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Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre
European Journal of Cancer 79 (2017) 185e192
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Clinical Trial
Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre Margarida Matias a, Gwe´nae¨l Le Teuff b,c, Laurence Albiges a, Annalisa Guida a, Caroline Brard b,c, Giulia Bacciarelo a, Yohann Loriot a, Christophe Massard a, Nathalie Lassau d,e, Karim Fizazi a, Bernard Escudier a,* a
Department of Medical Oncology, Gustave Roussy, F-94805, Villejuif, France Department of Biostatistics and Epidemiology, Gustave Roussy, Universite´ Paris-Saclay, Villejuif, F-94805, France c Universite´ Paris-Saclay, University of Paris-Sud, UVSQ, CESP, INSERM, Villejuif, F-94085, France d Department of Imaging and IR4M UMR808, Gustave Roussy, F-94805, Villejuif, France e Universite´ Paris-Sud, IR4M UMR808, Villejuif, F-94085, France b
Received 21 January 2017; received in revised form 7 April 2017; accepted 10 April 2017
KEYWORDS Metastatic renal cell carcinoma; Axitinib; Second or further nextline; Prospective study; Effectiveness; Safety
Abstract Background: Axitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials. Methods: A prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored. Results: One-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in
* Corresponding author: Gustave Roussy, Universite´ Paris-Saclay, De´partement de me´decine Oncologique, Villejuif, F-94805, France. E-mail addresses: [email protected] (M. Matias), [email protected] (G. Le Teuff), laurence.albiges@ gustaveroussy.fr (L. Albiges), [email protected] (A. Guida), [email protected] (C. Brard), giulia.baciarello@ gustaveroussy.fr (G. Bacciarelo), [email protected] (Y. Loriot), [email protected] (C. Massard), nathalie. [email protected] (N. Lassau), [email protected] (K. Fizazi), [email protected], [email protected] (B. Escudier). http://dx.doi.org/10.1016/j.ejca.2017.04.015 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n Z 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF. Conclusion: Efficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy. ª 2017 Elsevier Ltd. All rights reserved.
1. Introduction Renal cell carcinoma (RCC) is the eighth most common malignancy affecting adults, accounting for 3e4% of new cancer cases in the United States. It is diagnosed in more than 200,000 patients worldwide every year and accounts for approximately 100,000 deaths annually [1]. In the past 7 years, targeted agents have dramatically improved outcome of patients with metastatic RCC (mRCC) [1]. Several targeted agents are now approved for mRCC, and new agents have been recently developed still increasing the number of approved drugs [2,3]. Axitinib has shown activity in mRCC in the AXIS trial [4,5] that compared axitinib to sorafenib in patients who progressed after first-line therapy. Patients treated with axitinib had a significant higher objective response rate (ORR) (19% versus 11%) and a higher progression-free survival (PFS) (8.3 versus 4.7 months). Based on these positive results, axitinib was approved and became available in France in November 2012. However, real world efficacy data are still rare, and prospective evaluation has not yet been reported. The aim of this study is to report the efficacy and toxicity of axitinib in patients with mRCC in current clinical practice and to explore the association between clinical markers and outcomes. In addition, a subgroup of patients had prospective evaluation of dynamic contrast-enhanced ultrasound (DCE-US) as previously reported by our group to determine whether it is possible to predict early clinical benefit to the drug [6]. 2. Materials and methods 2.1. Patients We conducted a prospective evaluation of all patients with mRCC who started treatment with axitinib in second or further next-line at Gustave Roussy, from November 2012 to October 2015. All patients who received at least one dose of axitinib were eligible. These patients had progressed after at least one vascular endothelial growth factor (VEGF)-targeted agent and received axitinib outside of a clinical trial.
Collected patient characteristics were age, gender, Eastern Cooperative Oncology Group Performance Status (ECOG PS), risk group (defined according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), tumour histology, number and location of metastatic sites, prior nephrectomy, number and type of prior systemic treatments. Followup data were collected. Axitinib was given according to standard recommendations with a starting dose of 5 mg twice daily (bid) (10 mg/d). Whenever possible, dose titration (DT) was performed every 2 weeks up to a first step of 7 mg bid (14 mg/d), and if still possible, until a second and final step of 10 mg bid (20 mg/d) in patients without hypertension or adverse reactions above grade (G)2. As well, whenever indicated, dose reduction for toxicity was performed based on the same recommendations. Information related to DT and reduction was collected through the whole treatment duration. Evaluation of response was performed by computed tomography (CT) scan, according to Response Evaluation Criteria in Solid Tumours, (RECIST) version 1.1 criteria [7], every 2e3 months. For each patient, the best response during treatment, including complete response (CR), partial response (PR), stable disease (SD) or progression of disease (PD), was measured. ORR was defined as the percentage of PR or CR during treatment. Patients who stopped treatment for toxicity before tumour assessment were not considered for response evaluation. Tumour shrinkage (TS) 10% at the first CT scan was also measured. The decrease in vascularisation of targeted lesions, evaluated by DCE-US between axitinib initiation and 30 days after initiation, was measured in a subset of patients. PFS was defined from the time between axitinib start (t0) and documented progression/death. Time to treatment failure (TTF) was defined from t0 to either documented progression/death or interruption of treatment for toxicity. Overall survival (OS) was defined from t0 to the date of death from any cause. For each outcome, patients with no event of interest are censored at the date of last visit.
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We also collected toxicity data during axitinib treatment using the NCI CTCAE (Common Terminology Criteria for Adverse Events). 2.2. Statistical analysis The patients’ characteristics, treatment and toxicities were described. The best response distribution was reported with a waterfall plot. ORR was reported and its duration estimated using the KaplaneMeier method. The median follow-up was estimated using the Schemper’s method. In an exploratory setting, we evaluated the association between patient’s characteristics at baseline (number of metastatic sites (1e2, 3), IMDC risk group (poor, intermediate, good), axitinib line (second, third or next-line)), G3 toxicity, G3 hypertension, DT and ORR, PFS, TTF and OS. Outcome was measured at 2, 4 and 8 weeks from axitinib initiation. For ORR, odds ratios (OR) and 95% confidence interval (95% CI) were estimated using a logistic model. For PFS, TTF and OS, hazard ratios (HRs) and 95% CI were estimated through a Cox model. The proportional hazards assumption was checked using martingalebased residuals [8], and no violation of the assumption was observed. As G3 hypertension and DT were timedependent exposure, a 2-weeks landmark analysis for survival outcomes was performed. This 2-week
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landmark analysis will be completed by KaplaneMeier curves. Sensitivity analyses were performed for 4- and 8week landmark points. Tumour shrinkage of target lesions 10% measured at 8 weeks was included for the 8week landmark survival analyses. The Firth’s penalised likelihood approach was used for regression models [9] with no selection process of covariates. The cut-off date was 1st May 2016. The statistical analysis was performed in software suite SAS version 9.3 (SAS Institute, Cary NC). 3. Results 3.1. Patients’ characteristics One-hundred six mRCC patients, with a median followup of 20.0 months (min: 0.9, max: 40.2) received axitinib in second- (40%) or further next-lines (39% in third and 22% in fourth or next- lines). The number of previous lines ranged from 1 to 6. As described in Table 1, 74% of patients were male and 55% presented metastatic disease at diagnosis. IMDC risk group was good, intermediate or poor in 13%, 54% and 32%, respectively and 90% had clear cell histology. The number of metastatic sites ranged from 1 to 8. Eighty-six percent of patients had prior nephrectomy and 57% had received local therapy for metastases. The most common first-line therapy was
Table 1 Patients’ characteristics. Baseline characteristics Age, median (IQR) Gender, n (%) Male Female Stage at diagnosis, n (%) Localised Metastatic Risk group (IMDC), n (%) Good Intermediate Poor Na Histology, n (%) Clear cell adenocarcinoma Papillary carcinoma (type 2) Juvenile carcinoma Chromophobe carcinoma Histological grade, n (%) 1e2 3e4 Na Number of metastatic sites, n (%) 1 2 3 (range: 3e8)
54 (46e60) 74 (70) 32 (30) 48 (45) 58 (55) 14 (13) 57 (54) 34 (32) 1 (1) 95 (90) 5 (5) 4 (4) 2 (2)
30 (28) 67 (63) 9 (9) 8 (8) 17 (16) 81 (76)
Site of metastases, n (%) Lung Thoracic lymph nodes Bone Liver Abdominal lymph nodes Renal Adrenal Pleura Renal lodge Others Prior nephrectomy, n (%) Local therapy for metastasis, n (%) Surgery Radiotherapy Radiofrequency/Cryotherapy Number of previous lines of treatment before axitinib, n (%) 1 line 2 lines 3 lines (range: 3e6) First line treatment, n (%) Sunitinib Others TKI Bevacizumab mTOR inhibitors Second line treatment, n (%) Everolimus TKI or anti-VEGF therapy
78 58 44 31 31 27 23 22 20 53 91 61 41 40 13
(74) (55) (42) (29) (29) (25) (22) (21) (19) (50) (86) (57) (39) (38) (12)
42 (40) 41 (39) 23 (22) 77 (73) 14 (13) 9 (8) 6 (6) 40 (63) 24 (38)
IQR: interquartile range; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium, bid: twice daily; na: not available.
