Акситиниб в лечении RCC поздних стадий

1. Введение

Рак почек — восьмой по распространенности рак в Соединенных Штатах с 65,150 новыми случаями и 13,680 смертельными исходами в 2013, и ежегодным приростом ~ 3% за прошлое десятилетие [1,2]. Существенные различия в инциденте рака почек наблюдаются среди различных географических и этнических популяций, например, возраст-стандартизированные инциденты на 100,000 человек ежегодно высокие в Северной Америке и большей части Европы (7.9 — 11.8); умеренные в южной Европе и Японии (6.3 и 4.9о) и низкие в других азиатских странах и Африке (1.0 — 2.8), согласно данным GLOBOCAN за 2008 год [2-4]. Такие различия могут объясняться вариациями в использовании диагностических образных исследований, доступности медицинской помощи, генетической предрасположенности, образе жизни и/или факторах внешней среды.

Почечно-клеточная карцинома (RCC) наиболее распространенный (~ 90%) тип рака почек, из которого 85% приходится на светлоклеточную карциному [5]. В случаях ранней диагностики RCС, частичная или радикальная нефрэктомия для хирургически операбельных опухолей или термическая абляция для неоперабельных опухолей обеспечивают эффективное и часто куративное лечение. Однако вследствие отсутствия ранних клинических симптомов у некоторых пациентов диагностируется метастатическая или поздних стадий почечно-клеточная карцинома (mRCC), для которых 5-летняя выживаемость составляет приблизительно 12% [2]; другие имеют рецидивы mRCC после начального лечения локализованного или регионального заболевания. Для mRCC иммунотерапия с цитокинами (интерлeйкин 2 [IL-2] и интерферон-альфа [IFN-a]) оставалась стандартом лечения в последние десятилетия с относительно умеренной клинической успешностью [6,7]. Однако, лучшее понимание патогенеза RCС, в частности, открытие факта, что светлоклеточная RCС часто характеризуется инактивацией гена-супрессора опухолей von Hippel-Lindau, который контролирует экспрессию множественных гипоксия-индуцибельных генов, вовлеченных в пролиферацию опухолевых клеток и ангиогенез, таких как фактор роста сосудистого эндотелия (VEGF) и тромбоцит-продуцируемый фактор роста (PDGF) [8-10] — привело к таргетингу ангиогенеза для лечения светлоклеточной RCС.



Hideyuki Akaza & Tomofusa Fukuyama. Axitinib for the treatment of advanced renal cell carcinoma. Expert Opin. Pharmacother. (2014) 15(2):283-297


  1. Introduction

Kidney cancer is the eighth most common cancer in the United States, with an estimated 65,150 new cases and 13,680 deaths from the disease in 2013, and an annual increase of ~ 3% reported in the past decade [1,2]. Globally, significant differences in kidney cancer incidence have been observed among different geographic and ethnic populations, for example, age-standardized new cases per 100,000 persons per year were high in North America and most of Europe (7.9 -11.8); modest in southern Europe and Japan (6.3 and 4.9, respectively) and low in other Asian countries and Africa (1.0 -2.8), according to GLOBOCAN 2008 data [2-4]. Such differences may be explained by variations in utilization of diagnostic imaging tests, access to healthcare, genetic predisposition, lifestyle and/or environmental factors.

Renal cell carcinoma (RCC) is the most common (~ 90%) type of kidney cancer, of which 85% are clear-cell histology [5]. When RCC is diagnosed early, partial or radical nephrectomy for surgically resectable tumors or thermal ablation for nonresectable tumors provides an effective and often curative treatment. Due to lack of early clinical symptoms, however, some patients present with advanced or metastatic renal cell carcinoma (mRCC) at diagnosis, for whom the 5-year survival is around 12% [2]; others present with mRCC due to relapse following the initial treatment for localized or regional disease. For mRCC, immunotherapy with cytokines (interleukin-2 [IL-2] and interferon-alfa [IFN-a]) remained the standard of care over the past several decades, with relatively modest clinical benefits [6,7]. However, advanced understanding of RCC pathogenesis -in particular, the discovery that clear-cell RCC is often characterized by inactivation of the von Hippel-Lindau tumor suppressor gene, which controls the expression of multiple hypoxia-inducible genes involved in tumor cell proliferation and angiogenesis such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) [8-10] -has led to targeting of angiogenesis for treatment of clear-cell RCC.

