Drug Profile
Axitinib in metastatic renal cell carcinoma Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Expert Rev. Anticancer Ther. 15(5), 499–507 (2015)
Laurence Albiges, Marco Gizzi, Edith Carton and Bernard Escudier* Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France *Author for correspondence: Tel.: +33 142 115 410 Fax: +33 142 115 305 [email protected]
Axitinib is the most recent targeted therapy approved by the US FDA and EMA in the treatment of metastatic renal cell carcinoma (mRCC). It is a second-generation, orally available, potent tyrosine kinase inhibitor targeting selectively VEGF receptor (VEGFR)-1, -2 and -3, resulting in inhibition of angiogenesis, metastasis and tumor growth. Based on the results of a randomized pivotal Phase III clinical trial, axitinib stands as one of the two recommended agents for patients with mRCC who progressed after first-line tyrosine kinase inhibitor therapy. Its potent and selective inhibition of VEGFR was the rationale for its development in the second-line setting after failure of prior cytokines or sunitinib. Here we examine the preclinical and clinical data of axitinib for mRCC, and its use in the treatment algorithm. KEYWORDS: axitinib . clear cell . metastatic renal cell carcinoma . VEGFR TKI
Renal cell carcinoma (RCC) is the most common form of renal cancer. It accounts for 4% of all the adult malignancies. In the US, approximately 64,000 new cases and almost 14,000 deaths are reported due to RCC each year [1]. RCC is more common in men than in women [2] and occurs predominantly between the sixth and the eighth decade of life with the median age at diagnosis being around 64 years [3]. When nephrectomy is performed for a localized tumor, the risk of developing recurrent disease is estimated to be 20–30% [3,4]. Less than one-third of patients are initially diagnosed with metastatic disease and the median overall survival in the metastatic setting is 22 months [5]. Before 2005, the recommended treatment option for systemic disease was immunotherapy, with either IL-2 or IFN-a [6]. Those treatments were used in the first-line setting, and there was no recommended treatment for the second line. A better understanding of the pathogenesis of RCC has led to the development and approval of several molecularly targeted therapies since 2005 and significant improvement in patient outcome. Indeed, about 80% of sporadic RCC cases present a clear cell histopathology [7], driven by Von Hippel–Lindau tumor suppressor gene alterations resulting in an increased transcription of several hypoxia-inducible genes including VEGF, a key player in tumor angiogenesis [8–11]. VEGF binds to several distinct informahealthcare.com
10.1586/14737140.2015.1033408
receptors. VEGF receptor (VEGFR)-1 is involved in tumor growth and angiogenesis, VEGFR-2 plays a role in endothelial cell proliferation, migration and survival, and angiogenesis, while VEGFR-3 is implicated in lymphangiogenesis [12–14]. Therefore, inhibition of the VEGF/VEGFR axis is one of the two cornerstones of systemic therapies available in metastatic renal cell carcinoma (mRCC) and includes five approved agents: four multitargeted tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib, axitinib) and the humanized anti-VEGF monoclonal antibody (bevacizumab with interferon). Unlike bevacizumab that can selectively inhibit VEGF, the commonly used TKIs interfere with several growth factor receptors in addition to VEGFRs. Sunitinib and pazopanib inhibit predominantly VEGFRs and platelet-derived growth factor receptor, and c-Kit, whereas sunitinib may also target fms-like tyrosine kinase (Flt)-3. Sorafenib inhibits VEGFRs, platelet-derived growth factor receptor, c-Kit, Flt-3 and the serine–threonine kinase Raf-1 (TABLE 1) [15]. As a potent and specific antiVEGFR therapy, axitinib has been developed in mRCC. In this article, we sought to review the clinical activity of axitinib and its place in the treatment algorithm for mRCC. Mechanism of action & pharmacology
Axitinib (Inlyta, Pfizer) is an orally administered kinase inhibitor, whose molecular
2015 Informa UK Ltd
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Drug Profile
Albiges, Gizzi, Carton & Escudier
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Table 1. Inhibitory concentrations (IC50 in nmol) for targets with multitargeted tyrosine kinase inhibitors [15,18–21]. Drug
VEGFR-1
VEGFR-2
VEGFR-3
PDGFR-a
PDGFR-b
c-Kit
RET
Raf
Flt-3
Axitinib
0.1
0.2
0.1–0.3
5
1.6
1.7
>1000
NA
>1000
Pazopanib
10
30
47
71
84
74
>1000
NA
>1000
Sunitinib
10
10
10
5–10
10
13
100–200
NA
1–10
Sorafenib
NA
90
20
50–60
50–60
68
100–150
5–10
46
Flt-3: fms-like tyrosine kinase-3; NA: Non applicable; RET: Ret proto-oncogene; VEGFR: VEGF receptor.
formula is C22H18N4OS and molecular weight is 386.47 Da (FIGURE 1). The recommended dose is 5 mg twice a day with possible dose adaptation up to 10 mg twice daily [16]. Treatment is administered with continuous daily dosing, until disease progression or unacceptable toxicity. It is supplied as red, film-coated tablets containing either 1 or 5 mg of axitinib. The dosing is independent of age. It can be administered concomitantly with food intake and has to be taken whole with a glass of water. Pharmacokinetics
In pharmacological studies, it was found to be rapidly absorbed, with peak plasma concentrations measurable within 2–6 h after dosing in the fed state [16]. Peak plasma concentrations are reached in 1–2 h after dosing in the fasted state, while the plasma half-life remains unchanged. At a steady state, axitinib exhibits linear pharmacokinetics within the 2–20 mg dose range [16]. Based on the plasma half-life, steady state is expected within 2–3 days of dosing. Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin [16]. The plasma half-life ranges from 2.5 to 6.1 h. Axitinib is metabolized primarily in the liver, via the CYP450, and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1 [16]. The main circulating metabolites of axitinib are not active. Following oral administration of a 5 mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and 23% in urine [16]. Concomitant uses of CYP3A4 inducers or inhibitors are not recommended, and proton pump inhibitors reduce the rate of axitinib absorption, leading to a decrease in Cmax, but without significant impact on area under the curve [16].