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sunitinib (73%). Evaluation of vascularisation at days 0, 15 and 30 by DCE-US was assessed in 12 patients.
(Waterfall plot, Supplementary Fig. 1). The median duration of response was 10.4 months (95% CI: 8.8e16.2).
3.2. Treatment The median duration of axitinib was 7.3 months (95% CI: 5.6e9.0) (Table 2). All (but two) patients started axitinib at 5 mg bid. DT to 7 mg bid was performed in 38% of patients (n Z 40), and to 10 mg bid in 19% of patients (n Z 20). Dose >5 mg bid could be maintained for a median time of 3.1 months (range: 0.4e17.4). A dose reduction below 5 mg bid was observed in 32 (30%) out of all included patients (n Z 106) and 6 (15%) out of patients that performed dose titration (n Z 40). Adverse events leading to a dose reduction below 5 mg bid in 6 out of the 40 patients that had performed dose titration to 7 mg bid were: reintroduction at reduced doses after suspension of treatment for difficulty of cicatrisation post surgical procedure (n Z 2); G3 hypertension and G2 headache (n Z 1); G3 fatigue, G2 diarrhoea and dysphonia (n Z 1); G2 fatigue, weight loss and diarrhoea (n Z 1) and G2 arthralgia (n Z 1). At the time of analysis, 12 patients (11%) remained on treatment. Main reasons for interruption of treatment were PD (n Z 55), toxicity (n Z 18), or both (n Z 11). Treatment suspension was needed in 31 patients (29%), mainly for toxicity (n Z 18). 3.3. Efficacy 3.3.1. Objective response rate Best response was PR (32%, n Z 33), SD (40%, n Z 41) and PD (27%, n Z 28). Response was not available for four patients who stopped treatment for toxicity (4%)
3.3.2. Time-to-event outcomes: progression-free survival, time-to-failure and overall survival Median (m) PFS was 8.3 months (95% CI: 6.3e9.6) (with 6.3 months (3.9e10.1) and 8.8 months (7.0e10.7) for patients treated in second- and third- or further nextline respectively), mTTF was 5.8 months (4.5e8.3) (with 4.7 months (2.9e8.3) and 7.0 months (3.9e8.8) for patients treated in second- and third- or further next-line, respectively) and mOS was 16.4 months (12.4e24.9) (with 14.9 months (7.8e26.3) and 16.4 months (11.5e27.6) for patients treated in second- and third- or further next-line, respectively). 3.3.3. Safety Most adverse events (AEs) were grade 1e2 (Table 3, last column). Fatigue and hypertension were the most common AEs. Hypertension was the most common G3e4 AE (G3: 39%, G4: 2%). The other common G3 AEs were fatigue (10%) and diarrhoea (6%). When compared to AEs described in the AXIS trial [5], G3e4 hypertension was more frequent while diarrhoea and anorexia were less commonly observed. The pattern of other toxicities was similar to those previously reported [5]. The majority of AEs were manageable with dose modification and supportive care. Hypertension was generally easily managed with antihypertensive drugs [10]. The AEs that led to treatment interruption (n Z 18) were: G4 hypertension with posterior reversible encephalopathy syndrome (PRES) (n Z 1), ischaemic stroke (n Z 1), G3 fatigue (n Z 3), G3 nausea and
Table 2 Received treatment and clinical outcomes. Received treatment Axitinib duration (months) median (95%CI) DT to 7 mg bid, n (%) At 2 weeks, n (%) DT to 10 mg bid, n (%) At 4 weeks, n (%) Clinical outcomes Best responsea Complete response, n (%) Partial response, n (%) Stable disease, n (%) Progression of disease, n (%) Not assessed, n (%) Objective response rate, n (%) No Yes Missing
7.3 (5.6e9.0) 40 (38) 16 (15) 20 (19) 7 (7)
0 (0) 33 (32) 41 (40) 28 (27) 4 69 (68) 33 (32) 4
Time dose >5 mg bid (months), median (range) Dose <5 mg bid, n (%) Dose reduction at 2 weeks, n (%) Dose reduction at 4 weeks, n (%)
32 (30) 7 (7) 14 (13)
Events Progression/death, n (%) Treatment failureb, n (%) Death, n (%) PFS (months), median (95% CI) TTF (months), median (95% CI)
89 (84) 95 (90) 59 (56) 8.3 (6.3e9.6) 5.8 (4.5e8.3)
OS (months), median (95% CI)
16.4 (12.4e24.9)
3.1 (0.4e17.4)
DT: dose titration; bid: twice daily; med: median, PFS: progression free survival, TTF: time to treatment failure, OS: overall survival. a Patients who interrupted treatment for toxicity before tumour assessment (n Z 4) were not considered in the evaluation of response. Patients who presented clinical progression or died before tumour assessment (n Z 5) were considered as presenting progression of disease. b The reasons for treatment failure were progression/death (n Z 56), toxicity (n Z 18), progression þ toxicity (n Z 11) and other causes (n Z 10).