Box 1. Drug summary.

Axitinib for the treatment of advanced renal cell carcinoma box 1

To date, five agents (anti-VEGF monoclonal antibody bevacizumab and tyrosine kinase inhibitors [TKIs] sorafenib, sunitinib, pazopanib and axitinib [Box 1]) [11-16] that target angiogenesis via blocking VEGF/vascular endothelial growth factor receptor (VEGFR) signaling pathways and two agents (temsirolimus and everolimus) [17,18] that target indirectly via blocking mammalian target of rapamycin (mTOR) have been approved for treatment of advanced RCC in a number of countries (Table 1). Although these agents provide improved efficacy and better tolerability than cytokines, none are curative and the disease eventually progresses in many patients.

The recommended therapies for patients with predominantly clear-cell mRCC are provided by the National Comprehensive Cancer Network (NCCN) guidelines [5], according to line of therapy, prior therapy, the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score and based on the level of evidence and consensus (Table 2A). Treatment algorithms recommended by the European Society for Medical Oncology (ESMO) Clinical Practice [19,20] and the European Association of Urology (EAU) [21] are generally in-line with NCCN recommendations (Table 2A), except the use of different classifications for level of evidence and grade of recommendation (Table 2B). In addition to these clinical practice guidelines, systemic analyses of clinical trial data [22-25] have offered treatment recommendations for targeted agents.

While targeted therapies have now become the treatment of choice for mRCC in Western countries, cytokines are still used in Asian countries. For instance, the Japanese Urological Association (JUA) recommends IFN-a or IL-2 monotherapy for the management of RCC (Table 2A) [26]. Furthermore, treatment recommendations in many Asian countries have also taken into account the level of healthcare resources available [27]. The published Asia Consensus Statements for the NCCN guidelines (NCCN-ACS, Kidney Cancer) [28] provide documentation of modifications from the ‘parent’ NCCN guidelines, adjusting to Asian-specific kidney cancer treatments. While the frequency of immunotherapy is declining with introduction of targeted therapy, it will likely remain a viable treatment option for mRCC in Asian countries, especially with the finding that genetic polymorphisms in STAT3 gene may affect responsiveness to IFN-a in Japanese patients [29]. It is noteworthy that IL-2 is used at a relatively low dose in Japan compared with Western countries, resulting in a better tolerability. In addition, low-dose IL-2 in combination with IFN-a showed a significantly better (35.7%) response rate in Japanese mRCC patients with lung metastasis [26,30].

  1. Overview of the market

Several targeted-therapy agents currently available for treatment of mRCC were approved on the basis of their ability to prolong progression-free survival (PFS) in pivotal clinical trials, but only temsirolimus showed a statistically significant improvement in overall survival (OS) compared with IFN-a (in treatment-naЁive patients with poor risk) (Table 1). Lack of a significant OS benefit with other targeted therapies may be explained, at least in part, by the fact that many patients enrolled in clinical trials proceeded to receive other targeted therapies post-study or crossed over to the experimental arm, confounding the effect of the experimental drug on OS [31-33]. In the absence of clear OS benefit, it is also relevant to evaluate the effect of these agents on patient-reported quality of life as an additional endpoint [34]. These agents have been on the market only for the past several years and information regarding their long-term efficacy and safety has been limited [35-37].

Table 1. Summary of pivotal clinical trials for drugs approved for treatment of advanced renal cell carcinoma.