O
H N
CH3 S
H N N
N
Figure 1. Chemical structure of axitinib [16].
500
Pharmacodynamics
In a study measuring the exposure–response relationship of axitinib in patients with advanced solid tumors, a >50% decrease in the volume transfer coefficient (Ktrans) and initial area under the curve was demonstrated by day 2 of therapy, which persisted through week 4 of treatment [17]. The IC50 for axitinib is 10-fold lower for the VEGF family receptors than for the tyrosine kinase receptors of other family receptor [15,18–21]. Moreover, in contrast to the first-generation VEGFR TKIs, axitinib does not significantly inhibit in vitro other receptor kinases such as Flt-3, FGF receptor (FGFR)-1, ret proto-oncogene (RET), EGF receptor (EGFR) and hepatocyte growth factor (c-Met). Dose adjustment related to co-morbidities & aging
No starting dose adjustments have been made in pre-existing mild-to-severe renal impairment, but caution is advised in endstage renal disease (creatinine clearance 65 years part of a clinical trial testing axitinib in patients with RCC, no overall differences were observed in the safety and efficacy of the drug between patients who were >65 years and younger patients [16]. No dosage adjustment is thus required in elderly patients. Dose modification guidelines
Unlike other prior VEGFR TKIs, axitinib has been developed with an intra-patient dose escalation model. Dose increase or reduction is recommended based on individual safety and tolerability. During the course of treatment, patients who tolerate the drug for two consecutive weeks without adverse reactions >grade 2 (according to Common Terminology Criteria for Adverse Events) and are normotensive are candidates for dose increase. When a dose increase is possible, the first escalated dose is 7 mg twice daily, which is further increased to 10 mg twice daily using the same criteria (maximal dose). In contrast, when the tolerance to axitinib is poor with grade 2 or more related adverse events (AEs), the dose can be decreased to 3 mg or even 2 mg two-times a day (b.i.d.) to maximize compliance and not alter the quality of life. Expert Rev. Anticancer Ther. 15(5), (2015)
Axitinib in mRCC
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Safety profile
The toxicity of this second-generation TKI is similar to the toxicity profile of the first-generation agents, with hypertension, fatigue and gastrointestinal toxicities being the most common and expected class- and dose-related AEs [23,24]. Moreover, in Phase II studies performed in RCC, no unexpected AEs occurred [23,24]. The increased experience in side effect management over the past few years with the generation of first VEGFR TKI has increased awareness about toxicities and their management with dose modification and appropriate supportive care [19]. Hypertension is one of the most frequent side effects observed in patients undergoing antiangiogenic therapy, with an estimated incidence ranging from 5 to 60%, consisting of de novo hypertension (HTA) (20%) or degradation of a preexisting HTA (80%) [25]. Grade 3 or 4 hypertension is reported in approximately 17% of axitinib-treated patients, while hypertension of any level is observed in 43% of treated patients. Interestingly, a recent meta-analysis has also shown that the incidence of hypertension was higher in kidney cancer than in the other tumor types treated with axitinib [26]. Moreover, in this meta-analysis, axitinib was also shown to be more likely to induce hypertension (40.1%) than the other TKIs used in RCC, such as sorafenib (23.4%, p < 0.0001), sunitinib (21.6%, p < 0.0001) and pazopanib (35.5%, p = 0.34). Multiple antihypertensive drugs are being used to treat antiangiogenic therapy-induced hypertension, including calcium channel blockers, inhibitors of the angiotensin system (ASI), b-blockers and diuretics. Specific antihypertensive agents are primarily selected based on patient’s co-morbidities. Angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers are good choices for the treatment of antiangiogenic therapy-induced hypertension, particularly in the setting of proteinuria. Recently it was also demonstrated that ASI had a favorable impact in terms of progression-free survival (PFS) and overall survival (OS) on the outcome in sunitinib-treated patients with mRCC, with no difference observed between patients who received ASI before starting sunitinib and those who received ASI within the first month of sunitinib treatment [27,28]. Indeed, combined data from five Phase II multicenter trials of axitinib in mRCC, non-small cell lung cancer, melanoma and thyroid cancer, defining hypertension as diastolic blood pressure (DBP) >90 mmHg, reported an overall reduction in risk of death of 33% in multivariate analyses among those developing hypertension (p = 0.036), as well as a better objective response rate (p < 0.001) and a trend toward better PFS (10.2 vs 7.1 months; p = 0.107) [29]. Those results were also obtained in a pooled analysis of the two axitinib Phase II mRCC studies exploring the relationships between pharmacokinetics, DBP and clinical efficacy with an increased OS in patients with at least one DBP measurement >90 mmHg during treatment (p < 0.05), which showed a median OS of 130 weeks for patients with DBP >90 mmHg compared with 42 weeks for patients not having DBP >90 mmHg [30]. There was no correlation between increases in informahealthcare.com
Drug Profile
area under the curve and changes in DBP, suggesting that the occurrence of increased DBP may not be related to higher drug levels, and therefore could probably be investigated as a potential prognostic biomarker [29]. Other AEs
