Tanya B Dorff, Sumanta K Pal and David I Quinn. Novel tyrosine kinase inhibitors for renal cell carcinoma. Expert Rev. Clin. Pharmacol. 7(1), 67–73 (2014)
Nearly 65,000 people are diagnosed with renal cell carcinoma (RCC) each year in the USA . Up to 30% of patients present metastatic disease  and another 25% relapse after curative-intent nephrectomy . For these patients, systemic therapy formerly consisted of cytokines, IFN-a and IL-2, until understanding of the biology of RCC led to the development of agents targeting the VEGF. Agents inhibiting the VEGF receptors such as sunitinib, sorafenib and bevacizumab have achieved tremendous success in RCC, with trials typically showing a doubling of time to disease progression compared to interferon or placebo [4–6]. However, the tyrosine kinase inhibitors (TKI) targeting VEGF also inhibit other receptor tyrosine kinases, including platelet derived growth factor receptor (PDGFR) and c-kit. The ‘off-target’ inhibitions are thought to account for some of their toxicities such as hand-foot syndrome, which necessitate dose reductions and interruptions for patients. Thus, one potential strategy which has been investigated has been narrowing the spectrum of receptors inhibited, while increasing the potency of binding to VEGF receptors. This has led to the development of drugs such as axitinib and tivozanib. Alternatively, novel TKIs can target additional pathways felt to relate to RCC biology or resistance to VEGF inhibition. This type of strategy is being pursued via agents such as cabozantinib and dovitinib. In this review, we will highlight four new agents with ongoing large-scale clinical trials in metastatic RCC: tivozanib; dovitinib; regorafenib; and cabozantinib.
Importantly, non-clear cell RCCs have unique biology which is not dominanted by VEGF and could benefit substantially from novel TKI development targeting their unique biology. For instance, hereditary papillary RCC type 1 is related to c-MET mutation . Inhibiting signaling through the MET pathway has already shown promise in early phase clinical trials , and additional trials are underway with tivantinib (ARQ 197) and foretinib. We will review the development of tivantinib and foretinib as examples of a promising approach for alternate histology renal cancers.
Due to the perception that the toxicities of early VEGF receptor TKIs could be related to ‘offtarget’ inhibition of other receptors, and that efficacy may be limited by relatively low binding affinity to VEGF receptors, additional compounds were sought for development which would be more narrowly and potently focused on VEGF receptors. Tivozanib emerged as a potent VEGF receptor TKI with high activity against VEGFR2, and strong inhibition of VEGFR1 and VEGFR3, but without binding to PDGFR and c-kit [9,10].
Phase I studies identified excess toxicity at 2 mg/day dosing on the schedule of 4 weeks-on, 2 weeks-off due to dose-limiting toxicities of ataxia, hypertension and proteinuria . The 1.5 mg/day dose resulted in grade 3 hypertension without proteinuria, and this dose was selected for Phase II testing. Plasma VEGF-A concentrations increased after exposure to tivozanib, and soluble VEGFR2 levels declined. A strong efficacy signal was seen for the nine patients with RCC in this study: two had partial responses and six had disease stabilization. A Phase Ib study of the 1.5 mg dose scheduled for 3 weeks-on followed by 1 week-off revealed a favorable toxicity profile, and this dosing schedule was selected for further testing.