Axitinib for the treatment of advanced renal cell carcinoma T1

Axitinib for the treatment of advanced renal cell carcinoma T1 - 2

Axitinib for the treatment of advanced renal cell carcinoma T1 - 3

Targeted-therapy agents may potentially lose their effectiveness due to development of resistance. The underlying mechanisms for resistance to VEGF-targeted agents are not well understood, but up-regulation of alternative proangiogenic proteins, down-regulation of angiostatic factors and/or genetic mutations have been proposed [38]. Intense clinical evaluations have led to establishing recommendations for sequential targeted-therapies [5,19,21,26] using agents with a similar mode of action (e.g., TKI followed by another TKI) or different modes of action (e.g., TKI followed by mTOR inhibitor) in order to overcome resistance. As TKIs are now standard of care for treatment of patients with previously untreated mRCC with the MSKCC favorable/intermediate risk factors in the Western countries, selecting a second-line agent (TKI vs mTOR inhibitor) in post-TKI therapy is becoming more critical and challenging (Table 1). With mRCC becoming more of a chronic disease, additional studies are warranted to formulate effective strategies not only for the second-line post-TKI, but also for the thirdand fourthline treatments.

Combination therapy is another approach to improve efficacy and combat development of resistance. However, bevacizumab plus IFN-a is the only proven combination therapy for mRCC to date. Other combinations such as two VEGF-targeted drugs to maximally block VEGF/ VEGFR signaling pathways or a VEGF-targeted agent in combination with another agent targeting a different signaling pathway to concomitantly block several signaling pathways involved in angiogenesis and tumor cell proliferation have been under active investigation. The results have been generally disappointing, mainly due to increased toxicities [39-43], leaving room for additional novel and effective treatment options.

A search of ClinicalTrials.gov identified several emerging novel compounds in late-stage clinical development for treatment of mRCC (Table 3). Undoubtedly, an increased number of targeted treatment options for mRCC will pose additional challenges to physicians and patients in terms of integrating them into effective treatment algorithms. With a rapidly changing landscape, it is critical that various urology and kidney cancer associations regularly update their recommendations for treatment of mRCC based on strong clinical evidence in order to help physicians and patients individualize treatments for maximal outcomes.

Table 2A. Summary of targeted treatment recommendations (level of evidence) for advanced renal cell carcinoma.

Axitinib for the treatment of advanced renal cell carcinoma T2A

  1. Introduction to the compound

Axitinib (AG-013736) is a potent and selective inhibitor of VEGFRs 1, 2 and 3 [44]. Compared with sorafenib, sunitinib and pazopanib, which are multi-targeted TKIs, axitinib exhibits a higher potency (in the picomolar range) against VEGFRs and greater selectivity for VEGFRs [44,45]. In pre-clinical studies, axitinib blocked VEGF-mediated endothelial cell survival, tube formation and downstream signaling pathways through endothelial nitric oxide synthase, Akt and extracellular signalregulated kinase [44]. In animal studies, axitinib produced dose-dependent blockade of VEGFR-2 phosphorylation, reduction in vascular permeability and angiogenesis and induction of tumor cell apoptosis, providing evidence for therapeutic potential [44].

3.1. Chemistry

The physicochemical properties of axitinib are summarized in Table 4. While initial clinical trials were conducted with a crystal polymorph formulation (Form VI) of axitinib, a new formulation (Form XLI) with improved photostability and thermodynamic stability and more favorable physical properties for manufacturing was later developed and evaluated in subsequent clinical trials. Form XLI is the commercial formulation.

3.2. Pharmacokinetics and metabolism

Axitinib is orally bioavailable, with mean absolute bioavailability of 58% [46]. Following oral administration, axitinib is absorbed rapidly, with the maximum plasma concentrations reached within 4 h. Although axitinib is more soluble in acidic pH, the presence of the strong acid-suppressing agent, rabeprazole, did not significantly decrease the extent of absorption (only the rate) [47]; hence, antacids may be co-administered with axitinib.

Axitinib pharmacokinetics are dose-proportional up to 20 mg twice daily (b.i.d.) [46]. It highly (> 99%) binds to plasma proteins, predominantly to albumin and moderately to a1-acid glycoprotein [48]. A marginal, but not significant, trend for axitinib plasma exposure to increase with lower serum albumin has been observed [48]. Axitinib has an effective plasma half-life ranging from 2.5 to 6.1 h [46], which is considerably shorter than sunitinib (41 -86 h) [49], sorafenib (20 -27 h) [50] or pazopanib (31 h) [51]. Axitinib is metabolized primarily by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent, by CYP2C19 and CYP1A2 (< 10%), and uridine diphosphate glucuronosyltransferase (UGT) 1A1 [46]. Thus, concomitant use of a strong CYP3A4/5 inhibitor, which leads to increased axitinib plasma exposure [52], should be avoided. If a strong CYP3A4/5 inhibitor is necessary, the axitinib dose should be reduced by approximately half [53].