The other treatment-related AEs in the Phase III trial included diarrhea (57.9%), nausea, fatigue, hand-foot syndrome (27.9%), anorexia (38.7%), weight loss (29%), dysphonia (31.8%), cough (18.7%) and dyspnea (18.7%) [31]. Biological drug-related side effects included creatine elevation (55%), hypocalcemia (39%), anemia (33%), lymphopenia (33%), polyglobulia (1.4%), hypothyroidia (20.9%) and lipase elevation (27%) [31]. In terms of safety and tolerability emerging data of long-tem exposure to axitinib did not identify unanticipated or more severe AEs [32]. In a western study on cytokine-refractory mRCC, patients had received axitinib for more than 3 years and did not present cumulative toxicity [33]. However, given the more recent approval of axitinib, less long-term observations are available to date for this compound. Long-term exposure is better characterized for sunitinib, with a report mentioning hypothyroidia and cardiovascular events (hypertension) as the most commons AEs seen after 2 years of exposure to the drug [34]. Careful assessment of renal function by estimating creatinine and estimated creatinine clearance is required to rule out a preexisting nephropathy before prescribing axitinib. Moreover, like other TKIs, systematic tracking of thyroid dysfunction must be performed before starting treatment and a substitution therapy is required in case of hypothyroidism. Finally, in case of pretherapeutic dysphonia, vocal cords must be seen by a specialist to rule out a laryngeal recurrent nerve paralysis that can be secondary to cervical or mediastinal metastasis. In conclusion, axitinib has a slightly better safety profile than other TKIs. The side effects affecting the head and neck sphere (dysphonia, cough and dyspnea) and polycythemia, which were not initially observed with the older TKIs, seem to be most frequent. Efficacy
The first Phase I study of axitinib included 36 patients with advanced solid malignancies treated with total daily dose ranging from 10 to 60 mg (TABLE 2) [35]. This trial was the first to define the maximal tolerated dose of axitinib as 5 mg orally twice a day. Significant dose-limiting toxicities were noticed and included mostly hypertension, diarrhea and stomatitis. Importantly, the incidence and severity of hypertension were already noted to be proportional to drug dosage. Linear pharmacokinetics was observed in the dose range evaluated in this trial [35]. Subsequent Phase I studies conducted among Asian population have confirmed similar pharmacokinetics and adverse effect profile of axitinib in non-Caucasian patients [36]. The efficacy of axitinib in mRCC was first reported in 52 cytokine-refractory patients [37]. The overall response rate 501
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Table 2. Summary of efficacy findings in key Phase II trials. Best response
Cytokine refractory (n = 52) [33]
Sorafenib refractory (n = 62) [38]
ORR
23 (44)
14
CR
2 (4)
0
PR
21 (40)
14 (23)
SD
11 (18)
> or =8 weeks
22 (42)
> or =24 weeks
13 (25)
Disease progression
4 (8)
25 (40)
Missing data
3 (6)
12 (19)
PFS (months)
13.7
7.4
OS (months)
29.9
13.6
Data are given as n (%). CR: Complete response; ORR: Overall response rate; OS: Overall survival; PR: Partial response; PFS: Progression-free survival; SD: Stable.
was 44%, with the median time to progression being 15.7 months and median OS being 29.9 months. Treatmentrelated AEs included diarrhea, hypertension, fatigue, nausea and hoarseness. Twenty eight patients (54%) had grade 3 or 4 treatment-related AEs, which included hypertension (n = 8), diarrhea (n = 5) and fatigue (n = 4), most of which were manageable through dose modification and/or supportive care. Overall, 10 patients did not continue in the study due to development of non-fatal treatment-related AEs. A potential association was noted between increased diarrhea and clinical response, but the events of diarrhea appeared to stabilize over time in treatment responders. The clinical benefit of axitinib in mRCC was further demonstrated in a Phase II trial, which involved patients with refractory disease to sorafenib [38]. Sorafenib and sunitinib refractory patients (group 1, n = 14), cytokine and sorafenib refractory patients (group 2, n = 29) and sorafenib alone refractory patients (group 3, n = 15) were treated with axitinib at the recommended Phase II dose of 10 mg/day. The objective response rate (ORR) was 7, 28, and 27% and the median PFS was 7.1, 9.0 and 7.7 months in groups 1, 2, and 3, respectively. For nine patients, the axitinib dose was reduced to 2–4 mg twice daily, for a mean duration of 4 cycles. These results have led to the development of a randomized Phase III trial of axitinib in patients with mRCC. In another Phase II study in Japanese patients with mRCC refractory to previous cytokine-based treatment, the patients (n = 64) received continuous dosing of axitinib (starting dose: 5 mg twice daily) [39]. An ORR of 55% was reported in this study and the median PFS was 12.9 months (95% CI: 9.8, 15.6). Another Phase II trial of 62 patients was conducted to evaluate the response to axitinib in patients who had received 502
prior VEGF therapy with sorafenib [40]. In this single-arm study, dose escalation was permitted if the standard 5 mg b.i.d. dosing was tolerated. Also, the protocol allowed for dose reduction or interruption for grade 3–4 (severe, disabling or lifethreatening) non-hematologic toxicities (as per National Cancer Institute-Common Terminology Criteria for AEs, version 3.0). A total of 53.2% of patients were able to tolerate dose increases to 7 or 10 mg b.i.d., while 17.7% of patients required dose reduction to £5 mg b.i.d. The primary endpoint of ORR was 22.6% (95% CI: 12.9–35.0%). With a median follow-up of 22.7 months, the median PFS was 7.4 months (95% CI: 6.7–11.0 months) and the median OS was 13.6 months (95% CI: 8.4–18.8 months). Interestingly, 80% of the evaluable patients had some degree of tumor shrinkage. Finally, another randomized, double-blind, multicenter, Phase II study enrolled 213 patients with treatment-naive mRCC to receive axitinib 5 mg twice daily during a 4-week lead-in period [41]. Patients with blood pressure 150/90 mmHg or lower without antihypertensive therapy, and who neither developed grade 2 toxicity or more nor required dose reduction were randomly assigned (1:1) to either masked titration with axitinib to twice daily doses of 7 mg and, if tolerated, to 10 mg or placebo titration. Patients