Fibroblast Growth Factor Receptor Inhibitors: Dovitinib (TKI1258, CHIR-258), BIBF 1120, Lenvatinib (E7080), Regorafenib (BAY 73-4506)
The family of fibroblast growth factor receptors (FGFRs) is known to be overexpressed in RCC. Activating mutations of FGFRs and their ligands have been associated with neoplastic progression and tumor vascularization in RCC. This pathway is believed to potently inactivate angiogenesis in the stromal compartment parallel to VEGFR inhibition, while also directly antagonizing FGFR-driven proliferation in tumor cells.
Dovitinib is an orally bioavailable inhibitor of FGFR-1,-2, and -3; VEGFR-1, -2, -3; and PDGFR-beta. A phase II study has been completed in patients with unresectable or metastatic RCC who have received previous VEGFR-TKI therapy. In a preliminary report, 8% of evaluable patients experienced a PR and 8% had SD for 4 months or more, yielding a benefit rate of 16% in the second-line setting. Median PFS and overall survival (OS) were 6.1 months and 16 months, respectively. There is currently a phase III study of dovitinib vs sorafenib(Drug information on sorafenib) underway for patients who have been treated with both a VEGF-targeted agent and an mTOR inhibitor. This study is expected to complete accrual in May 2013.
BIBF 1120 is an inhibitor of VEGFRs, PDGFRs, and FGFRs. Of 10 RCC patients in a phase I study of BIBF 1120, 1 patient had a CR, 1 had PR and the majority of the remaining 8 patients had SD. An ongoing phase II study comparing BIBF 1120 with sunitinib in the first-line setting for RCC was recently completed. Results are eagerly anticipated.
Lenvatinib is another orally bioavailable inhibitor of multiple receptor tyrosine kinases, including VEGFRs, PDGFR-beta, FGFR-1, and c-Kit.  This agent is still in early development and has completed phase I testing in advanced solid tumors to determine dosing. In this phase I dose-escalation study of 27 patients, common adverse events were hematuria, fatigue, hypertension, increased transaminase levels, headache, proteinuria, diarrhea, and increased lactate dehydrogenase. Of the 25 evaluable patients, there was 1 PR in a patient with colon cancer, and 21 patients with SD. The patient with a PR achieved this reduction at cycle 4 and continued for a total of 10 cycles, at which time progression of disease was noted. An ongoing phase I/II study with a randomized phase II portion is evaluating lenvatinib alone or in combination with everolimus in patients with RCC who are refractory to VEGF-targeted treatment. Accrual should be complete by September 2013.
Regorafenib is another orally bioavailable TKI with activity against multiple proangiogenic signals, including the FGFR, VEGFR, and PDGFR families, as well as c-Kit, RET, and B-RAF. A phase II trial of regorafenib for therapy-naive RCC has been completed. In a preliminary report on 33 evaluable patients, 27% experienced a PR and 42% had SD, for a benefit rate of 69%. Common treatment-related adverse events for all enrolled patients were hand-foot skin syndrome, fatigue, mucositis, hypertension, rash, alopecia, diarrhea, dysphonia, and anorexia.
Angiopoietin-TIE2 Inhibitor: AMG386 (2xCon4[C])
While VEGF and the VEGFR family of receptors are strongly associated with angiogenesis, there remain a number of additional signaling pathways that may drive this process and that are amenable to pharmacologic intervention; these include the angiopoietin-TIE2 axis. Ang-1, Ang-2, and Ang-4 are the known ligands for the TIE2 receptor expressed on vascular endothelial cells. AMG386 is a neutralizing peptibody targeted against Ang-1/2 that prevents interaction with the TIE2 receptor.