Table 2B. Classifications of levels of evidence and grades of recommendations.

Axitinib for the treatment of advanced renal cell carcinoma T2B

Table 3. Summary of selected emerging novel agents in late stage clinical development for advanced renal cell carcinoma.

Axitinib for the treatment of advanced renal cell carcinoma T3

Co-administration of a strong CYP3A4/5 inducer is not recommended since it may compromise the efficacy of axitinib [53].

The two major metabolites in plasma, sulfoxide and glucuronide products, are considered pharmacologically inactive [46]. The main elimination route of axitinib is via hepatobiliary excretion. While mild hepatic impairment (Child Pugh class A) did not substantially affect axitinib pharmacokinetics, moderate hepatic impairment (Child Pugh class B) led to a two-fold increase in plasma exposure [48]. Hence, it is recommended that the starting dose of axitinib be reduced by half in the patients with moderate hepatic impairment. With regard to renal impairment, there are no clinical data available, but it is unlikely to impact axitinib pharmacokinetics, due to negligible urinary excretion of axitinib [46]. Furthermore, an axitinib population pharmacokinetic analysis based on pooled data from 590 healthy volunteers and cancer patients did not predict any significant impact of renal impairment on axitinib pharmacokinetics to warrant dose adjustment [46,54]. None of the other covariates tested in the analysis (age, sex, race, body weight, body surface area, study population and genetic polymorphisms in UGT1A1 and CYP2C19 genes) made clinically meaningful contributions to variability in axitinib pharmacokinetics [54,55].

Table 4. Physicochemical properties of axitinib.

Axitinib for the treatment of advanced renal cell carcinoma T4

3.3. Pharmacodynamics

In the first-in-human (FIH) study, vascular response (i.e., volume transfer constant and initial area under the curve) was measured following administration of axitinib in 26 patients. Based on evaluable data obtained in 17 patients, an inverse linear relationship was demonstrated between axitinib plasma concentrations and changes in tumor blood flow, supporting the purported anti-angiogenic activity of axitinib [56].

Occurrence of elevated blood pressure (BP) or hypertension has been widely reported with use of bevacizumab and anti-angiogenic TKIs, including axitinib [57-60]. An association between efficacy (PFS and OS) and diastolic BP, independent of plasma exposure, was demonstrated with axitinib treatment in a retrospective pharmacokinetic—pharmacodynamic analysis of data pooled from three earlier Phase II clinical trials in mRCC patients [54].

Other pharmacodynamic parameters evaluated as potential markers for axitinib efficacy include plasma levels of VEGF and soluble vascular endothelial growth factor receptor (sVEGFR). In Phase I clinical trials in Japanese patients with solid tumors, including mRCC, increases in VEGF plasma levels accompanied by decreased plasma levels of sVEGFR-2 and sVEGFR-3 were observed, with no notable change in soluble stem cell factor receptor [61,62]. In a Japanese Phase II clinical trial, mRCC patients with greater decreases in plasma concentration of sVEGFR-2 had significantly higher objective response rate (ORR) and longer PFS than those with smaller decreases (ORR: 64.5 vs 37.5%; p = 0.045; median PFS: 12.9 vs 9.2 months; p = 0.01) [63].

3.4. Clinical efficacy

3.4.1. Phase I studies

The safety, pharmacokinetics and preliminary efficacy of axitinib were evaluated in the FIH Phase I clinical trial in 36 patients with solid tumors, including six with RCC [47]. In this dose-escalation study, axitinib doses up to 30 mg b.i.d. were tested and the maximum tolerated dose was determined to be 5 mg b.i.d., which was recommended for subsequent Phase II/III clinical trials. Of the three confirmed partial responses, two were achieved in patients with RCC after 8 -10 weeks of treatment. Preliminary anti-tumor activity of axitinib was reported in two additional Phase I clinical trials conducted in 18 heavily pre-treated Japanese patients with solid tumors including RCC [61,62].