who did not meet these criteria continued without titration. Ninety one patients were not randomized, and 56 were randomized between placebo and axitinib titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomized groups. The ORR was significantly higher in the axitinib titration group compared to the placebo titration group (54 vs 34%; p = 0.019), supporting the concept of individual dose titration in selected patients. The randomized, open-label, Phase III AXIS trial was the pivotal study that led to the registration of the drug by both the US and European authorities [31]. In this trial, 723 patients with clear-cell mRCC were randomized to receive second-line axitinib 5 mg twice daily or sorafenib 400 mg twice daily (TABLE 3). Patient selection was carefully restricted to only one prior therapy; however, this treatment could have been a variety of agents, including cytokines (35%), combination of bevacizumab and IFN-a (8%), temsirolimus (3%) or sunitinib (54%). The primary objective of the study was to demonstrate a benefit in PFS (evaluated by an independent committee). The secondary objectives were ORR, OS and safety. The primary endpoint of this study was met as axitinib led to significant improvement of PFS compared to sorafenib (hazard ratio [HR]: 0.67), with a median PFS of 6.7 months in the axitinib arm (n = 361) compared to 4.7 months with sorafenib (n = 362) (p < 0.001). In subgroup analysis, when axitinib was administered after sunitinib, it still had a clinical benefit over sorafenib (HR: 0.74), with the median PFS being 4.8 months in the axitinib arm (n = 194) and 3.4 months in the sorafenib arm (n = 195). In contrast, the benefit was greater in favor of axitinib in the subgroup pre-treated with cytokines, with the HR being 0.52 and the median PFS being 12 versus 6.6 months. Expert Rev. Anticancer Ther. 15(5), (2015)
Axitinib in mRCC
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Table 3. Summary of efficacy in the two major Phase III trials. AXIS trial Second line N = 723 R (1:1) [31]
ORR (independent radiologic review committee)
ORR (post sunitinib)
mPFS (months)
mPFS post cytokines (months)
mPFS post sunitinib (months)
mOS (months)
Axitinib 5 g b.i.d.
19%
11.3%
6.7
12.1
4.8
20.1
Sorafenib 400 g b.i.d.
9% p < 0.0001
7.7%
4.7 p < 0.0001
6.5 p < 0.0001
3.4 p < 0.0107
19.2 p = 0.374
AGILE First line N = 288 R (2:1) [43]
ORR (independent radiologic review committee)
mPFS (months)
mPFS if previous nephrectomy (months)
mPFS if ECOG PS 0 (months)
mOS (months)
Axitinib 5 mg b.i.d.
32.3%
10.1
10.3
13.7
No mature data
Sorafenib 400 mg b.i.d.
14.6% p < 0.0006
6.5 p < 0.038
6.4 p < 0.009
6.6 p < 0.002
No mature data
b.i.d.: Two-times a day; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Objective response rate.
With regard to the secondary endpoints, ORR in the overall improvement in median PFS was not achieved (10.1 vs population was 19.4% for axitinib and 9.4% for sorafenib, 6.5 months; stratified HR: 0.77; 95% CI: 0.56–1.05; while in the sunitinib–pre-treated population, ORR was p = 0.038), even though a clinical activity was seen with a 11.3 versus 7.7% in favor of axitinib. Secondary analysis of the 3.6 months improvement in PFS. One of the reasons contribAXIS trial suggested that within the 54% of patients (in both uting to this negative result is that the statistical design was sorafenib and axitinib arms) who had received prior sunitinib, probably too ambitious. Indeed, the study was powered to those who had received ‡9 months of front-line VEGFR inhib- detect a 78% improvement in median PFS from 5.5 months itor tended to have greater PFS (6.3 vs 4.5 months for axitinib; with sorafenib to 9.8 months with axitinib, corresponding to 4.6 vs 2.9 months for sorafenib). These data have to be consid- an HR of 0.56 (1-sided a = 0.025). ered as hypothesis-generating given the retrospective nature and Axitinib yielded an ORR of 32.3%, compared with a rate of the small subsets with overlapping CI values. There was no sta- 14.6% with sorafenib (HR: 0.64; p = 0.002). A subgroup analtistically significant difference in OS between the arms. These ysis in patients with an Eastern Cooperative Oncology Group results provide evidence favoring lack of cross-resistance performance status of 0 and who underwent a nephrectomy between different VEGFR inhibitors and support the use of demonstrated a significant improvement in median PFS with sequential VEGFR inhibitors, although optimal sequencing axitinib. Nevertheless, despite promising results and strong to maximize PFS and ultimately OS in mRCC is currently the subject of Table 4. Major clinical side effects from AXIS trial [31]. ongoing research [42]. Toxicities reported Adverse events Axitinib (n = 359) Sorafenib (n = 355) in this pivotal trial are summarized in All grades Grade 3 All grades Grade 3 TABLES 4 & 5. or more or more Due to the proven PFS benefit obtained with axitinib in the second-line Diarrhea 197 (55%) 38 (11%) 189 (53%) 26 (7%) setting, another randomized Phase III Hypertension 145 (40%) 56 (16%) 103 (29%) 39 (11%) trial comparing axitinib and sorafenib Fatigue 140 (39%) 41 (11%) 112 (32%) 18 (5%) was performed in treatment-naive mRCC patients [43]. A total of 288 patients from Decreased appetite 123 (34%) 18 (5%) 101 (29%) 13 (4%) 13 countries were randomly assigned Nausea 116 (32%) 9 (3%) 77 (22%) 4 (1%) (2:1) to receive either axitinib 5 mg twice 111 (31%) 0 48 (14%) 0 daily (192 patients) or sorafenib 400 mg Dysphonia twice daily (96 patients) (TABLE 3). The priPalmar-plantar erythrodysaesthesia 98 (27%) 18 (5%) 181 (51%) 57 (16%) mary endpoint was PFS, assessed by a Vomiting 85 (24%) 12 (3%) 61 (17%) 3 (1%) masked independent review committee in the intention-to-treat population. The Hypothyroidia 69 (19%) 1 (
Axitinib in metastatic renal cell carcinoma Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Expert Rev. Anticancer Ther. 15(5), 499–507 (2015)
Laurence Albiges, Marco Gizzi, Edith Carton and Bernard Escudier* Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France *Author for correspondence: Tel.: +33 142 115 410 Fax: +33 142 115 305 [email protected]