A randomized discontinuation design was used for the Phase II study of tivozanib in RCC . Two hundred and seventy two patients with metastatic RCC (83% clear cell) were enrolled. Prior VEGF-targeted therapy was not required, but 46% had received prior treatment; 73% of patients had undergone nephrectomy. After 16 weeks of treatment with tivozanib 1.5 mg on the 3 week-on, 1 week-off schedule, patients who had experienced partial response (>25% reduction in measurements of disease volume) continued to take tivozanib, and those with disease progression (>25% increase in tumor measurements) discontinued therapy. The 118 patients with stable disease were randomly assigned to placebo or to continue tivozanib. In this group, the median progression-free survival (PFS) was 10.3 months for tivozanib compared to 3.3 months for placebo. The adverse events in this trial reflected the Phase I experience, with a high rate of hypertension, and a new side effect of dysphonia became recognized as a frequent side effect. TIVO-1 was an open-label, randomized Phase III trial for patients with clear cell RCC and no more than one prior systemic therapy, which could not include VEGF or mTOR targeted therapy, with a primary endpoint of PFS (TABLE 1). A total of 517 patients were randomized to receive tivozanib 1.5 mg/ day for 3 week-on, 1 week-off or to receive sorafenib 400 mg twice daily (b.i.d.) without a break. Disease progression was assessed every 8 weeks. The trial met its primary endpoint, with median PFS performed by central review of 11.9 months for tivozanib compared to 9.1 months for sorafenib (hazard ratio: 0.797; 95% CI: 0.58–0.98; p = 0.042). By investigator determination, the median PFS for tivozanib was 14.7 months compared to 9.6 months for sorafenib (hazard ratio: 0.72; p = 0.003) . The secondary endpoint of response rate also favored tivozanib, with an overall response rate of 33% for tivozanib compared to 23% for sorafenib. The secondary endpoint of overall survival was not statistically significantly different, which was 28.8 months for tivozanib compared to 29.3 months for sorafenib. One potential explanation for this is that cross-over to tivozanib was allowed for patients on the sorafenib arm who experienced disease progression; 155 patients (60%) crossed-over to tivozanib after sorafenib. In addition, 64% of patients on the tivozanib arm did not proceed further to receive any further therapy, which may have limited their survival. Notably, sorafenib pre-treated patients did experience significant responses to tivozanib; 8% had partial response with median duration 11 months, and 65% had stable disease for a median duration of 12.7 months (minimum 7 months), with overall 71% of patients showing some degree of tumor volume reduction .
During TIVO-1, the toxicity profile of tivozanib was similar to that described in the Phase II study. Patients treated with tivozanib were more likely to experience hypertension (44 vs 34% for sorafenib) and dysphonia (21 vs 5%) but less likely to experience hand-foot syndrome (13 vs 54% for sorafenib), diarrhea (22 vs 32% for sorafenib) and alopecia (2 vs 21% for sorafenib) . On both arms, patients who had diastolic hypertension (>90 mmHg) had significantly better PFS; for patients treated with tivozanib the difference was 18.3 months compared to 9.1 months for patients who did not experience diastolic hypertension, and for sorafenib patients the median PFS was 16.7 months with diastolic hypertension compared to 9 months without diastolic hypertension .
Recently, development of tivozanib was halted after the Oncology Drug Advisory Committee voted not to recommend approval of tivozanib for RCC , and due to concern of increased risk of death on the tivozanib arm. Subsequently, a head-to-head trial of tivozanib versus sunitinib with a primary endpoint of patient preference was halted. While this agent clearly has efficacy, the landscape for RCC is crowded, and we may be reaching the ceiling for effectiveness of purely VEGFtargeted agents. Additional study in VEGF-targeted therapy pre-treated patients may be warranted.
Dovitinib (formerly TKI-258)
The FGF receptor (FGFR) pathway plays a significant role in angiogenesis (FIGURE 1), which may be particularly important for cell survival in the setting of VEGF inhibition [16,17]. Solid tumors including RCC have been shown to overexpress FGF and FGFR, with implications for driving cancer behavior . These characteristics make FGFR a rational target for combination therapy with VEGF receptor TKIs. Dovitinib is a potent inhibitor of all three FGFRs (1, 2 and 3) as well as all three VEGF receptors, and has some PDGFR inhibition activity as well . In renal cancer xenograft models, dovitinib achieved 83% reductions in tumor volume , which compared favorably to other available TKIs tested in the same preclinical model.