3.4.2. Phase II studies

In a non-randomized, open-label, uncontrolled Phase II clinical trial, 52 patients with mRCC previously treated with cytokines received axitinib at a starting dose of 5 mg b.i.d. [64]. Two complete and 21 partial responses were observed, with ORR of 44.2% (95% confidence interval [CI], 30.5 -58.7) and median response duration of 23.0 months. Median time to progression was 15.7 months (95% CI, 8.4 -23.4) and median OS was 29. 9 months (95% CI, 20.3 to not estimable). A 5-year survival rate from the same study was reported as 20.6% (95% CI, 10.9 -32.4) [37].

The clinical benefit of axitinib in mRCC was demonstrated in another open-label Phase II clinical trial that enrolled 62 patients with sorafenib-refractory mRCC [65]. Partial response was observed in 14 patients and ORR was 22.6% (95% CI, 12.9 -35.0). Median PFS and OS were 7.4 months (95% CI, 6.7 -11.0) and 13.6 months (95% CI, 8.4 -18.8), respectively.

To comply with Japanese regulatory authority requirements, axitinib was evaluated in 64 Japanese patients with cytokine-refractory mRCC in an open-label Phase II clinical trial [63]. The ORR and median PFS were 50% (95%, CI 37.2 -62.8) and 11.0 months (95%, CI 9.2 -12.0), respectively, as assessed by independent review committee (IRC).

In most Phase II/III clinical trials, axitinib dose could be increased from 5 to 7 mg b.i.d., and then to a maximum of 10 mg b.i.d. in patients who did not experience axitinibrelated adverse events (AEs) greater than Grade 2 of Common Terminology Criteria for Adverse Events version 3.0 [66] for a consecutive 2-week period, were normotensive and not taking anti-hypertensive medications. Axitinib dose could be temporarily interrupted or reduced to 3 mg b.i.d., and then to 2 mg b.i.d., if necessary, due to toxicity. In order to prospectively assess the benefit of axitinib dose titration, a randomized Phase II clinical trial in treatment-naЁive patients with mRCC was initiated in 2009; in this trial, patients receiving up to two anti-hypertensive medications were eligible for dose titration if they tolerated the starting dose of axitinib. The primary endpoint of ORR was 54% (95% CI, 40 -67) in the active-titration arm compared with 34% (95% CI, 22 -48) in the placebo-titration arm (p = 0.019) [67], providing evidence for the clinical benefit of axitinib dose titration in selected patients and potential as first-line therapy in mRCC.

3.4.3. Phase III studies

A pivotal randomized Phase III clinical trial (AXIS) was conducted globally, to directly compare the efficacy and safety of axitinib with sorafenib in patients with clear-cell mRCC that progressed after first-line treatment consisting of sunitinib, bevacizumab plus IFN-a, temsirolimus or cytokines [16]. Patients stratified by prior therapy and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) were randomly assigned to receive either axitinib at a starting dose of 5 mg b.i.d. (n = 361) or sorafenib 400 mg b.i.d. (n = 362). The primary endpoint of median PFS assessed by a blinded IRC was significantly longer with axitinib versus sorafenib (6.7 vs 4.7 months; hazard ratio [HR] 0.665; 95% CI, 0.544 -0.812; stratified one-sided p < 0.0001). The superiority of axitinib over sorafenib was maintained in predefined subgroup analyses of PFS based on prior treatment, age, sex, MSKCC risk category and region. Although no patient achieved a complete response, ORR was significantly higher with axitinib versus sorafenib (19 vs 9%, respectively; p = 0.0001). A subgroup analysis in Japanese patients from this trial also demonstrated a good response with axitinib [68]. According to a recent update from the AXIS trial [69], although investigator-assessed median PFS remained statistically higher with axitinib versus sorafenib (8.3 vs 5.7 months; p < 0.0001), median OS did not differ between the two treatment groups. Median OS was 20.1 months (95% CI, 16.7 -23.4) with axitinib versus 19.2 months (95% CI, 17.5 — 22.3) with sorafenib; HR 0.969 (95% CI, 0.800 -1.174; one-sided p = 0.3744). Although OS data can be impacted by crossover between the experimental and control arms or subsequent treatments received by patients following discontinuation from the trial, no crossover was permitted in the AXIS trial and nature and portion of patients who received each type of subsequent therapies were similar between arms [69]. Therefore, axitinib demonstrated superiority over sorafenib in terms of PFS and ORR, but not OS as second-line therapy.