Axitinib is the most recent targeted therapy approved by the US FDA and EMA in the treatment of metastatic renal cell carcinoma (mRCC). It is a second-generation, orally available, potent tyrosine kinase inhibitor targeting selectively VEGF receptor (VEGFR)-1, -2 and -3, resulting in inhibition of angiogenesis, metastasis and tumor growth. Based on the results of a randomized pivotal Phase III clinical trial, axitinib stands as one of the two recommended agents for patients with mRCC who progressed after first-line tyrosine kinase inhibitor therapy. Its potent and selective inhibition of VEGFR was the rationale for its development in the second-line setting after failure of prior cytokines or sunitinib. Here we examine the preclinical and clinical data of axitinib for mRCC, and its use in the treatment algorithm. KEYWORDS: axitinib . clear cell . metastatic renal cell carcinoma . VEGFR TKI
Renal cell carcinoma (RCC) is the most common form of renal cancer. It accounts for 4% of all the adult malignancies. In the US, approximately 64,000 new cases and almost 14,000 deaths are reported due to RCC each year [1]. RCC is more common in men than in women [2] and occurs predominantly between the sixth and the eighth decade of life with the median age at diagnosis being around 64 years [3]. When nephrectomy is performed for a localized tumor, the risk of developing recurrent disease is estimated to be 20–30% [3,4]. Less than one-third of patients are initially diagnosed with metastatic disease and the median overall survival in the metastatic setting is 22 months [5]. Before 2005, the recommended treatment option for systemic disease was immunotherapy, with either IL-2 or IFN-a [6]. Those treatments were used in the first-line setting, and there was no recommended treatment for the second line. A better understanding of the pathogenesis of RCC has led to the development and approval of several molecularly targeted therapies since 2005 and significant improvement in patient outcome. Indeed, about 80% of sporadic RCC cases present a clear cell histopathology [7], driven by Von Hippel–Lindau tumor suppressor gene alterations resulting in an increased transcription of several hypoxia-inducible genes including VEGF, a key player in tumor angiogenesis [8–11]. VEGF binds to several distinct informahealthcare.com
10.1586/14737140.2015.1033408
receptors. VEGF receptor (VEGFR)-1 is involved in tumor growth and angiogenesis, VEGFR-2 plays a role in endothelial cell proliferation, migration and survival, and angiogenesis, while VEGFR-3 is implicated in lymphangiogenesis [12–14]. Therefore, inhibition of the VEGF/VEGFR axis is one of the two cornerstones of systemic therapies available in metastatic renal cell carcinoma (mRCC) and includes five approved agents: four multitargeted tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib, axitinib) and the humanized anti-VEGF monoclonal antibody (bevacizumab with interferon). Unlike bevacizumab that can selectively inhibit VEGF, the commonly used TKIs interfere with several growth factor receptors in addition to VEGFRs. Sunitinib and pazopanib inhibit predominantly VEGFRs and platelet-derived growth factor receptor, and c-Kit, whereas sunitinib may also target fms-like tyrosine kinase (Flt)-3. Sorafenib inhibits VEGFRs, platelet-derived growth factor receptor, c-Kit, Flt-3 and the serine–threonine kinase Raf-1 (TABLE 1) [15]. As a potent and specific antiVEGFR therapy, axitinib has been developed in mRCC. In this article, we sought to review the clinical activity of axitinib and its place in the treatment algorithm for mRCC. Mechanism of action & pharmacology
Axitinib (Inlyta, Pfizer) is an orally administered kinase inhibitor, whose molecular
2015 Informa UK Ltd
ISSN 1473-7140
499
Drug Profile
Albiges, Gizzi, Carton & Escudier
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/24/15 For personal use only.
Table 1. Inhibitory concentrations (IC50 in nmol) for targets with multitargeted tyrosine kinase inhibitors [15,18–21]. Drug
VEGFR-1
VEGFR-2
VEGFR-3
PDGFR-a
PDGFR-b
c-Kit
RET
Raf
Flt-3
Axitinib
0.1
0.2
0.1–0.3
5
1.6
1.7
>1000
NA
>1000
Pazopanib
10
30
47
71
84
74
>1000
NA
>1000
Sunitinib
10
10
10
5–10
10
13
100–200
NA
1–10
Sorafenib
NA
90
20
50–60
50–60
68
100–150
5–10
46
Flt-3: fms-like tyrosine kinase-3; NA: Non applicable; RET: Ret proto-oncogene; VEGFR: VEGF receptor.
formula is C22H18N4OS and molecular weight is 386.47 Da (FIGURE 1). The recommended dose is 5 mg twice a day with possible dose adaptation up to 10 mg twice daily [16]. Treatment is administered with continuous daily dosing, until disease progression or unacceptable toxicity. It is supplied as red, film-coated tablets containing either 1 or 5 mg of axitinib. The dosing is independent of age. It can be administered concomitantly with food intake and has to be taken whole with a glass of water. Pharmacokinetics
In pharmacological studies, it was found to be rapidly absorbed, with peak plasma concentrations measurable within 2–6 h after dosing in the fed state [16]. Peak plasma concentrations are reached in 1–2 h after dosing in the fasted state, while the plasma half-life remains unchanged. At a steady state, axitinib exhibits linear pharmacokinetics within the 2–20 mg dose range [16]. Based on the plasma half-life, steady state is expected within 2–3 days of dosing. Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin [16]. The plasma half-life ranges from 2.5 to 6.1 h. Axitinib is metabolized primarily in the liver, via the CYP450, and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1 [16]. The main circulating metabolites of axitinib are not active. Following oral administration of a 5 mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and 23% in urine [16]. Concomitant uses of CYP3A4 inducers or inhibitors are not recommended, and proton pump inhibitors reduce the rate of axitinib absorption, leading to a decrease in Cmax, but without significant impact on area under the curve [16].
