‐1/KDR, PDGFRβ, and FGFR1. In mice, SU6668 treatment resulted in regression or growth arrest of all large established human tumor xenografts examined associated with loss of tumor cellularity. The events underlying loss of tumor cellularity were elucidated in detail in several tumor models. SU6668 treatment induced apoptosis in tumor microvessels within 6 h of the initiation of treatment. Dose‐dependent decreases in tumor microvessel density were observed within 3 days of the first treatment. These changes were accompanied by decreased tumor cell proliferation and increased tumor cell apoptosis. Rapid increases in VEGF transcript levels were seen, consistent with the induction of tumor hypoxia. Using Western blot analyses, we determined that these in vivo antiangiogenic and proapoptotic effects of SU6668 occur at doses comparable to those required to inhibit Flk‐1/KDR and PDGFRβ phosphorylation in tumors. Potent, dose‐dependent inhibition of Flk‐1/KDR activity in vivo was independently demonstrated using vascular permeability as a readout. These data demonstrate that SU6668‐induced inhibition of angiogenic receptor tyrosine kinase activity in vivo is associated with rapid vessel killing in tumors, leading to broad and potent antitumor effects.

Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248

Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PDGFRβ and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors. [Mol Cancer Ther 2006;5(5);1280–9]

SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-β, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774–82]

Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.

Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non–small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. Experimental Design: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors. Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.

Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

PURPOSE Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. RESULTS One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. CONCLUSION The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96–7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease. Clin Cancer Res; 20(9); 2445–56. ©2014 AACR.

Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors

Introduction: The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors. Methods: Forty-six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response. Results: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients. Conclusion: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.

BACKGROUND This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. METHODS Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. RESULTS The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. CONCLUSIONS Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.