Table 3 Maximum grade of Axitinib-related adverse events during the whole treatment duration according to common toxicity criteria (CTC) version 4.0*. Toxicity
Adverse events, n (%)
Fatigue Hypertension Diarrhoea Dysphonia Palmar-plantar erythrodysesthesia Mucositis Weight loss Hypothyroidism Anorexia Respiratory disorders Arthralgia Abdominal pain Nausea/vomiting Constipation Headache Depression Oedema Dysgeusia OJN aggravation Epistaxis Haemorrhoids Pruritus Total
Dose titrationa (n Z 40)
Total (n Z 106)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
19 (29) 3 (5) 13 (20) 21 (32) 3 (5)
21 (32) 11 (17) 21 (32) 7 (11) 3 (5)
7 (11) 27 (41) 3 (5) 2 (3) 3 (5)
0 0 0 0 0
(0) (0) (0) (0) (0)
7 (11) 27 (41) 3 (5) 2 (3) 3 (5)
11 (28) 2 (5) 9 (23) 17 (43) 4 (10)
13 (33) 6 (15) 12 (30) 8 (20) 6 (15)
4 (10) 14 (35) 3 (8) 0 (0) 2 (5)
0 2 0 0 0
(0) (5) (0) (0) (0)
4 (10) 16 (40) 3 (8) 0 (0) 2 (5)
30 (28) 5 (5) 22 (21) 38 (36) 7 (7)
34 (32) 17 (16) 33 (31) 15 (14) 9 (8)
11 (10) 41 (39) 6 (6) 2 (2) 5 (5)
0 2 0 0 0
(0) (2) (0) (0) (0)
11 (10) 43 (41) 6 (6) 2 (2) 5 (5)
8 (12) 1 (2) 5 (8) 4 (6) 2 (3) 2 (3) 2 (3) 1 (2) 2 (3) 1 (2) 1 (2) 2 (3) 0 (0) 0 (0) 1 (2) 1 (2) 1 (2) 42 (64)
3 (5) 10 (15) 4 (6) 4 (6) 2 (3) 2 (3) 1 (2) 1 (2) 1 (2) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 49 (74)
1 (2) 0 (0) 0 (0) 1 (2) 0 (0) 1 (2) 2 (3) 3 (5) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 37 (56)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
1 (2) 0 (0) 0 (0) 1 (2) 0 (0) 1 (2) 2 (3) 3 (5) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 37 (56)
4 (10) 2 (5) 3 (8) 3 (8) 4 (10) 1 (3) 2 (5) 2 (5) 0 (0) 2 (5) 1 (3) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 31 (78)
3 (8) 3 (8) 3 (8) 2 (5) 2 (5) 2 (5) 2 (5) 0 (0) 1 (3) 2 (5) 1 (3) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 30 (75)
0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 19 (48)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (5)
0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 21 (53)
12 (11) 3 (3) 8 (8) 7 (7) 6 (6) 3 (3) 4 (4) 3 (3) 2 (2) 3 (3) 2 (2) 3 (3) 0 (0) 0 (0) 1 (1) 1 (1) 1 (1) 73 (69)
6 (6) 13 (12) 7 (7) 6 (6) 4 (4) 4 (4) 3 (3) 1 (1) 2 (2) 3 (3) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 79 (75)
1 (1) 1 (1) 0 (0) 1 (1) 0 (0) 2 (2) 2 (2) 3 (3) 2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 56 (53)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (2)
1 (1) 1 (1) 0 (0) 1 (1) 0 (0) 2 (2) 2 (2) 3 (3) 2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 58 (55)
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No dose titration (n Z 66)
a Among patients with a dose titration to 7 mg bid during axitinib treatment (n Z 40), the cumulative number of patients with a dose titration occurring at 2, 4 and 8 weeks was 16, 25 and 32.8 patients have a dose titration after 8 weeks.
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vomiting (n Z 3), G3 abdominal pain (n Z 2), G3 handfoot syndrome (HFS) and fatigue (n Z 1), worsened pre-existing controlled osteonecrosis of the jaw (n Z 1), G3 arthralgia (n Z 1), G3 mucositis (n Z 1), G2 diarrhoea and fatigue (n Z 2), G2 diarrhoea and weight loss (n Z 1), G2 diarrhoea and HFS (n Z 1). In patients with a dose-titration (n Z 40), only 2 patients had G4 adverse events (G4 hypertension) with dose titration to 7 mg bid and 10 mg bid, respectively while patients without dose-titration (n Z 66) had no G4 adverse event. Otherwise, the number of toxicities and their grade are comparable between these two subgroups of patients. 3.4. Exploratory analyses 3.4.1. Objective response rate The models, estimating the adjusted association between G3 hypertension and DT measured at 2 (model 1), 4 (model 2) and 8 weeks (model 3) after axitinib initiation and the probability of ORR, fitted similarly with AIC values varying from 96.72 to 98.61 (Supplementary Table 1). G3 toxicity is omitted because of this strong correlation with G3 hypertension (p < 0.0001). Poor IMDC risk group is negatively associated with ORR (for example, OR Z 0.19 95% CI Z [0.05; 0.72] (p Z 0.0144) for model 1). G3 hypertension at 2 weeks is marginally positively associated to ORR (OR Z 2.94 [0.91, 9.53] (p Z 0.0720)) with similar results at 4 and 8 weeks while DT evaluated was significantly associated to ORR at 2 weeks (OR Z 4.06 [1.02, 16.19] (p Z 0.0472)) but not at 4 and 8 weeks.
3.4.2. Correlation with outcomes The 2-week landmark analysis showed that age, IMDC risk group and G3 hypertension are significantly correlated to PFS, TTF and OS (Table 4) (Supplementary Fig. 2 for KaplaneMeier curves). For example, G3 hypertension at 2 weeks has a protector effect with HR Z 0.35 [0.18, 0.66] for PFS, 0.39 [0.21, 0.71] for TTF and 0.20 [0.08, 0.50] for OS. DT at 2 weeks (but not at 4 and 8 weeks) was also significantly associated to PFS (HR Z 0.48 [0.25, 0.91]) and TTF (HR Z 0.50 [0.27, 0.92]) but not to OS (HR Z 0.68 [0.31, 1.51]). The association between G3 hypertension at 4 and 8 weeks after axitinib initiation was maintained (Supplementary Tables 2 and 3). These findings confirm the results indicating that hypertension induced by antiangiogenic agents is associated with better outcome [11,12]. The number of metastatic sites is associated with OS (for example, HR Z 3.94 [1.48e10.51] for 2-weeks landmark analysis). Tumour shrinkage 10% at 8 weeks is significantly associated with PFS (HR Z 0.30 [0.17, 0.55]) and TTF (HR Z 0.33 [0.19, 0.58]) but not with OS (Supplementary Table 3).
3.4.3. Decrease vascularisation by DCE-US DCE-US at baseline was performed in 16 patients. Of those, in 12 patients it was possible monitoring vascularisation at Days 0, 15 and 30. When evaluating decrease vascularisation at day 30 (D30), determined by Area under the curve (AUC), univariate analysis shows that there was no impact on decrease vascularisation on ORR. However, median PFS, TTF and OS were significantly longer in patients with decrease
Table 4 Multivariable analyses of progression-free survival, time-to failure and overall survival e 2-weeks landmark analysis. Variable
Sex Age at diagnosis Stage at diagnosis Histology Number of metastatic sites IMDC risk group Axitinib line Grade 3 hypertension at 2 weeks Dose titration at 2 weeks
Male Female IeIII IV Clear cell carcinoma Other 1e2 3 Good/intermediate Poor 2nd line 3rd line No Yes No Yes
Progression free survival (n Z 103, events Z 87)
Time to treatment failure (n Z 103, events Z 93)
Overall survival (n Z 103, events Z 57)
HR [95% CI] (p-value)
HR [95% CI] (p-value)
HR [95% CI] (p-value)
1 1.07 0.95 1 1.03 1 1.70 1 1.81 1 3.84 1 0.62 1 0.35 1 0.48
1 1.11 0.96 1 0.86 1 1.61 1 1.09 1 3.80 1 0.84 1 0.39 1 0.50
1 1.80 0.97 1 1.07 1 2.28 1 3.94 1 3.42 1 0.54 1 0.20 1 0.68
[0.65, 1.78] (0.7860) [0.93, 0.98] (<0.0001) [0.64, 1.65] (0.9084) [0.85, 3.40] (0.1315) [0.98, 3.35] (0.0593) [2.21, 6.69] (<0.0001) [0.38, 1.00] (0.0497) [0.18, 0.66] (0.0013) [0.25, 0.91] (0.0248)
[0.68, 1.83] (0.6716) [0.94, 0.99] (0.0016) [0.55, 1.33] (0.492) [0.80, 3.22] (0.1815) [0.61, 1.95] (0.7680) [2.23, 6.47] (<0.0001) [0.53, 1.33] (0.4572) [0.21, 0.71] (0.0022) [0.27, 0.92] (0.0269)
[0.99, 3.30] (0.0557) [0.95, 1.00] (0.0353) [0.61, 1.88] (0.8221) [1.01, 5.13] (0.0464) [1.48, 10.51] (0.0061) [1.89, 6.19] (<0.0001) [0.30, 0.97] (0.0401) [0.08, 0.50] (0.0005) [0.31, 1.51] (0.3427)
IMDC Z International Metastatic Renal Cell Carcinoma Database Consortium, HR Z hazard ratio, CI Z confidence interval. Patients who suspended treatment for toxicity, died or progressed before the 2-weeks landmark point were excluded (n Z 2). One patient was excluded because of missing IMDC risk group.
