Methods: We included patients coming from 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 to either axitinib 5 mg twice daily or sorafenib 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. Overall survival with second-line axitinib or sorafenib was significantly longer in patients with smaller vs larger tumour burden, except in those treated with the cytokine-to-axitinib sequence Table 3 ; Figure 2.
Patients with longer duration of prior treatment with sunitinib or cytokines were subsequently administered axitinib or sorafenib for a longer period Table 5. Patients with longer vs shorter duration of prior sunitinib had more axitinib dose interruptions and fewer dose increases; however, the percentage of patients with dose interruptions due to AEs was similar Patients with longer vs shorter duration of cytokine treatment had more axitinib dose interruptions and reductions, and more patients had interruptions due to AEs Similar numbers of patients in prior therapy duration subgroups had sorafenib dose interruptions and reductions.
Because the study did not limit enrolment by type of prior therapy — that is, sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokine treatment — the patient population reflected real-world treatment patterns at the time of trial initiation. The trial design, wherein patients were stratified by prior therapy before randomisation, allowed for direct comparison of prior therapy groups, noting small sample sizes and varying population totals due to global treatment trends, as well as examination of prior therapy features response to and duration of treatment and post-treatment tumour burden.
The aim of the present post hoc analysis was to help guide clinicians on the efficacy and safety profile of sequential therapies based on the initial treatment choice. Response to prior sunitinib or cytokine therapy was not associated with longer PFS or OS in patients administered second-line axitinib or sorafenib.
Similar to these findings, a retrospective analysis of an international database of patients with mRCC also found no correlation between response to first-line and second-line VEGF-targeted therapy Al-Marrawi et al , However, it should be noted that response to a particular therapy appears to influence survival with that therapy.
In contrast, longer prior treatment with sunitinib or cytokines was generally associated with longer OS with second-line axitinib or sorafenib. This may, at least in part, reflect underlying tumour biology, that is, patients with slower growing tumours would be expected to be able to remain on sunitinib or cytokines for a longer period and to survive longer with subsequent therapy.
The relationship between prior treatment duration and PFS with second-line axitinib or sorafenib was less clear; significantly longer PFS was only observed in patients treated with axitinib who previously received cytokine therapy for a longer vs shorter duration.
This may reflect higher potency of axitinib compared with sorafenib in patients with slower progressing disease. Similar to the results reported here for patients treated with sunitinib followed by axitinib or sorafenib, an association between PFS during first-line and second-line VEGF-targeted therapy was not observed in the retrospective database analysis of patients with mRCC Al-Marrawi et al , In addition, smaller tumour burden following treatment with sunitinib or cytokines was associated with longer OS with either second-line axitinib or sorafenib.
Longer PFS was also seen in patients who had smaller vs larger tumour burden following sunitinib therapy, but reached significance only in the sorafenib arm. Other retrospective studies have identified a correlation between tumour burden and survival in previously treated patients with mRCC. Results reported here and in other studies suggest that patients with a lower initial tumour burden are likely to take longer to reach a lethal tumour burden and may reflect slower-growing disease; however, these data do not assist in selection of a particular agent for second-line or subsequent targeted therapy based on this characteristic.
As has been previously reported for this study Motzer et al , b , patients previously treated with cytokines had longer PFS and OS with axitinib or sorafenib than those previously treated with sunitinib. Consistent with those findings, median OS from start of prior treatment was nearly twice as long in patients previously treated with cytokines vs sunitinib. In addition, patients who were previously treated with cytokines for long periods without disease progression may have had inherently less-aggressive disease than those previously treated with sunitinib.
As a result, different prognostic factors between the prior cytokine and prior sunitinib groups may partially account for differences in OS from the start of previous therapy. Several distinctions emerged in the toxicity profiles of second-line treatment with axitinib and sorafenib in patients who had received prior sunitinib vs cytokines, and may, in part, reflect sequential use of therapies with similar vs different mechanisms of action.
Class effects of VEGF pathway-targeted agents include hypertension, fatigue, asthenia, diarrhoea, nausea, anorexia, hand—foot syndrome, and rash Cohen and Oudard, The safety profile of second-line axitinib and sorafenib differed modestly by duration of prior therapy.
Optimising drug sequencing in patients with mRCC to extend disease control is a key area of clinical research Gore and Larkin, ; Hudes et al , Data from head-to-head randomised clinical trials comparing VEGF pathway and mTOR inhibitors support the use of VEGFR tyrosine kinase inhibitors in the first-line setting Motzer et al , a and in the second-line setting following disease progression on sunitinib Hutson et al , However, there are currently insufficient clinical data directly comparing efficacy of different VEGF pathway-targeted agents, and so clinical decisions are based on drug toxicity profiles and patient preferences and comorbidities Sonpavde et al , The retrospective, post hoc analyses presented here are limited by small subgroups and lack of correction for multiple comparisons; significant results should be viewed as exploratory and should be confirmed in future studies.
In general, these data suggest that outcome to second-line therapy is better when duration of first-line treatment is longer, and that tumour burden is likely to be predictive of survival as previously suggested Basappa et al , ; Iacovelli et al , ; Stein et al , However, for a given agent, differences in toxicity profiles by prior therapy and differences in outcome by response to prior therapy, length of prior therapy, or baseline SLD are not convincing enough to aid in selection of a second-line treatment.
This study was sponsored by Pfizer Inc. PZ has served as an advisor for Pfizer and Novartis. GK has served as an advisor for Pfizer. SK, employed at Pfizer at the time of the study described here, is currently employed by Mirna Therapeutics and owns stock in Pfizer and Mirna Therapeutics. BIR has served as an advisor for and received research funding from Pfizer. HYL declares no conflict of interest. National Center for Biotechnology Information , U. Journal List Br J Cancer v.
Br J Cancer. Published online May Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC.
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.
0コメント