O
H N
CH3 S
H N N
N
Figure 1. Chemical structure of axitinib [16].
500
Pharmacodynamics
In a study measuring the exposure–response relationship of axitinib in patients with advanced solid tumors, a >50% decrease in the volume transfer coefficient (Ktrans) and initial area under the curve was demonstrated by day 2 of therapy, which persisted through week 4 of treatment [17]. The IC50 for axitinib is 10-fold lower for the VEGF family receptors than for the tyrosine kinase receptors of other family receptor [15,18–21]. Moreover, in contrast to the first-generation VEGFR TKIs, axitinib does not significantly inhibit in vitro other receptor kinases such as Flt-3, FGF receptor (FGFR)-1, ret proto-oncogene (RET), EGF receptor (EGFR) and hepatocyte growth factor (c-Met). Dose adjustment related to co-morbidities & aging
No starting dose adjustments have been made in pre-existing mild-to-severe renal impairment, but caution is advised in endstage renal disease (creatinine clearance 65 years part of a clinical trial testing axitinib in patients with RCC, no overall differences were observed in the safety and efficacy of the drug between patients who were >65 years and younger patients [16]. No dosage adjustment is thus required in elderly patients. Dose modification guidelines
Unlike other prior VEGFR TKIs, axitinib has been developed with an intra-patient dose escalation model. Dose increase or reduction is recommended based on individual safety and tolerability. During the course of treatment, patients who tolerate the drug for two consecutive weeks without adverse reactions >grade 2 (according to Common Terminology Criteria for Adverse Events) and are normotensive are candidates for dose increase. When a dose increase is possible, the first escalated dose is 7 mg twice daily, which is further increased to 10 mg twice daily using the same criteria (maximal dose). In contrast, when the tolerance to axitinib is poor with grade 2 or more related adverse events (AEs), the dose can be decreased to 3 mg or even 2 mg two-times a day (b.i.d.) to maximize compliance and not alter the quality of life. Expert Rev. Anticancer Ther. 15(5), (2015)
Axitinib in mRCC
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Safety profile
The toxicity of this second-generation TKI is similar to the toxicity profile of the first-generation agents, with hypertension, fatigue and gastrointestinal toxicities being the most common and expected class- and dose-related AEs [23,24]. Moreover, in Phase II studies performed in RCC, no unexpected AEs occurred [23,24]. The increased experience in side effect management over the past few years with the generation of first VEGFR TKI has increased awareness about toxicities and their management with dose modification and appropriate supportive care [19]. Hypertension is one of the most frequent side effects observed in patients undergoing antiangiogenic therapy, with an estimated incidence ranging from 5 to 60%, consisting of de novo hypertension (HTA) (20%) or degradation of a preexisting HTA (80%) [25]. Grade 3 or 4 hypertension is reported in approximately 17% of axitinib-treated patients, while hypertension of any level is observed in 43% of treated patients. Interestingly, a recent meta-analysis has also shown that the incidence of hypertension was higher in kidney cancer than in the other tumor types treated with axitinib [26]. Moreover, in this meta-analysis, axitinib was also shown to be more likely to induce hypertension (40.1%) than the other TKIs used in RCC, such as sorafenib (23.4%, p < 0.0001), sunitinib (21.6%, p < 0.0001) and pazopanib (35.5%, p = 0.34). Multiple antihypertensive drugs are being used to treat antiangiogenic therapy-induced hypertension, including calcium channel blockers, inhibitors of the angiotensin system (ASI), b-blockers and diuretics. Specific antihypertensive agents are primarily selected based on patient’s co-morbidities. Angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers are good choices for the treatment of antiangiogenic therapy-induced hypertension, particularly in the setting of proteinuria. Recently it was also demonstrated that ASI had a favorable impact in terms of progression-free survival (PFS) and overall survival (OS) on the outcome in sunitinib-treated patients with mRCC, with no difference observed between patients who received ASI before starting sunitinib and those who received ASI within the first month of sunitinib treatment [27,28]. Indeed, combined data from five Phase II multicenter trials of axitinib in mRCC, non-small cell lung cancer, melanoma and thyroid cancer, defining hypertension as diastolic blood pressure (DBP) >90 mmHg, reported an overall reduction in risk of death of 33% in multivariate analyses among those developing hypertension (p = 0.036), as well as a better objective response rate (p < 0.001) and a trend toward better PFS (10.2 vs 7.1 months; p = 0.107) [29]. Those results were also obtained in a pooled analysis of the two axitinib Phase II mRCC studies exploring the relationships between pharmacokinetics, DBP and clinical efficacy with an increased OS in patients with at least one DBP measurement >90 mmHg during treatment (p < 0.05), which showed a median OS of 130 weeks for patients with DBP >90 mmHg compared with 42 weeks for patients not having DBP >90 mmHg [30]. There was no correlation between increases in informahealthcare.com
Drug Profile
area under the curve and changes in DBP, suggesting that the occurrence of increased DBP may not be related to higher drug levels, and therefore could probably be investigated as a potential prognostic biomarker [29]. Other AEs