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vascularisation: Median PFS was 10.2 (4.2-NE) versus 4 months (1.1-NE) (p Z 0.0051), median TTF was 10.2 (2.9e13.5) versus 4 (1.1-NE) (p Z 0.022), and median OS was not achieved (4.2-NE) versus 5.1 months (1.3NE) (p Z 0.0034), on subgroups with and without decrease vascularisation at Day 30 (vascularisation at Day 30 was inferior or superior to baseline, respectively). Decrease vascularisation was not included in the multivariable models due to the very small number of patients evaluated by this technique (n Z 12). 4. Discussion We report herein the first prospective data of axitinib in mRCC patients in real word practice. Until now, only retrospective studies have been reported [13e16]. Our results are consistent to those of the AXIS trial demonstrating efficacy of axitinib as second line treatment in mRCC patients [4,5], with ORR, progression-free survival and overall survival of respectively 32% [23e42], 8.3 months [6.3e9.6] and 16.4 months [12.4e24.9]. Exploratory analyses showed that IMDC risk group is significantly associated to ORR and G3 hypertension marginally associated to ORR. We observed that DT at 2 first weeks was significantly associated to better ORR (OR Z 4.06 [1.02, 16.19] (p Z 0.0472)) but not at 4 and 8 weeks. This association between DT and ORR is consistent with the previous prospective data [17]. IMDC risk group and G3 hypertension are also associated to the 3 survival outcomes. The association between hypertension and survival is consistent to 2 previous studies concerning mRCC patients treated with axitinib: (1) In the AXIS trial [5], in a post hoc 12-week landmark analysis, median OS was longer in patients with a diastolic blood pressure (DBP) 90 versus <90 mm Hg (p Z 0.0116); 2) In an exploratory analysis of a Japanese phase II study [18], median OS was also longer in patients with DBP 90 mmHg compared to DBP <90 mmHg during the first cycle of axitinib. Tumor shrinkage 10% at first CT scan was strongly associated with progression-free survival and time to treatment failure. As previously reported with sunitinib [19], and more recently with other antiangiogenic agents [20,21], our study confirms that the 10% threshold evaluated by CT scan can be also applied to axitinib and is a very good marker to predict PFS and TTF. Our results are supported by a recent meta-analysis [22] of different phase 2 and 3 trials of 4334 patients with mRCC treated with different antioangiogenic agents confirm that the early tumour shrinkage 10% at first post-baseline assessment was related to better PFS and OS. Axitinib used in third or further next-lines (versus second line) was associated with better progression-free survival on the 2-weeks landmark, although not significant at 4 and 8-weeks landmarks. These results demonstrate that axitinib is active not only in second-, but also in later lines of therapy.
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In our study, the multivariable models concerning the 2-week landmark analysis showed that dose titration at 2-weeks was associated to better ORR, PFS and TTF, but not OS. However, these results were not confirmed at the 4-weeks or 8-weeks landmark analyses. The results of the randomised phase II study of axitinib with or without dose titration in first-line mRCC [17] showed that axitinib titration was associated to a superior ORR compared to placebo titration (54% versus 34%, p Z 0.019) and the hazard ratio for PFS favoured axitinib versus placebo titration, however not statistically significant (HR:0.85 (0.54e1.35), p Z 0.24). The recently published article concerning the OS analysis from the referred trial [23] showed that the median OS was durationwise longer in patients with first-line mRCC who received axitinib versus placebo titration (42.7 versus 30.4 months, respectively, however, without statistical significance). However, the two populations are not comparable, because: (1) axitinib as used on first line on the described trial and in second or later lines in our study; (2) on the referred trial, patients eligible for dose titration (without relevant toxicities) were randomised in order to perform or not dose titration. On the contrary, in our study, all patients without relevant toxicities performed dose titration. Therefore, the results of both studies cannot be compared. Our study confirms that development of G 3 hypertension at 2 weeks is associated with better outcome in patients treated with axitinib [12]. These results suggest that early development of hypertension might be an option as surrogate of survival in these populations of patients. Tumour shrinkage 10% on first CT scan could also be considered as a potential surrogate of survival. Notwithstanding, in our study, although the Hazard Ratio favoured tumour shrinkage 10% (HR: 0.62), it was not statistically significantly associated with overall survival. Thus, further prospective studies for validating these findings are required. Our study demonstrates that decreasing vascularisation detected by DCE-US at D30 may have a prognostic role. However, only 12 patients were evaluated by this method, at days 0, 15 and 30, which is an important limitation to draw accurate conclusions. One limitation of our study is to have been performed in a large specialised centre. The second limitation is the interpretation of the multivariable survival analyses because of the instability of the results through the different landmark analyses. It is why we reported only results with some stability and not pick-up significant results through the different exploratory analyses. Nevertheless, this study confirms the efficacy of axitinib in real life for the management of mRCC patients. In conclusion, our study confirms the efficacy and the safety of axitinib in mRCC patients. Obviously, this efficacy should be considered with interest, especially when new drugs such as nivolumab and cabozantinib
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become available. The role of axitinib in this new environment will require further evaluation. Funding This work was not supported by any funding. Disclosures The authors declare that there is no conflict of interest regarding this study. Conflict of interest None declared. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2017.04.015.
References [1] Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 2011;11:113e26. http: //dx.doi.org/10.2165/11591240-000000000-00000. [2] Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803e13. http: //dx.doi.org/10.1056/NEJMoa1510665. [3] Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814e23. http: //dx.doi.org/10.1056/NEJMoa1510016. [4] Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931e9. http://dx.doi.org/10.1016/S0140-6736(11) 61613-9. [5] Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14:552e62. http://dx.doi.org/10.1016/S1470-2045(13)70093-7. [6] Katabathina VS, Lassau N, Pedrosa I, Ng CS, Prasad SR. Evaluation of treatment response in patients with metastatic renal cell carcinoma: role of state-of-the-art cross-sectional imaging. Curr Urol Rep 2012;13:70e81. http://dx.doi.org/10.1007/s11934011-0233-x. [7] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45: 228e47. http://dx.doi.org/10.1016/j.ejca.2008.10.026. [8] Lin D, Wei L, Ying Z. Checking the Cox model with cumulative sums of martingale-based residuals. Biometrika 1993;80:557e72. http://dx.doi.org/10.1093/biomet/80.3.557. [9] Heinze G, Puhr R. Bias-reduced and separation-proof conditional logistic regression with small or sparse data sets. Stat Med 2010; 29:770e7. http://dx.doi.org/10.1002/sim.3794.