The Phase I trial of dovitinib in metastatic RCC pre-treated with standard therapy, which escalated the dose from 500 mg orally (p.o.) daily for 5 days-on, 2 days-off up to 600 mg on the same schedule, enrolled 20 patients . At the 600 mg dose there were two dose-limiting toxicities (DLTs; hypertensive crisis and grade 3 asthenia) in four evaluable patients, and the Bayesian logistical regression model design indicated a reduction back to the 500 mg dose. With 500 mg dovitinib dosed 5 dayson, 2 days-off there was one DLT of sinus bradycardia, and this dose was declared the maximum tolerated dose. Nausea, vomiting, diarrhea and asthenia were the most common side effects.
Table 1. A summary of available Phase II/III clinical trial data in clear cell renal cell carcinoma patients for novel tyrosine kinase inhibitors reviewed in this article.
Grade 3 adverse events also included weight loss, anemia, dysphagia, neutropenia and palmar-plantar erythrodysesthesia.
As part of the Phase I/II study of dovitinib in VEGFtargeted therapy pre-treated RCC patients, exploratory biomarkers were evaluated. At baseline, patients were found to have elevated VEGF and basic FGF, which may reflect their prior exposure to VEGF recept or antagonists . Treatment with dovitinib resulted in induction of circulating FGF23, indicating that inhibition of FGFR 1 had been achieved. Similarly, there were significant decreases in soluble VEGFR2, and modest decreases in VEGF and placental growth factor.Paired tumor biopsies were done in select patients, which revealed pERK inhibition, further corroborating the on-target effect of FGF receptor inhibition .
The Phase II portion of the dovitinib study enrolled 59 patients with metastatic RCC who had been treated with a VEGF-targeted therapy and/or mTOR-targeted therapy . The objective response rate was 8%, with 42% of patients having stable disease for >4 months. Median PFS was 6.1 months. Further development of this agent includes the GOLD trial (NCT01223027), which is an ongoing randomized Phase III study of dovitinib compared to sorafenib after failure of one VEGF TKI and one mTOR inhibitor. The results of this trial may define whether FGFR inhibition is advantageous compared to VEGF and PDGF inhibition. A Phase II trial of nintedanib versus sunitinib did not suggest an advantage, with a median PFS of 8.44 months for nintedanib compared to 8.38 months with sunitinib . As the field of therapeutics for RCC becomes more crowded, combining novel treatments with existing agents is an attractive alternative strategy for drug development, provided the combination does not cause excess toxicity. Dovitinib has been tested in combination with everolimus in a dose-finding study; the results are pending (NCT01714765).
Regorafenib (formerly BAY 73-4506)
The angiopoietins are an important pro-angiogenic growth factor family that signal through the Tie2 receptor [24,25]. Tie2 has been shown to have strong expression in renal glomeruli of both normal and malignant kidney tissue, but is found only in tumor vascular endothelial cells, and not normal vasculature .
In RCC cell lines, angiopoietin expression was affected by hypoxia, linking it to control by Von-Hippel Lindau. Furthermore, stronger expression of these proteins is associated with higher tumor grade. AMG 386, a peptibody targeting angiopoietin, had shown activity against RCC in Phase Ib testing when combined with sunitinib or sorafenib , and went on to a combination study of sorafenib alone or with one of the two doses . Although the latter study failed to meet its endpoint of prolonged PFS for the combination compared to sorafenib alone, AMG 386 established angiopoietin as a viable target in RCC.
Regorafenib is a TKI which inhibits Tie2, in addition to VEGF, PDGF, FGF and c-kit. In the Phase I trial of regorafenib, doses were escalated from 10 mg up to 220 mg per day p. o. . At the highest level, there was dose-limiting hand-foot syndrome in five of 12 patients, compared to two of 12 treated at the 160 mg dose. Thus, 160 mg/day p.o. for 21 days-on, 7 days-off became the recommended dosing schedule for regorafenib. Additional grade 3 and 4 toxicities identified in the Phase I trial included diarrhea, fatigue, hypertension, mucositis, rash and voice changes.
A Phase II study was conducted in 49 patients with previously untreated advanced RCC, with a primary endpoint of objective response. The overall response rate was 40% (90% CI: 27.7–52.5%) with a median duration of response 14.1 months; 81% of patients had some disease reduction .