The other treatment-related AEs in the Phase III trial included diarrhea (57.9%), nausea, fatigue, hand-foot syndrome (27.9%), anorexia (38.7%), weight loss (29%), dysphonia (31.8%), cough (18.7%) and dyspnea (18.7%) [31]. Biological drug-related side effects included creatine elevation (55%), hypocalcemia (39%), anemia (33%), lymphopenia (33%), polyglobulia (1.4%), hypothyroidia (20.9%) and lipase elevation (27%) [31]. In terms of safety and tolerability emerging data of long-tem exposure to axitinib did not identify unanticipated or more severe AEs [32]. In a western study on cytokine-refractory mRCC, patients had received axitinib for more than 3 years and did not present cumulative toxicity [33]. However, given the more recent approval of axitinib, less long-term observations are available to date for this compound. Long-term exposure is better characterized for sunitinib, with a report mentioning hypothyroidia and cardiovascular events (hypertension) as the most commons AEs seen after 2 years of exposure to the drug [34]. Careful assessment of renal function by estimating creatinine and estimated creatinine clearance is required to rule out a preexisting nephropathy before prescribing axitinib. Moreover, like other TKIs, systematic tracking of thyroid dysfunction must be performed before starting treatment and a substitution therapy is required in case of hypothyroidism. Finally, in case of pretherapeutic dysphonia, vocal cords must be seen by a specialist to rule out a laryngeal recurrent nerve paralysis that can be secondary to cervical or mediastinal metastasis. In conclusion, axitinib has a slightly better safety profile than other TKIs. The side effects affecting the head and neck sphere (dysphonia, cough and dyspnea) and polycythemia, which were not initially observed with the older TKIs, seem to be most frequent. Efficacy
The first Phase I study of axitinib included 36 patients with advanced solid malignancies treated with total daily dose ranging from 10 to 60 mg (TABLE 2) [35]. This trial was the first to define the maximal tolerated dose of axitinib as 5 mg orally twice a day. Significant dose-limiting toxicities were noticed and included mostly hypertension, diarrhea and stomatitis. Importantly, the incidence and severity of hypertension were already noted to be proportional to drug dosage. Linear pharmacokinetics was observed in the dose range evaluated in this trial [35]. Subsequent Phase I studies conducted among Asian population have confirmed similar pharmacokinetics and adverse effect profile of axitinib in non-Caucasian patients [36]. The efficacy of axitinib in mRCC was first reported in 52 cytokine-refractory patients [37]. The overall response rate 501
Drug Profile
Albiges, Gizzi, Carton & Escudier
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Table 2. Summary of efficacy findings in key Phase II trials. Best response
Cytokine refractory (n = 52) [33]
Sorafenib refractory (n = 62) [38]
ORR
23 (44)
14
CR
2 (4)
0
PR
21 (40)
14 (23)
SD
11 (18)
> or =8 weeks
22 (42)
> or =24 weeks
13 (25)
Disease progression
4 (8)
25 (40)
Missing data
3 (6)
12 (19)
PFS (months)
13.7
7.4
OS (months)
29.9
13.6
Data are given as n (%). CR: Complete response; ORR: Overall response rate; OS: Overall survival; PR: Partial response; PFS: Progression-free survival; SD: Stable.
was 44%, with the median time to progression being 15.7 months and median OS being 29.9 months. Treatmentrelated AEs included diarrhea, hypertension, fatigue, nausea and hoarseness. Twenty eight patients (54%) had grade 3 or 4 treatment-related AEs, which included hypertension (n = 8), diarrhea (n = 5) and fatigue (n = 4), most of which were manageable through dose modification and/or supportive care. Overall, 10 patients did not continue in the study due to development of non-fatal treatment-related AEs. A potential association was noted between increased diarrhea and clinical response, but the events of diarrhea appeared to stabilize over time in treatment responders. The clinical benefit of axitinib in mRCC was further demonstrated in a Phase II trial, which involved patients with refractory disease to sorafenib [38]. Sorafenib and sunitinib refractory patients (group 1, n = 14), cytokine and sorafenib refractory patients (group 2, n = 29) and sorafenib alone refractory patients (group 3, n = 15) were treated with axitinib at the recommended Phase II dose of 10 mg/day. The objective response rate (ORR) was 7, 28, and 27% and the median PFS was 7.1, 9.0 and 7.7 months in groups 1, 2, and 3, respectively. For nine patients, the axitinib dose was reduced to 2–4 mg twice daily, for a mean duration of 4 cycles. These results have led to the development of a randomized Phase III trial of axitinib in patients with mRCC. In another Phase II study in Japanese patients with mRCC refractory to previous cytokine-based treatment, the patients (n = 64) received continuous dosing of axitinib (starting dose: 5 mg twice daily) [39]. An ORR of 55% was reported in this study and the median PFS was 12.9 months (95% CI: 9.8, 15.6). Another Phase II trial of 62 patients was conducted to evaluate the response to axitinib in patients who had received 502
prior VEGF therapy with sorafenib [40]. In this single-arm study, dose escalation was permitted if the standard 5 mg b.i.d. dosing was tolerated. Also, the protocol allowed for dose reduction or interruption for grade 3–4 (severe, disabling or lifethreatening) non-hematologic toxicities (as per National Cancer Institute-Common Terminology Criteria for AEs, version 3.0). A total of 53.2% of patients were able to tolerate dose increases to 7 or 10 mg b.i.d., while 17.7% of patients required dose reduction to £5 mg b.i.d. The primary endpoint of ORR was 22.6% (95% CI: 12.9–35.0%). With a median follow-up of 22.7 months, the median PFS was 7.4 months (95% CI: 6.7–11.0 months) and the median OS was 13.6 months (95% CI: 8.4–18.8 months). Interestingly, 80% of the evaluable patients had some degree of tumor shrinkage. Finally, another randomized, double-blind, multicenter, Phase II study enrolled 213 patients with treatment-naive mRCC to receive axitinib 5 mg twice daily during a 4-week lead-in period [41]. Patients with blood pressure 150/90 mmHg or lower without antihypertensive therapy, and who neither developed grade 