[10] Halimi J-M, Azizi M, Bobrie G, Bouche´ O, Deray G, des Guetz G, et al. Vascular and renal effects of anti-angiogenic therapy. Ne´phrologie The´rapeutique 2008;4:602e15. http: //dx.doi.org/10.1016/j.nephro.2008.10.002. [11] Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763e73. http://dx.doi.org/10.1093/jnci/djr128. [12] Rini BI, Schiller JH, Fruehauf JP, Cohen EEW, Tarazi JC, Rosbrook B, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 2011;17:3841e9. http://dx.doi.org/10.1158/1078-0432.CCR-10-2806. [13] Mizuno R, Kosaka T, Mikami S, Oya M. Efficacy of axitinib in patients with metastatic renal cell carcinoma previously treated with both VEGFR-TKI and mTORI. ASCO Meet Libr 2014. doi: J Clin Oncol 32, 2014 (suppl; abstr e15585). [14] MacLean EA, Mehle K, Eremina D, Quigley JM. Retrospective study of real world axitinib use in the United States. ASCO Meet Libr 2014. J Clin Oncol 2014;32 (suppl; abstr e15576). [15] MacLean E, Cisar L, Mehle K, Eremina D, Quigley JM. Realworld axitinib use in the United States: a retrospective study using linked datasets. J Manag Care Spec Pharm 2016;22. http: //dx.doi.org/10.18553/jmcp.2016.22.6.723. 723e732u. [16] D’Aniello C, Vitale MG, Farnesi A, Calvetti L, Laterza MM, Cavaliere C, et al. Axitinib after sunitinib in metastatic renal cancer: preliminary results from Italian “Real-World” SAX study. Front Pharmacol 2016;7:331. http://dx.doi.org/10.3389/fphar.2016.00331. [17] Rini BI, Melichar B, Ueda T, Gru¨nwald V, Fishman MN, Arranz JA, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised doubleblind phase 2 trial. Lancet Oncol 2013;14:1233e42. http: //dx.doi.org/10.1016/S1470-2045(13)70464-9. [18] Eto M, Uemura H, Tomita Y, Kanayama H, Shinohara N, Kamei Y, et al. Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokinerefractory metastatic renal cell carcinoma. Cancer Sci 2014;105: 1576e83. http://dx.doi.org/10.1111/cas.12546. [19] Thiam R, Fournier LS, Trinquart L, Medioni J, Chatellier G, Balvay D, et al. Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib. Ann Oncol 2010;21:936e41. http: //dx.doi.org/10.1093/annonc/mdp466. [20] Ishihara H, Yagisawa T, Kondo T, Omae K, Takagi T, Iizuka J, et al. Effect of the timing of best tumor shrinkage on survival of patients with metastatic renal cell carcinoma who received firstline tyrosine kinase inhibitor therapy. Int J Clin Oncol 2017;22: 126e35. http://dx.doi.org/10.1007/s10147-016-1032-7. [21] Krajewski KM, Franchetti Y, Nishino M, Fay AP, Ramaiya N, Van den Abbeele AD, et al. 10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study. Oncologist 2014;19:507e14. http://dx.doi.org/10.1634/theoncologist.2013-0391. [22] Gru¨nwald V, Lin X, Kalanovic D, Simantov R. Early tumour shrinkage: a tool for the detection of early clinical activity in metastatic renal cell carcinoma. Eur Urol 2016;70:1006e15. http: //dx.doi.org/10.1016/j.eururo.2016.05.010. [23] Rini BI, Tomita Y, Melichar B, Ueda T, Gru¨nwald V, Fishman MN, et al. Overall survival analysis from a randomized phase II study of axitinib with or without dose titration in firstline metastatic renal cell carcinoma. Clin Genitourin Cancer 2016;14:499e503. http://dx.doi.org/10.1016/j.clgc.2016.04.005.
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Clinical Trial
Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre Margarida Matias a, Gwe´nae¨l Le Teuff b,c, Laurence Albiges a, Annalisa Guida a, Caroline Brard b,c, Giulia Bacciarelo a, Yohann Loriot a, Christophe Massard a, Nathalie Lassau d,e, Karim Fizazi a, Bernard Escudier a,* a
Department of Medical Oncology, Gustave Roussy, F-94805, Villejuif, France Department of Biostatistics and Epidemiology, Gustave Roussy, Universite´ Paris-Saclay, Villejuif, F-94805, France c Universite´ Paris-Saclay, University of Paris-Sud, UVSQ, CESP, INSERM, Villejuif, F-94085, France d Department of Imaging and IR4M UMR808, Gustave Roussy, F-94805, Villejuif, France e Universite´ Paris-Sud, IR4M UMR808, Villejuif, F-94085, France b
Received 21 January 2017; received in revised form 7 April 2017; accepted 10 April 2017
KEYWORDS Metastatic renal cell carcinoma; Axitinib; Second or further nextline; Prospective study; Effectiveness; Safety
Abstract Background: Axitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials. Methods: A prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored. Results: One-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in
* Corresponding author: Gustave Roussy, Universite´ Paris-Saclay, De´partement de me´decine Oncologique, Villejuif, F-94805, France. E-mail addresses: [email protected] (M. Matias), [email protected] (G. Le Teuff), laurence.albiges@ gustaveroussy.fr (L. Albiges), [email protected] (A. Guida), [email protected] (C. Brard), giulia.baciarello@ gustaveroussy.fr (G. Bacciarelo), [email protected] (Y. Loriot), [email protected] (C. Massard), nathalie. [email protected] (N. Lassau), [email protected] (K. Fizazi), [email protected], [email protected] (B. Escudier). http://dx.doi.org/10.1016/j.ejca.2017.04.015 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n Z 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF. Conclusion: Efficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy. ª 2017 Elsevier Ltd. All rights reserved.
1. Introduction Renal cell carcinoma (RCC) is the eighth most common malignancy affecting adults, accounting for 3e4% of new cancer cases in the United States. It is diagnosed in more than 200,000 patients worldwide every year and accounts for approximately 100,000 deaths annually [1]. In the past 7 years, targeted agents have dramatically improved outcome of patients with metastatic RCC (mRCC) [1]. Several targeted agents are now approved for mRCC, and new agents have been recently developed still increasing the number of approved drugs [2,3]. Axitinib has shown activity in mRCC in the AXIS trial [4,5] that compared axitinib to sorafenib in patients who progressed after first-line therapy. Patients treated with axitinib had a significant higher objective response rate (ORR) (19% versus 11%) and a higher progression-free survival (PFS) (8.3 versus 4.7 months). Based on these positive results, axitinib was approved and became available in France in November 2012. However, real world efficacy data are still rare, and prospective evaluation has not yet been reported. The aim of this study is to report the efficacy and toxicity of axitinib in patients with mRCC in current clinical practice and to explore the association between clinical markers and outcomes. In addition, a subgroup of patients had prospective evaluation of dynamic contrast-enhanced ultrasound (DCE-US) as previously reported by our group to determine whether it is possible to predict early clinical benefit to the drug [6]. 2. Materials and methods 2.1. Patients We conducted a prospective evaluation of all patients with mRCC who started treatment with axitinib in second or further next-line at Gustave Roussy, from November 2012 to October 2015. All patients who received at least one dose of axitinib were eligible. These patients had progressed after at least one vascular endothelial growth factor (VEGF)-targeted agent and received axitinib outside of a clinical trial.
Collected patient characteristics were age, gender, Eastern Cooperative Oncology Group Performance Status (ECOG PS), risk group (defined according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), tumour histology, number and location of metastatic sites, prior nephrectomy, number and type of prior systemic treatments. Followup data were collected. Axitinib was given according to standard recommendations with a starting dose of 5 mg twice daily (bid) (10 mg/d). Whenever possible, dose titration (DT) was performed every 2 weeks up to a first step of 7 mg bid (14 mg/d), and if still possible, until a second and final step of 10 mg bid (20 mg/d) in patients without hypertension or adverse reactions above grade (G)2. As well, whenever indicated, dose reduction for toxicity was performed based on the same recommendations. Information related to DT and reduction was collected through the whole treatment duration. Evaluation of response was performed by computed tomography (CT) scan, according to Response Evaluation Criteria in Solid Tumours, (RECIST) version 1.1 criteria [7], every 2e3 months. For each patient, the best response during treatment, including complete response (CR), partial response (PR), stable disease (SD) or progression of disease (PD), was measured. ORR was defined as the percentage of PR or CR during treatment. Patients who stopped treatment for toxicity before tumour assessment were not considered for response evaluation. Tumour shrinkage (TS) 10% at the first CT scan was also measured. The decrease in vascularisation of targeted lesions, evaluated by DCE-US between axitinib initiation and 30 days after initiation, was measured in a subset of patients. PFS was defined from the time between axitinib start (t0) and documented progression/death. Time to treatment failure (TTF) was defined from t0 to either documented progression/death or interruption of treatment for toxicity. Overall survival (OS) was defined from t0 to the date of death from any cause. For each outcome, patients with no event of interest are censored at the date of last visit.