The efficacy and safety of axitinib was compared with sorafenib in another randomized Phase III clinical trial that originally enrolled only previously treated patients with mRCC, but was amended to include treatment-naЁive patients. In treatment-naЁive patients, IRC-assessed median PFS (primary endpoint) was numerically longer with axitinib than sorafenib (10.1 vs 6.5 months, respectively), but the difference did not reach statistical significance (HR 0.77; 95% CI, 0.56 -1.05; p = 0.038); ORR was significantly higher with axitinib versus sorafenib (32 vs 15%; p = 0.0006) [70]. In a pre-specified analysis, median PFS was found to be longer in axitinib-treated versus sorafenib-treated patients with ECOG performance status 0 (13.7 vs 6.6 months; HR 0.64; 95% CI, 0.42 -0.99; p = 0.022), but not in those with ECOG performance status 1. Although the study did not achieve its primary endpoint statistically, it suggested the efficacy of axitinib as first-line therapy in mRCC.

3.5. Safety and tolerability

The safety profile for axitinib in patients with mRCC is as expected of the class of anti-angiogenic TKIs [13-15]. In the AXIS trial, discontinuation due to treatment-related AEs was lower with axitinib compared with sorafenib (4 vs 8%, respectively). Common treatment-emergent, non-hematologic AEs (all grades) reported in patients with mRCC treated with axitinib in Phase II/III clinical trials [16,63-65,67,68,70] included hypertension (range, 40 -84%), fatigue (range, 33 -77%), hand—foot syndrome (range, 26 -75%), diarrhea (range, 50 -64%), dysphonia (range, 23 -53%) loss of appetite/anorexia (range, 29 — 48%), hypothyroidism (range, 18 -48%), nausea (range, 25 -44%), decreased weight (range, 25 -37%) and vomiting (range, 16 -32%). The frequently observed Grade 3 or 4 non-hematologic AEs were hypertension (range, 14 -18%, except 70% in Japanese patients), hand—foot syndrome (range, 4 -22%), fatigue (range, 5 -16%) and diarrhea (range, 5 -15%). Anemia and lymphopenia were frequently observed hematologic AEs in patients treated with axitinib, but were mostly grade 1 or 2. Thus, axitinib is generally well tolerated and the majority of AEs are mild-to-moderate in severity and manageable with either dose reductions and/or standard medications.

It is noteworthy that the nature and incidence of AEs reported in axitinib-treated Japanese patients were similar to those experienced by Caucasians in general. However, some differences were observed in the incidence rate of AEs (e.g., hypertension) [68], which cannot be explained by differences in axitinib pharmacokinetics since they were seemingly comparable between young, healthy Japanese and Caucasian men [71]. However, differences in AEs between Asians and Caucasians have also been reported for sunitinib [72].

3.6. Regulatory affairs

Based on the results of the AXIS trial, axitinib was approved by the US Food and Drug Administration in January 2012 for the treatment of advanced RCC after failure of one prior systemic therapy [53]. This was followed by approval in the European Union, Japan and a number of other countries. Additionally, axitinib has been incorporated into treatment guidelines as second-line therapy for advanced RCC with high level of evidence by the NCCN, EAU and ESMO.

  1. Conclusions

Axitinib is a potent and more-selective inhibitor of VEGFRs than other approved anti-angiogenic TKIs. It is generally well tolerated, with AEs that are mild-to-moderate in severity and manageable with dose reductions and/or standard medications. In 2012, based on the significant improvement in PFS compared with sorafenib in the pivotal Phase III clinical trial in previously treated patients [16], axitinib was approved in several countries worldwide for treatment of mRCC after failure of one prior systemic therapy (or specified as prior sunitinib or cytokines in some countries). Axitinib is recommended as second-line therapy in patients with clear-cell mRCC based on high level evidence by the key oncology and urology associations worldwide [5,19,21].