In a phase I study, AMG386 demonstrated antitumor efficacy, with treatment-related adverse events of fatigue and peripheral edema. Of the 29 evaluable patients, there was 1 who experienced a PR and 16 patients with SD. The PR was noted at week 68 in a patient with refractory ovarian cancer. After 156 weeks of treatment, she withdrew from the study with a continued PR. Unlike with VEGF-targeted therapies, the incidence of hypertension with AMG386 was low and not considered treatment-related. A phase Ib study evaluated AMG386 combined with sunitinib or sorafenib in patients with RCC. An interim analysis showed 1 CR, 7 PRs and 6 patients with SD among those receiving AMG386/sunitinib (n = 15); and 5 PRs and 9 patients with SD among those receiving AMG386/sorafenib (n = 17). While both sunitinib and sorafenib have demonstrated clinical benefit for patients with RCC, these phase I data suggested the possibility of a more potent antitumor effect gained from the addition of AMG386 (as compared to monotherapy with the VEGFR STIs) without substantial increase in harm. Given the high level of activity and acceptable toxicity, the combination was pursued in more advanced testing.
In a phase II trial, 152 treatment-naive patients were randomized 1:1:1 to receive sorafenib combined with AMG386 (10 or 3 mg/kg) or placebo once weekly; ORR was 38%, 37% and 24%, respectively, although PFS was similar for all three arms.. This response rate can be compared with the 10% PR rate observed in the phase III study of sorafenib in RCC. After making this comparison, it appears that despite the recognized activity of sorafenib, the addition of AMG386 does appear to augment its antitumor effect. Thus, a combination such as this may be worth additional study. An ongoing phase II trial is evaluating AMG386 combined with sunitinib as first-line therapy in metastatic RCC (mRCC), or for cytokine-refractory mRCC; the expected completion date is sometime in 2014.
AKT Inhibitors: MK-2206
AKT has long been viewed as a convergence point for multiple oncogenic and pro-angiogenic signals. To date, few effective inhibitors of AKT have been developed, mainly because of excessive clinical toxicity. MK-2206 is a novel targeted small molecule that is a putative allosteric inhibitor of AKT activation. A randomized phase II study comparing MK-2206 vs everolimus as second-line therapy following VEGF-targeted therapy is now underway. Dose-limiting toxicities of this agent included skin rash, nausea, pruritus, hyperglycemia, and diarrhea.
MET Inhibitor: Foretinib (GSK136089, GSK089, XL880)
MET overexpression has been implicated as a pro-oncogenic and tumor survival mechanism in a number of tumor models, including RCC—and especially in non–clear-cell carcinomas, including chromophobe and papillary RCCs. A MET mutation in RCC is considered rare outside of lung carcinomas and papillary RCC. Foretinib is an orally available inhibitor of MET and the VEGFR family. A trial in patients with papillary RCC has been completed, and results are currently pending. Patients in this study were stratified based on the status of MET pathway activation (activation MET mutation, MET [7q31] amplification, or trisomy 7). In a preliminary report of this study, of 35 evaluable patients, there were 4 who experienced confirmed PRs and 27 patients with SD. In addition to MET status, the investigators will report on the utility of shed MET, VEGF, and shed VEGFR2 as pharmacodynamic markers of foretinib activity.
IFN-alfa and IL-2 have continued to be considered active and usable therapies in RCC. The historic use of these agents and the observation of long-term complete remissions following treatment in a small number of patients have kept them in the armamentarium for RCC. The toxicity of these immunotherapies has made them less desirable than VEGF- and mTOR-targeted therapies. However, RCC is still considered an immunologically active disease in which immunotherapy holds promise. Thus, a number of noncytokine strategies have been and are being explored.