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We also collected toxicity data during axitinib treatment using the NCI CTCAE (Common Terminology Criteria for Adverse Events). 2.2. Statistical analysis The patients’ characteristics, treatment and toxicities were described. The best response distribution was reported with a waterfall plot. ORR was reported and its duration estimated using the KaplaneMeier method. The median follow-up was estimated using the Schemper’s method. In an exploratory setting, we evaluated the association between patient’s characteristics at baseline (number of metastatic sites (1e2, 3), IMDC risk group (poor, intermediate, good), axitinib line (second, third or next-line)), G3 toxicity, G3 hypertension, DT and ORR, PFS, TTF and OS. Outcome was measured at 2, 4 and 8 weeks from axitinib initiation. For ORR, odds ratios (OR) and 95% confidence interval (95% CI) were estimated using a logistic model. For PFS, TTF and OS, hazard ratios (HRs) and 95% CI were estimated through a Cox model. The proportional hazards assumption was checked using martingalebased residuals [8], and no violation of the assumption was observed. As G3 hypertension and DT were timedependent exposure, a 2-weeks landmark analysis for survival outcomes was performed. This 2-week
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landmark analysis will be completed by KaplaneMeier curves. Sensitivity analyses were performed for 4- and 8week landmark points. Tumour shrinkage of target lesions 10% measured at 8 weeks was included for the 8week landmark survival analyses. The Firth’s penalised likelihood approach was used for regression models [9] with no selection process of covariates. The cut-off date was 1st May 2016. The statistical analysis was performed in software suite SAS version 9.3 (SAS Institute, Cary NC). 3. Results 3.1. Patients’ characteristics One-hundred six mRCC patients, with a median followup of 20.0 months (min: 0.9, max: 40.2) received axitinib in second- (40%) or further next-lines (39% in third and 22% in fourth or next- lines). The number of previous lines ranged from 1 to 6. As described in Table 1, 74% of patients were male and 55% presented metastatic disease at diagnosis. IMDC risk group was good, intermediate or poor in 13%, 54% and 32%, respectively and 90% had clear cell histology. The number of metastatic sites ranged from 1 to 8. Eighty-six percent of patients had prior nephrectomy and 57% had received local therapy for metastases. The most common first-line therapy was
Table 1 Patients’ characteristics. Baseline characteristics Age, median (IQR) Gender, n (%) Male Female Stage at diagnosis, n (%) Localised Metastatic Risk group (IMDC), n (%) Good Intermediate Poor Na Histology, n (%) Clear cell adenocarcinoma Papillary carcinoma (type 2) Juvenile carcinoma Chromophobe carcinoma Histological grade, n (%) 1e2 3e4 Na Number of metastatic sites, n (%) 1 2 3 (range: 3e8)
54 (46e60) 74 (70) 32 (30) 48 (45) 58 (55) 14 (13) 57 (54) 34 (32) 1 (1) 95 (90) 5 (5) 4 (4) 2 (2)
30 (28) 67 (63) 9 (9) 8 (8) 17 (16) 81 (76)
Site of metastases, n (%) Lung Thoracic lymph nodes Bone Liver Abdominal lymph nodes Renal Adrenal Pleura Renal lodge Others Prior nephrectomy, n (%) Local therapy for metastasis, n (%) Surgery Radiotherapy Radiofrequency/Cryotherapy Number of previous lines of treatment before axitinib, n (%) 1 line 2 lines 3 lines (range: 3e6) First line treatment, n (%) Sunitinib Others TKI Bevacizumab mTOR inhibitors Second line treatment, n (%) Everolimus TKI or anti-VEGF therapy
78 58 44 31 31 27 23 22 20 53 91 61 41 40 13
(74) (55) (42) (29) (29) (25) (22) (21) (19) (50) (86) (57) (39) (38) (12)
42 (40) 41 (39) 23 (22) 77 (73) 14 (13) 9 (8) 6 (6) 40 (63) 24 (38)
IQR: interquartile range; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium, bid: twice daily; na: not available.
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sunitinib (73%). Evaluation of vascularisation at days 0, 15 and 30 by DCE-US was assessed in 12 patients.
(Waterfall plot, Supplementary Fig. 1). The median duration of response was 10.4 months (95% CI: 8.8e16.2).
3.2. Treatment The median duration of axitinib was 7.3 months (95% CI: 5.6e9.0) (Table 2). All (but two) patients started axitinib at 5 mg bid. DT to 7 mg bid was performed in 38% of patients (n Z 40), and to 10 mg bid in 19% of patients (n Z 20). Dose >5 mg bid could be maintained for a median time of 3.1 months (range: 0.4e17.4). A dose reduction below 5 mg bid was observed in 32 (30%) out of all included patients (n Z 106) and 6 (15%) out of patients that performed dose titration (n Z 40). Adverse events leading to a dose reduction below 5 mg bid in 6 out of the 40 patients that had performed dose titration to 7 mg bid were: reintroduction at reduced doses after suspension of treatment for difficulty of cicatrisation post surgical procedure (n Z 2); G3 hypertension and G2 headache (n Z 1); G3 fatigue, G2 diarrhoea and dysphonia (n Z 1); G2 fatigue, weight loss and diarrhoea (n Z 1) and G2 arthralgia (n Z 1). At the time of analysis, 12 patients (11%) remained on treatment. Main reasons for interruption of treatment were PD (n Z 55), toxicity (n Z 18), or both (n Z 11). Treatment suspension was needed in 31 patients (29%), mainly for toxicity (n Z 18). 3.3. Efficacy 3.3.1. Objective response rate Best response was PR (32%, n Z 33), SD (40%, n Z 41) and PD (27%, n Z 28). Response was not available for four patients who stopped treatment for toxicity (4%)
3.3.2. Time-to-event outcomes: progression-free survival, time-to-failure and overall survival Median (m) PFS was 8.3 months (95% CI: 6.3e9.6) (with 6.3 months (3.9e10.1) and 8.8 months (7.0e10.7) for patients treated in second- and third- or further nextline respectively), mTTF was 5.8 months (4.5e8.3) (with 4.7 months (2.9e8.3) and 7.0 months (3.9e8.8) for patients treated in second- and third- or further next-line, respectively) and mOS was 16.4 months (12.4e24.9) (with 14.9 months (7.8e26.3) and 16.4 months (11.5e27.6) for patients treated in second- and third- or further next-line, respectively). 3.3.3. Safety Most adverse events (AEs) were grade 1e2 (Table 3, last column). Fatigue and hypertension were the most common AEs. Hypertension was the most common G3e4 AE (G3: 39%, G4: 2%). The other common G3 AEs were fatigue (10%) and diarrhoea (6%). When compared to AEs described in the AXIS trial [5], G3e4 hypertension was more frequent while diarrhoea and anorexia were less commonly observed. The pattern of other toxicities was similar to those previously reported [5]. The majority of AEs were manageable with dose modification and supportive care. Hypertension was generally easily managed with antihypertensive drugs [10]. The AEs that led to treatment interruption (n Z 18) were: G4 hypertension with posterior reversible encephalopathy syndrome (PRES) (n Z 1), ischaemic stroke (n Z 1), G3 fatigue (n Z 3), G3 nausea and
Table 2 Received treatment and clinical outcomes. Received treatment Axitinib duration (months) median (95%CI) DT to 7 mg bid, n (%) At 2 weeks, n (%) DT to 10 mg bid, n (%) At 4 weeks, n (%) Clinical outcomes Best responsea Complete response, n (%) Partial response, n (%) Stable disease, n (%) Progression of disease, n (%) Not assessed, n (%) Objective response rate, n (%) No Yes Missing
7.3 (5.6e9.0) 40 (38) 16 (15) 20 (19) 7 (7)
0 (0) 33 (32) 41 (40) 28 (27) 4 69 (68) 33 (32) 4
Time dose >5 mg bid (months), median (range) Dose <5 mg bid, n (%) Dose reduction at 2 weeks, n (%) Dose reduction at 4 weeks, n (%)
32 (30) 7 (7) 14 (13)
Events Progression/death, n (%) Treatment failureb, n (%) Death, n (%) PFS (months), median (95% CI) TTF (months), median (95% CI)
89 (84) 95 (90) 59 (56) 8.3 (6.3e9.6) 5.8 (4.5e8.3)
OS (months), median (95% CI)
16.4 (12.4e24.9)
3.1 (0.4e17.4)
DT: dose titration; bid: twice daily; med: median, PFS: progression free survival, TTF: time to treatment failure, OS: overall survival. a Patients who interrupted treatment for toxicity before tumour assessment (n Z 4) were not considered in the evaluation of response. Patients who presented clinical progression or died before tumour assessment (n Z 5) were considered as presenting progression of disease. b The reasons for treatment failure were progression/death (n Z 56), toxicity (n Z 18), progression þ toxicity (n Z 11) and other causes (n Z 10).
