Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin‐2 and interferon (IFN)‐α, in recent years several targeted therapies ...have become available for first‐ and second‐line use. These include sorafenib, sunitinib, bevacizumab (plus IFN‐α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular‐targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular‐targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow‐up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression‐free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
This article reviews the clinical evidence supporting the benefits of targeted agents in the treatment of metastatic renal cell carcinoma, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
Summary Background Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as ...second-line treatment in patients with metastatic renal cell carcinoma. Methods We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov , number NCT01136733. Findings Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months 95% CI 5·9–20·1 vs 5·5 months 3·5–7·1; hazard ratio HR 0·40, 95% CI 0·24–0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months 95% CI 5·6–10·2; HR 0·66, 95% CI 0·30–1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38–0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 50%) compared with those assigned lenvatinib alone (41 79%) or lenvatinib plus everolimus (36 71%). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten 20%), in those assigned single-agent lenvatinib it was proteinuria (ten 19%), and in those assigned single-agent everolimus it was anaemia (six 12%). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Interpretation Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Funding Eisai Inc.
Summary Background In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer ...progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. Methods Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov , number NCT00678392. Findings Median overall survival was 20·1 months (95% CI 16·7–23·4) with axitinib and 19·2 months (17·5–22·3) with sorafenib (hazard ratio HR 0·969, 95% CI 0·800–1·174; one-sided p=0·3744). Median investigator-assessed PFS was 8·3 months (95% CI 6·7–9·2) with axitinib and 5·7 months (4·7–6·5) with sorafenib (HR 0·656, 95% CI 0·552–0·779; one-sided p<0·0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 17%), diarrhoea (40 11%), and fatigue (37 10%) in 359 axitinib-treated patients and hand–foot syndrome (61 17%), hypertension (43 12%), and diarrhoea (27 8%) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20·7 months (95% CI 18·4–24·6) versus 12·9 months (10·1–20·4) in the axitinib group (p=0·0116), and 20·2 months (17·1–32·0) versus 14·8 months (12·0–17·7) in the sorafenib group (one-sided p=0·0020). Interpretation Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. Funding Pfizer Inc.
Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
In this ...phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
Summary Background In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than ...those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov , NCT00920816. Findings Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months 95% CI 7·2–12·1 vs 6·5 months 4·7–8·3, respectively; stratified hazard ratio 0·77, 95% CI 0·56–1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 50% of 189 patients vs 38 40% of 96 patients), hypertension (92 49% vs 28 29%), weight decrease (69 37% vs 23 24%), decreased appetite (54 29% vs 18 19%), dysphonia (44 23% vs ten 10%), hypothyroidism (39 21% vs seven 7%), and upper abdominal pain (31 16% vs six 6%); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 39% of 96 patients vs 50 26% of 189), rash (19 20% vs 18 10%), alopecia (18 19% vs eight 4%), and erythema (18 19% vs five 3%). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 14% of 189 patients), diarrhoea (17 9%), asthenia (16 8%), weight decrease (16 8%), and PPE (14 7%); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 16% of 96 patients), diarrhoea (five 5%), and asthenia (five 5%). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding Pfizer Inc.
Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the ...pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.
Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval CI 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.
Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).
Summary Background The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the ...effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. Methods We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov , number NCT00678392. Findings A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. Interpretation Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. Funding Pfizer Inc.
Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the ...mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov , number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio HR 0·66 95% CI 0·53–0·83; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 95% CI 0·41–0·62; p<0·0001) and objective response (17% 13–22 with cabozantinib vs 3% 2–6 with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 15% in the cabozantinib group vs 12 4% in the everolimus group), diarrhoea (43 13% vs 7 2%), fatigue (36 11% vs 24 7%), palmar-plantar erythrodysaesthesia syndrome (27 8% vs 3 1%), anaemia (19 6% vs 53 17%), hyperglycaemia (3 1% vs 16 5%), and hypomagnesaemia (16 5% vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial ...targeted therapy in patients with metastatic renal cell carcinoma (RCC).
Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review.
A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio HR, 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%).
Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
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