IMA901 is a therapeutic cancer vaccine that consists of synthetic RCC tumor-associated peptides and that has been shown to cause T-cell activation. In a phase I study, 30 patients with stage III or IV RCC were each given 8 intradermal IMA901 vaccinations over 64 days. In this study, T-cell responses were measured in peripheral blood using IFN ELISPOT, human leukocyte antigen (HLA) multimer analysis, and CD4+ Foxp3+ regulatory T-cell levels. One patient had a PR and seven had SD; patients in whom multiple T-cell responses were elicited had better clinical outcomes.[32,33]
A randomized phase II study evaluated IMA901 (17 intradermal vaccinations over 9 months) with or without a single dose of cyclophosphamide(Drug information on cyclophosphamide) (300 mg/m2) administered prior to the first vaccination in patients with cytokine- or TKI-refractory RCC. After 6 months, the disease control rate was 31% in cytokine-refractory patients and 12% in TKI-refractory patients. While the impact of pretreatment cyclophosphamide was not reported at the initial presentation of the trial data, pretreatment cyclosphosphamide did appear to trend toward better overall survival. In patients who had received previous cytokine therapy, the OS rate at 18 months was 83% in those who received pretreatment cyclophosphamide vs 68% in those who did not receive this pretreatment.
IMPRINT is an ongoing phase III trial of IMA901 in combination with sunitinib for first-line treatment of RCC. Approximately 330 patients will be randomly assigned to receive IMA901 either with or without sunitinib. The primary endpoint of this study is overall survival, with secondary endpoints including PFS, safety and tolerability, and cellular immunomonitoring to assess T-cell response to IMA901.
AGS-003 is an autologous cell-based therapy in which mature dendritic cells are collected and electroporated with CD40L and autologous amplified tumor RNA. A phase II study of AGS-003 with sunitinib in newly diagnosed RCC was completed. The combination was well tolerated with no grade ≥ 3 treatment-related adverse events reported. Of 21 patients at poor or intermediate risk, 2 experienced a PR and 11 had SD; median PFS in this population was 12.5 months. This effect correlated with a decrease in the percentage of T-regulatory cells and a concurrent expansion of CD28+ effector memory cytotoxic T-lymphocytes, which may have been responsible for the overcoming of tumor-induced immunosuppression. The magnitude of this immunologically mediated clinical effect parallels the PFS seen with sunitinib alone and is likely to be biologically unrelated. Thus, a phase III randomized, blinded study is planned that will compare sunitinib alone vs sunitinib with AGS-003 in newly diagnosed patients.
Anti-CTLA-4 antigen: ipilimumb (Yervoy)
CTLA-4 (CD52) is an inducible receptor expressed by T cells that ligates the B7 family of molecules (primarily CD80 and CD86) on antigen-presenting cells. It serves as a natural inhibitor of T-cell activation and is overexpressed on cancer cells, including RCC cells. Suppression of this immune repressor was hypothesized to decrease a cancer’s ability to avoid immune surveillance.
Ipilimumab is a monoclonal antibody against CTLA-4 that has been tested in a number of cancers, including RCC. In a phase II RCC study, tumor regression was noted. However, this phenomenon was associated with major gastrointestinal and endocrine toxicities that have been attributed to iplimumab.
PD-1 antibody: BMS-936558 (MDX-1106, ONO-4538)
B7 homolog 1 (B7-H1) is a factor that participates in T-cell costimulation, functioning as a negative regulator of immunity.[41,42] It is expressed by aggressive RCC, displaying prognostic importance. B7-H1 impairs host immunity by interaction with the Programmed Death-1 receptor (PD-1). PD-1 is expressed on activated T cells, and like B7-H1, it is also upregulated in high-risk RCC. It is thought that this interaction may contribute to immune dysfunction in patients with RCC.
BMS-936558 is a fully human monoclonal antibody to PD-1. In a phase I dose-escalation study of 39 patients with advanced refractory solid tumors, BMS-936558 showed antitumor activity, including a PR in 1 patient with RCC. In a second phase I study, 126 patients, including 18 with RCC, were treated with escalating doses of BMS-936558. Of 16 patients with RCC who received a 10-mg/kg dose of BMS-936558, 5 achieved an objective response, with 1 CR; 6 had SD for > 4 months. The most common adverse events attributed to this agent include depressed CD4+ counts (36%), lymphopenia (26%), fatigue (15%), and musculoskeletal events (15%).
An ongoing, randomized, blinded phase II study is evaluating three doses of BMS-936558 in patients with RCC who have received prior antiangiogenic therapy. The estimated study completion date is April 2013.