Table 3 Maximum grade of Axitinib-related adverse events during the whole treatment duration according to common toxicity criteria (CTC) version 4.0*. Toxicity
Adverse events, n (%)
Fatigue Hypertension Diarrhoea Dysphonia Palmar-plantar erythrodysesthesia Mucositis Weight loss Hypothyroidism Anorexia Respiratory disorders Arthralgia Abdominal pain Nausea/vomiting Constipation Headache Depression Oedema Dysgeusia OJN aggravation Epistaxis Haemorrhoids Pruritus Total
Dose titrationa (n Z 40)
Total (n Z 106)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3e4
19 (29) 3 (5) 13 (20) 21 (32) 3 (5)
21 (32) 11 (17) 21 (32) 7 (11) 3 (5)
7 (11) 27 (41) 3 (5) 2 (3) 3 (5)
0 0 0 0 0
(0) (0) (0) (0) (0)
7 (11) 27 (41) 3 (5) 2 (3) 3 (5)
11 (28) 2 (5) 9 (23) 17 (43) 4 (10)
13 (33) 6 (15) 12 (30) 8 (20) 6 (15)
4 (10) 14 (35) 3 (8) 0 (0) 2 (5)
0 2 0 0 0
(0) (5) (0) (0) (0)
4 (10) 16 (40) 3 (8) 0 (0) 2 (5)
30 (28) 5 (5) 22 (21) 38 (36) 7 (7)
34 (32) 17 (16) 33 (31) 15 (14) 9 (8)
11 (10) 41 (39) 6 (6) 2 (2) 5 (5)
0 2 0 0 0
(0) (2) (0) (0) (0)
11 (10) 43 (41) 6 (6) 2 (2) 5 (5)
8 (12) 1 (2) 5 (8) 4 (6) 2 (3) 2 (3) 2 (3) 1 (2) 2 (3) 1 (2) 1 (2) 2 (3) 0 (0) 0 (0) 1 (2) 1 (2) 1 (2) 42 (64)
3 (5) 10 (15) 4 (6) 4 (6) 2 (3) 2 (3) 1 (2) 1 (2) 1 (2) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 49 (74)
1 (2) 0 (0) 0 (0) 1 (2) 0 (0) 1 (2) 2 (3) 3 (5) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 37 (56)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
1 (2) 0 (0) 0 (0) 1 (2) 0 (0) 1 (2) 2 (3) 3 (5) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 37 (56)
4 (10) 2 (5) 3 (8) 3 (8) 4 (10) 1 (3) 2 (5) 2 (5) 0 (0) 2 (5) 1 (3) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 31 (78)
3 (8) 3 (8) 3 (8) 2 (5) 2 (5) 2 (5) 2 (5) 0 (0) 1 (3) 2 (5) 1 (3) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 30 (75)
0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 19 (48)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (5)
0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 21 (53)
12 (11) 3 (3) 8 (8) 7 (7) 6 (6) 3 (3) 4 (4) 3 (3) 2 (2) 3 (3) 2 (2) 3 (3) 0 (0) 0 (0) 1 (1) 1 (1) 1 (1) 73 (69)
6 (6) 13 (12) 7 (7) 6 (6) 4 (4) 4 (4) 3 (3) 1 (1) 2 (2) 3 (3) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 79 (75)
1 (1) 1 (1) 0 (0) 1 (1) 0 (0) 2 (2) 2 (2) 3 (3) 2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 56 (53)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2
(0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (2)
1 (1) 1 (1) 0 (0) 1 (1) 0 (0) 2 (2) 2 (2) 3 (3) 2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 58 (55)
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No dose titration (n Z 66)
a Among patients with a dose titration to 7 mg bid during axitinib treatment (n Z 40), the cumulative number of patients with a dose titration occurring at 2, 4 and 8 weeks was 16, 25 and 32.8 patients have a dose titration after 8 weeks.
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vomiting (n Z 3), G3 abdominal pain (n Z 2), G3 handfoot syndrome (HFS) and fatigue (n Z 1), worsened pre-existing controlled osteonecrosis of the jaw (n Z 1), G3 arthralgia (n Z 1), G3 mucositis (n Z 1), G2 diarrhoea and fatigue (n Z 2), G2 diarrhoea and weight loss (n Z 1), G2 diarrhoea and HFS (n Z 1). In patients with a dose-titration (n Z 40), only 2 patients had G4 adverse events (G4 hypertension) with dose titration to 7 mg bid and 10 mg bid, respectively while patients without dose-titration (n Z 66) had no G4 adverse event. Otherwise, the number of toxicities and their grade are comparable between these two subgroups of patients. 3.4. Exploratory analyses 3.4.1. Objective response rate The models, estimating the adjusted association between G3 hypertension and DT measured at 2 (model 1), 4 (model 2) and 8 weeks (model 3) after axitinib initiation and the probability of ORR, fitted similarly with AIC values varying from 96.72 to 98.61 (Supplementary Table 1). G3 toxicity is omitted because of this strong correlation with G3 hypertension (p < 0.0001). Poor IMDC risk group is negatively associated with ORR (for example, OR Z 0.19 95% CI Z [0.05; 0.72] (p Z 0.0144) for model 1). G3 hypertension at 2 weeks is marginally positively associated to ORR (OR Z 2.94 [0.91, 9.53] (p Z 0.0720)) with similar results at 4 and 8 weeks while DT evaluated was significantly associated to ORR at 2 weeks (OR Z 4.06 [1.02, 16.19] (p Z 0.0472)) but not at 4 and 8 weeks.
3.4.2. Correlation with outcomes The 2-week landmark analysis showed that age, IMDC risk group and G3 hypertension are significantly correlated to PFS, TTF and OS (Table 4) (Supplementary Fig. 2 for KaplaneMeier curves). For example, G3 hypertension at 2 weeks has a protector effect with HR Z 0.35 [0.18, 0.66] for PFS, 0.39 [0.21, 0.71] for TTF and 0.20 [0.08, 0.50] for OS. DT at 2 weeks (but not at 4 and 8 weeks) was also significantly associated to PFS (HR Z 0.48 [0.25, 0.91]) and TTF (HR Z 0.50 [0.27, 0.92]) but not to OS (HR Z 0.68 [0.31, 1.51]). The association between G3 hypertension at 4 and 8 weeks after axitinib initiation was maintained (Supplementary Tables 2 and 3). These findings confirm the results indicating that hypertension induced by antiangiogenic agents is associated with better outcome [11,12]. The number of metastatic sites is associated with OS (for example, HR Z 3.94 [1.48e10.51] for 2-weeks landmark analysis). Tumour shrinkage 10% at 8 weeks is significantly associated with PFS (HR Z 0.30 [0.17, 0.55]) and TTF (HR Z 0.33 [0.19, 0.58]) but not with OS (Supplementary Table 3).