Toxicity was substantial; 61% of patients had at least one grade 3–4 adverse event, most commonly hand-foot syndrome, diarrhea, renal failure and fatigue. There were four deaths on study; two cardiac arrests (one in a patient who had begun interferon treatment-off study), one due to pulmonary embolism, and one due to hemoptysis. Correlative studies showed that placental growth factor increased after treatment whereas VEGFR 2 and TIMP2 decreased . Patients who had greater increases in CK18M30 were more likely to have tumor shrinkage of >40%. High baseline levels of angiopoietin 2 and soluble Tie2 showed some correlation with increased risk of disease progression. The authors concluded that further study of the agent should be biomarker-driven in order to select a population with greater likelihood to benefit, given the toxicity profile.
Figure 1. Receptor tyrosine kinases and their signaling cascades promoting angiogenesis and tumor progression, along with therapeutics available or in development, targeting these pathways in advanced renal cell carcinoma.
Cabozantinib (formerly XL184)
Another prominent cancer signaling pathway involved in angiogenesis and malignant behavior is the hepatocyte growth factor, which signals through the MET receptor (FIGURE 1) and is induced by hypoxia . It is felt to be an important resistance pathway for VEGF-targeted therapy, since increasing MET levels are seen after exposure to anti-angiogenic therapy . Cabozantinib was identified as a dual inhibitor of VEGFR2 and MET, with additional activity against RET, KIT, AXL and FLT3 . In vitro experiments confirmed that cabozantinib inhibited these targets, and further showed that this inhibition was associated with decreased cell proliferation and increased apoptosis, especially in SNU-5 and Hs746T cell lines.
In Phase I testing, the dose of cabozantinib was escalated from 0.08 mg/kg to 11.52 mg/kg p.o. per day, and then additional cohorts were tested using flat dosing of 175 mg/day, 250 mg/ day and 265 mg/day . The dose limiting toxicities included hand-foot syndrome, transaminitis, lipase elevation and mucositis. Additional common toxicities included diarrhea and hair color change. All patients with medullary thyroid cancer treated in the Phase I trial showed decrease in calcitonin and CEA, and three of 13 patients had a confirmed partial response. The maximum tolerated dose was determined to be 140 mg/day.
A separate Phase I trial of cabozantinib in patients with metastatic RCC was conducted to evaluate drug-drug interactions with the diabetes medication rosiglitazone. Twenty-five patients were enrolled, all of whom were pre-treated with at least one anti-angiogenic therapy, and 44% of whom had received three or more lines of systemic therapy . Median PFS was 14.7 months, and the objective response rate was 28%, with another 52% of patients experiencing stable disease. Significant instances of pain relief from symptomatic bone metastases were also noted during the trial. Fatigue, diarrhea, hypophosphatemia and hypoantremia were the most common events and sometimes reached grade 3 or 4 in severity. Other common adverse events experienced by >30% of patients included followed by hypothyroidism, nausea/vomiting, hypomagnesemia, proteinuria, hand-foot syndrome and dyspnea.
Cabozantinib has been US FDA approved for medullary thyroid cancer at a dose of 140 mg/day p.o. Evidence of activity at lower dose levels, however, was seen in a dose de-escalation trial in men with metastatic castration-resistant prostate cancer, and resulted in better tolerance to therapy . Based on these results, the Phase III registration trial for cabozantinib in prostate cancer is being conducted at a dose of 60 mg daily (NCT01605227). However the optimal dose for patients with RCC remains to be established. Two Phase III trials have been launched in RCC. One is the METEOR trial, which will compare cabozantinib 60 mg/day to everolimus in patients who have previously received treatment with at least one VEGF TKI (NCT01865747). The other trial is being led by Cancer and Leukemia Group B, and will compare cabozantinib to sunitinib in previously untreated patients with advanced RCC (NCT01835158).
Table 2. Additional tyrosine kinase inhibitors in early development which may become candidates for renal cell carcinoma therapy.