2 toxicity or more nor required dose reduction were randomly assigned (1:1) to either masked titration with axitinib to twice daily doses of 7 mg and, if tolerated, to 10 mg or placebo titration. Patients who did not meet these criteria continued without titration. Ninety one patients were not randomized, and 56 were randomized between placebo and axitinib titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomized groups. The ORR was significantly higher in the axitinib titration group compared to the placebo titration group (54 vs 34%; p = 0.019), supporting the concept of individual dose titration in selected patients. The randomized, open-label, Phase III AXIS trial was the pivotal study that led to the registration of the drug by both the US and European authorities [31]. In this trial, 723 patients with clear-cell mRCC were randomized to receive second-line axitinib 5 mg twice daily or sorafenib 400 mg twice daily (TABLE 3). Patient selection was carefully restricted to only one prior therapy; however, this treatment could have been a variety of agents, including cytokines (35%), combination of bevacizumab and IFN-a (8%), temsirolimus (3%) or sunitinib (54%). The primary objective of the study was to demonstrate a benefit in PFS (evaluated by an independent committee). The secondary objectives were ORR, OS and safety. The primary endpoint of this study was met as axitinib led to significant improvement of PFS compared to sorafenib (hazard ratio [HR]: 0.67), with a median PFS of 6.7 months in the axitinib arm (n = 361) compared to 4.7 months with sorafenib (n = 362) (p < 0.001). In subgroup analysis, when axitinib was administered after sunitinib, it still had a clinical benefit over sorafenib (HR: 0.74), with the median PFS being 4.8 months in the axitinib arm (n = 194) and 3.4 months in the sorafenib arm (n = 195). In contrast, the benefit was greater in favor of axitinib in the subgroup pre-treated with cytokines, with the HR being 0.52 and the median PFS being 12 versus 6.6 months. Expert Rev. Anticancer Ther. 15(5), (2015)
Axitinib in mRCC
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Table 3. Summary of efficacy in the two major Phase III trials. AXIS trial Second line N = 723 R (1:1) [31]
ORR (independent radiologic review committee)
ORR (post sunitinib)
mPFS (months)
mPFS post cytokines (months)
mPFS post sunitinib (months)
mOS (months)
Axitinib 5 g b.i.d.
19%
11.3%
6.7
12.1
4.8
20.1
Sorafenib 400 g b.i.d.
9% p < 0.0001
7.7%
4.7 p < 0.0001
6.5 p < 0.0001
3.4 p < 0.0107
19.2 p = 0.374
AGILE First line N = 288 R (2:1) [43]
ORR (independent radiologic review committee)
mPFS (months)
mPFS if previous nephrectomy (months)
mPFS if ECOG PS 0 (months)
mOS (months)
Axitinib 5 mg b.i.d.
32.3%
10.1
10.3
13.7
No mature data
Sorafenib 400 mg b.i.d.
14.6% p < 0.0006
6.5 p < 0.038
6.4 p < 0.009
6.6 p < 0.002
No mature data
b.i.d.: Two-times a day; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Objective response rate.
With regard to the secondary endpoints, ORR in the overall improvement in median PFS was not achieved (10.1 vs population was 19.4% for axitinib and 9.4% for sorafenib, 6.5 months; stratified HR: 0.77; 95% CI: 0.56–1.05; while in the sunitinib–pre-treated population, ORR was p = 0.038), even though a clinical activity was seen with a 11.3 versus 7.7% in favor of axitinib. Secondary analysis of the 3.6 months improvement in PFS. One of the reasons contribAXIS trial suggested that within the 54% of patients (in both uting to this negative result is that the statistical design was sorafenib and axitinib arms) who had received prior sunitinib, probably too ambitious. Indeed, the study was powered to those who had received ‡9 months of front-line VEGFR inhib- detect a 78% improvement in median PFS from 5.5 months itor tended to have greater PFS (6.3 vs 4.5 months for axitinib; with sorafenib to 9.8 months with axitinib, corresponding to 4.6 vs 2.9 months for sorafenib). These data have to be consid- an HR of 0.56 (1-sided a = 0.025). ered as hypothesis-generating given the retrospective nature and Axitinib yielded an ORR of 32.3%, compared with a rate of the small subsets with overlapping CI values. There was no sta- 14.6% with sorafenib (HR: 0.64; p = 0.002). A subgroup analtistically significant difference in OS between the arms. These ysis in patients with an Eastern Cooperative Oncology Group results provide evidence favoring lack of cross-resistance performance status of 0 and who underwent a nephrectomy between different VEGFR inhibitors and support the use of demonstrated a significant improvement in median PFS with sequential VEGFR inhibitors, although optimal sequencing axitinib. Nevertheless, despite promising results and strong to maximize PFS and ultimately OS in mRCC is currently the subject of Table 4. Major clinical side effects from AXIS trial [31]. ongoing research [42]. Toxicities reported Adverse events Axitinib (n = 359) Sorafenib (n = 355) in this pivotal trial are summarized in All grades Grade 3 All grades Grade 3 TABLES 4 & 5. or more or more Due to the proven PFS benefit obtained with axitinib in the second-line Diarrhea 197 (55%) 38 (11%) 189 (53%) 26 (7%) setting, another randomized Phase III Hypertension 145 (40%) 56 (16%) 103 (29%) 39 (11%) trial comparing axitinib and sorafenib Fatigue 140 (39%) 41 (11%) 112 (32%) 18 (5%) was performed in treatment-naive mRCC patients [43]. A total of 288 patients from Decreased appetite 123 (34%) 18 (5%) 101 (29%) 13 (4%) 13 countries were randomly assigned Nausea 116 (32%) 9 (3%) 77 (22%) 4 (1%) (2:1) to receive either axitinib 5 mg twice 111 (31%) 0 48 (14%) 0 daily (192 patients) or sorafenib 400 mg Dysphonia twice daily (96 patients) (TABLE 3). The priPalmar-plantar erythrodysaesthesia 98 (27%) 18 (5%) 181 (51%) 57 (16%) mary endpoint was PFS, assessed by a Vomiting 85 (24%) 12 (3%) 61 (17%) 3 (1%) masked independent review committee in the intention-to-treat population. The Hypothyroidia 69 (19%) 1 (