3.4.3. Decrease vascularisation by DCE-US DCE-US at baseline was performed in 16 patients. Of those, in 12 patients it was possible monitoring vascularisation at Days 0, 15 and 30. When evaluating decrease vascularisation at day 30 (D30), determined by Area under the curve (AUC), univariate analysis shows that there was no impact on decrease vascularisation on ORR. However, median PFS, TTF and OS were significantly longer in patients with decrease
Table 4 Multivariable analyses of progression-free survival, time-to failure and overall survival e 2-weeks landmark analysis. Variable
Sex Age at diagnosis Stage at diagnosis Histology Number of metastatic sites IMDC risk group Axitinib line Grade 3 hypertension at 2 weeks Dose titration at 2 weeks
Male Female IeIII IV Clear cell carcinoma Other 1e2 3 Good/intermediate Poor 2nd line 3rd line No Yes No Yes
Progression free survival (n Z 103, events Z 87)
Time to treatment failure (n Z 103, events Z 93)
Overall survival (n Z 103, events Z 57)
HR [95% CI] (p-value)
HR [95% CI] (p-value)
HR [95% CI] (p-value)
1 1.07 0.95 1 1.03 1 1.70 1 1.81 1 3.84 1 0.62 1 0.35 1 0.48
1 1.11 0.96 1 0.86 1 1.61 1 1.09 1 3.80 1 0.84 1 0.39 1 0.50
1 1.80 0.97 1 1.07 1 2.28 1 3.94 1 3.42 1 0.54 1 0.20 1 0.68
[0.65, 1.78] (0.7860) [0.93, 0.98] (<0.0001) [0.64, 1.65] (0.9084) [0.85, 3.40] (0.1315) [0.98, 3.35] (0.0593) [2.21, 6.69] (<0.0001) [0.38, 1.00] (0.0497) [0.18, 0.66] (0.0013) [0.25, 0.91] (0.0248)
[0.68, 1.83] (0.6716) [0.94, 0.99] (0.0016) [0.55, 1.33] (0.492) [0.80, 3.22] (0.1815) [0.61, 1.95] (0.7680) [2.23, 6.47] (<0.0001) [0.53, 1.33] (0.4572) [0.21, 0.71] (0.0022) [0.27, 0.92] (0.0269)
[0.99, 3.30] (0.0557) [0.95, 1.00] (0.0353) [0.61, 1.88] (0.8221) [1.01, 5.13] (0.0464) [1.48, 10.51] (0.0061) [1.89, 6.19] (<0.0001) [0.30, 0.97] (0.0401) [0.08, 0.50] (0.0005) [0.31, 1.51] (0.3427)
IMDC Z International Metastatic Renal Cell Carcinoma Database Consortium, HR Z hazard ratio, CI Z confidence interval. Patients who suspended treatment for toxicity, died or progressed before the 2-weeks landmark point were excluded (n Z 2). One patient was excluded because of missing IMDC risk group.
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vascularisation: Median PFS was 10.2 (4.2-NE) versus 4 months (1.1-NE) (p Z 0.0051), median TTF was 10.2 (2.9e13.5) versus 4 (1.1-NE) (p Z 0.022), and median OS was not achieved (4.2-NE) versus 5.1 months (1.3NE) (p Z 0.0034), on subgroups with and without decrease vascularisation at Day 30 (vascularisation at Day 30 was inferior or superior to baseline, respectively). Decrease vascularisation was not included in the multivariable models due to the very small number of patients evaluated by this technique (n Z 12). 4. Discussion We report herein the first prospective data of axitinib in mRCC patients in real word practice. Until now, only retrospective studies have been reported [13e16]. Our results are consistent to those of the AXIS trial demonstrating efficacy of axitinib as second line treatment in mRCC patients [4,5], with ORR, progression-free survival and overall survival of respectively 32% [23e42], 8.3 months [6.3e9.6] and 16.4 months [12.4e24.9]. Exploratory analyses showed that IMDC risk group is significantly associated to ORR and G3 hypertension marginally associated to ORR. We observed that DT at 2 first weeks was significantly associated to better ORR (OR Z 4.06 [1.02, 16.19] (p Z 0.0472)) but not at 4 and 8 weeks. This association between DT and ORR is consistent with the previous prospective data [17]. IMDC risk group and G3 hypertension are also associated to the 3 survival outcomes. The association between hypertension and survival is consistent to 2 previous studies concerning mRCC patients treated with axitinib: (1) In the AXIS trial [5], in a post hoc 12-week landmark analysis, median OS was longer in patients with a diastolic blood pressure (DBP) 90 versus <90 mm Hg (p Z 0.0116); 2) In an exploratory analysis of a Japanese phase II study [18], median OS was also longer in patients with DBP 90 mmHg compared to DBP <90 mmHg during the first cycle of axitinib. Tumor shrinkage 10% at first CT scan was strongly associated with progression-free survival and time to treatment failure. As previously reported with sunitinib [19], and more recently with other antiangiogenic agents [20,21], our study confirms that the 10% threshold evaluated by CT scan can be also applied to axitinib and is a very good marker to predict PFS and TTF. Our results are supported by a recent meta-analysis [22] of different phase 2 and 3 trials of 4334 patients with mRCC treated with different antioangiogenic agents confirm that the early tumour shrinkage 10% at first post-baseline assessment was related to better PFS and OS. Axitinib used in third or further next-lines (versus second line) was associated with better progression-free survival on the 2-weeks landmark, although not significant at 4 and 8-weeks landmarks. These results demonstrate that axitinib is active not only in second-, but also in later lines of therapy.
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In our study, the multivariable models concerning the 2-week landmark analysis showed that dose titration at 2-weeks was associated to better ORR, PFS and TTF, but not OS. However, these results were not confirmed at the 4-weeks or 8-weeks landmark analyses. The results of the randomised phase II study of axitinib with or without dose titration in first-line mRCC [17] showed that axitinib titration was associated to a superior ORR compared to placebo titration (54% versus 34%, p Z 0.019) and the hazard ratio for PFS favoured axitinib versus placebo titration, however not statistically significant (HR:0.85 (0.54e1.35), p Z 0.24). The recently published article concerning the OS analysis from the referred trial [23] showed that the median OS was durationwise longer in patients with first-line mRCC who received axitinib versus placebo titration (42.7 versus 30.4 months, respectively, however, without statistical significance). However, the two populations are not comparable, because: (1) axitinib as used on first line on the described trial and in second or later lines in our study; (2) on the referred trial, patients eligible for dose titration (without relevant toxicities) were randomised in order to perform or not dose titration. On the contrary, in our study, all patients without relevant toxicities performed dose titration. Therefore, the results of both studies cannot be compared. Our study confirms that development of G 3 hypertension at 2 weeks is associated with better outcome in patients treated with axitinib [12]. These results suggest that early development of hypertension might be an option as surrogate of survival in these populations of patients. Tumour shrinkage 10% on first CT scan could also be considered as a potential surrogate of survival. Notwithstanding, in our study, although the Hazard Ratio favoured tumour shrinkage 10% (HR: 0.62), it was not statistically significantly associated with overall survival. Thus, further prospective studies for validating these findings are required. Our study demonstrates that decreasing vascularisation detected by DCE-US at D30 may have a prognostic role. However, only 12 patients were evaluated by this method, at days 0, 15 and 30, which is an important limitation to draw accurate conclusions. One limitation of our study is to have been performed in a large specialised centre. The second limitation is the interpretation of the multivariable survival analyses because of the instability of the results through the different landmark analyses. It is why we reported only results with some stability and not pick-up significant results through the different exploratory analyses. Nevertheless, this study confirms the efficacy of axitinib in real life for the management of mRCC patients. In conclusion, our study confirms the efficacy and the safety of axitinib in mRCC patients. Obviously, this efficacy should be considered with interest, especially when new drugs such as nivolumab and cabozantinib
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become available. The role of axitinib in this new environment will require further evaluation. Funding This work was not supported by any funding. Disclosures The authors declare that there is no conflict of interest regarding this study. Conflict of interest None declared. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2017.04.015.
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