Tivantinib (formerly ARQ 197) & foretinib
Papillary RCC is the second most common subtype of renal cancer, accounting for 15% of total cases. Hereditary papillary RCC type I is related to mutation in the MET gene, which is also found in sporadic papillary RCC tumors . Applying MET-targeted therapy is a sensible approach for this disease. A Phase II study of foretinib, which inhibits MET, VEGF, Tie2 and other receptors was studied in papillary RCC, identified significant activity with a 13.5% overall response rate . The median duration of response was 18.5 months, which compares favorably to standard VEGF TKI in this subset of patients .
Tivantinib is an inhibitor of MET that was found to be highly selective compared to other candidate compounds. The Phase I study in solid tumors, escalated dosage from 10 mg b.i. d. for 2 weeks-on, 1 week-off up to 360 mg b.i.d. on a continuous schedule . The dose limiting toxicities for tivantinib were neutropenia, thrombocytopenia, vomiting and dehydration. These toxicities were seen at the highest dose level, but a maximum tolerated dose was not reached, and so 360 mg (p.o.) b.i.d. was selected as the dose for additional study. Toxicities in the 360 mg b.i.d. dose cohort also included fatigue, diarrhea, liver function test abnormalities and hyponatremia. All six RCC patients enrolled in this trial achieved stable disease, and four out of six patients stayed on study treatment for
>24 weeks. Additional testing of tivantinib in papillary RCC is underway, via the cooperative group trial SWOG S1107: Parallel Phase II Evaluation of ARQ197 and ARQ197 in combination with Erlotinib in Papillary RCC (NCT01688973).
Expert commentary & five-year view
Inhibition of VEGF and other tyrosine kinases has been an extremely successful strategy for patients with metastatic RCC. However, resistance and toxicity remain serious problems, and new therapies are thus still needed. Novel tyrosine kinases are being developed for the treatment of clear cell RCC with two main strategies: narrowing the focus of receptors inhibited to improve the side effect profile and targeting additional receptor pathways which may facilitate VEGF escape, such as angiopoietin/Tie2, FGFR and MET. We believe that the latter strategy is showing significant promise, and drugs such as cabozantinib are likely to find a place in the therapeutic armamentarium. Aside from the pathways reviewed, other putative VEGFresistance pathways which are being targeted include CD105 (e.g., TRC105, a monoclonal antibody), PI3K/AKT (e.g., BKM120), FLT3 (e.g., tandutinib) and matrix metalloproteinases (e.g, AE-941). TABLE 2 summarizes novel TKIs early in development which may become agents of interest in RCC.
For non-clear cell RCC, we are finally entering an age of targeted therapies that match the individual biology of alternate histology, and the way is being led by MET-targeted therapies such as tivantinib. Two ongoing trials may suggest which agents are most active and may translate into a future definitive trial; a randomized direct comparison of VEGF versus mTOR inhibition for papillary RCC (NCT01185366) and the SWOG S1107 with tivantinib and erlotinib. Success in clinical trials specific for papillary RCC will be critical for generating enthusiasm to tackle other non-clear cell RCC histologic subtypes.
Immune therapy may play an increasing role in metastatic RCC, as newer agents hold potential for combination with TKIs. Among the most promising targets in development for RCC are immune checkpoint inhibitors, such as the programmed death ligand pathway. Several agents are in advanced stages of testing, such as nivolumab (BMS 936558), which is being tested in a multi-arm Phase I combination study, paired with either sunitinib, pazopanib or ipilimumab (CheckMate016; NCT01472081).
- Novel tyrosine kinase inhibitors (TKIs) in development for renal cell carcinoma (RCC) may target additional pathways thought to confer VEGF resistance, such as FGF (e.g., dovitinib), Tie2 (e.g., regorafenib) and Met (e.g., cabozantinib).
- Novel TKIs in development for RCC have also taken the approach of narrowing receptor targeting to focus on VEGF with high affinity (e.g., tivozanib) with dual goals of improving efficacy as well as the toxicity profile.
- For non-clear cell RCC, novel TKIs are being tested. For example tivantinib, an inhibitor of Met, is being tested in papillary RCC in the SWOG cooperative group.
- Combinations of TKIs with immune therapy for RCC are under investigation.
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