Although the Phase III clinical trial in treatment-naЁive patients with mRCC did not meet its primary endpoint statistically, axitinib exhibited numerically longer PFS and significantly higher ORR compared with sorafenib. Furthermore, a pre-specified analysis showed a difference in PFS in favor of axitinib in patients with ECOG performance status 0. Thus, axitinib has clinical activity as first-line therapy in mRCC. A randomized, double-blind, placebo-controlled, Phase III clinical trial (ClinicalTrials.gov, NCT01599754) currently in progress in Asia will determine whether adjuvant therapy with axitinib is effective in preventing or delaying recurrence of RCC following nephrectomy in high-risk patients. Finally, it remains to be explored whether the efficacy of single-agent axitinib is further improved by combining it with other targeted agents in treating mRCC.

  1. Expert opinion

Axitinib demonstrated a statistically significantly longer PFS than sorafenib in patients with clear-cell mRCC previously treated with cytokines, sunitinib, bevacizumab/IFN-a or temsirolimus in a randomized Phase III clinical trial (AXIS), which led to its approval for the treatment of mRCC following failure of one prior systemic therapy. Axitinib is recommended as one of the second-line treatment options based on high level of evidence by the NCCN, EAU and ESMO guidelines (Table 2A). The AXIS trial was a pure second-line study of axitinib [16] and the RECORD-1 trial evaluated everolimus in the second-line and greater settings [18]. The differences in study design between these two trials reflect the level of recommendation for axitinib and everolimus as second-line therapy in the ESMO guidelines (i.e., axitinib as I,A/I,B recommendation and everolimus as II,A). To date, no headto-head clinical study has been conducted to directly compare axitinib with everolimus as second-line post-TKI therapy in mRCC. However, the investigator-assessed ORR with axitinib in all patients was 23% according to the updated results from the AXIS trial [69], whereas the IRC-assessed ORR was 1.8% with everolimus from the RECORD-1 trial update [73].

The safety profile for axitinib is generally similar to that of other approved TKIs. Results from AXIS indicated discontinuation due to treatment-related AEs with axitinib was lower than with sorafenib. With better tolerability and acceptable side effects, axitinib is becoming one of the well-established second-line treatment options for mRCC.

Based on the results from the ongoing Phase II and III clinical trials [67,70], axitinib is efficacious as first-line therapy in mRCC, especially for Japanese patients with median PFS of 27.6 months [74]. However, as with other currently approved targeted therapies, axitinib does not cure the disease. Therefore, additional studies are required to optimize sequential treatments as well as evaluate potential effects of axitinib in combination with chemotherapy or other targeted therapy in order to further improve its clinical benefit. For instance, axitinib, which is a selective TKI, is shown to prolong PFS post-treatment with sunitinib, a multi-targeted TKI, but it is not known whether the reverse sequence (i.e., axitinib followed by sunitinib) would provide a similar or better clinical benefit. Axitinib in combination with standard chemotherapeutic agents was found to be safe and generally tolerated at the full dosage of each drug in patients with advanced solid tumors, including mRCC, in Phase I clinical trials [75,76]. However, the results from randomized Phase II and III clinical trials of combination regimens including axitinib and chemotherapeutic agents in metastatic colorectal, breast or pancreatic cancer have been disappointing [77-79].

In all Phase III trials with targeted therapies, PFS benefit could be obtained, but not statistically significant differences in OS, expect with temsirolimus for poor-risk patients in first-line setting (Table 1). The reason(s) for lack of survival benefits offered by most of the targeted therapies is unclear, but warrants further investigation.

The incidence of RCC is steadily increasing in many regions of the world. While treatment options for mRCC will continue to expand, with a number of emerging compounds currently in late-stage clinical development, axitinib is expected to remain one of the widely accepted treatment options for mRCC over the next decade. At the same time, it is important to carefully formulate both an overall strategy for sequential targeted therapies and how to incorporate axitinib therapy in order to achieve the optimal benefit/risk balance for each patient. Data from head-to-head trials directly comparing targeted agents in patients with mRCC are needed to devise sequential treatment strategies. In addition, pharmacogenomic and biomarker analyses conducted in parallel with clinical studies may help to identify populations of patients with mRCC most likely to benefit from treatment with axitinib or other targeted agents.

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