The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.
To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.
Design, setting, and participants
Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.
Sequence of systemic targeted treatment with sunitinib (n
We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).
Results and limitations
Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8–5.4) for EV and 4.0 mo (3.2–4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p
The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.
Keywords: Metastasis, Renal cell carcinoma, Tyrosine kinase inhibitor, Progressive disease.
During the last few years, efficacious therapeutic options have been developed for patients with metastatic renal cell carcinoma (mRCC). Most patients are treated with receptor tyrosine kinase inhibitors (rTKIs), particularly sunitinib (Sun), based on the results obtained in two meta-analyses  and . Inevitably, most of the patients develop tumour resistance to the first rTKI therapy and therefore require further sequential therapy.
Based on a phase 3 trial, everolimus (EV) is an efficacious treatment option after failure of vascular endothelial growth factor receptor (VEGFr) targeted therapy, particularly rTKI treatment . Current guidelines for the treatment of mRCC have adopted EV as the treatment of choice after VEGF failure  and . However, some limited evidence suggests that following failure of one VEGFr targeted agent, patients may still have the potential to respond to another VEGFr inhibitor. Particularly rTKIs such as Sun and sorafenib (Sor) have been applied in sequence, although the data of a phase 2 study suggested limited efficacy of this sequencing regimen . Largely retrospective data form the basis for the sequential use of Sun and Sor or vice versa , , , , , and . However, studies sufficiently comparing different sequence options are still lacking.
In the context of insufficient comparative data on the best sequence of targeted treatments in mRCC patients, we collected the data of patients treated with two common sequence options: rTKI therapy followed by EV (rTKI-EV) versus rTKI therapy followed by another rTKI (rTKI-rTKI) in two treatment centres. The aim of our retrospective study was to compare these sequence options in terms of efficacy and toxicity.
2. Patients and methods
We retrospectively reviewed patients treated with first rTKI therapy (Sun or Sor) at two large academic centres between 2005 and 2010. Patients receiving the sequence rTKI-EV or rTKI-rTKI were included in this study. Either Sun or Sor was allowed as first rTKI treatments, so the rTKI-rTKI sequence subgroup included patients treated with Sun-Sor or vice versa, and the rTKI-EV subgroup included Sun-EV or Sor-EV. Further therapy lines were individualised and included EV, temsirolimus, dovitinib, interferon α, or bevacizumab plus interferon α. Immunotherapy was the only therapy allowed prior to rTKI treatment and was not considered as a targeted therapy line. Sun was administered daily either as 50
Associations between main characteristics (age, gender, Memorial Sloan-Kettering Cancer Centre [MSKCC] risk , and Eastern Cooperative Oncology Group performance group) and response to treatment were explored using the chi-square test and the Mann-Whitney U test as appropriate. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were applied to explore predictors of PFS, sequential treatment duration, and OS in univariate- and multivariable-adjusted analyses. Predictors of OS and PFS were further tested in stratified Kaplan-Meier analyses whenever appropriate. A p value
3.1. Patient characteristics
A total of 108 patients with first rTKI treatment were included in the study. Of these 46 received the rTKI-rTKI sequence, and 62 individuals received the rTKI-EV sequence. The rTKI-rTKI group included Sun-Sor (n
|Age (first targeted therapy), yr, median (IQR)||61.8 (54.5–69.2)||60.7 (53.9–67.2)||62.1 (54.9–69.9)||0.452|
|Sex, n (%)||Female||31 (28.7)||12 (26)||19 (30.6)||0.671|
|Male||77 (71.3)||34 (74)||43 (69.4)|
|MSKCC, n (%)||Good||18 (16.7)||5 (10.9)||13 (21.0)||0.89|
|Intermediate||49 (45.4)||16 (34.8)||33 (53.2)|
|Poor||3 (2.8)||1 (2.2)||2 (3.2)|
|Unknown||38 (35.2)||24 (52.2)||14 (22.6)||0.002|
|ECOG, n (%)||0||78 (72.2)||34 (73.9)||44 (70.9)|
|1||15 (13.9)||4 (8.6)||11 (17.7)||0.294|
|2||1 (0.9)||0 (0)||1 (1.6)|
|Unknown||14 (13)||8 (17.4)||6 (9.6)|
|Histology, n (%)||Clear cell||94 (87)||37 (80.4)||57 (91.9)|
|Non–clear cell||11 (10.2)||6 (13.0)||5 (8.0)||0.071|
|Unknown||3 (2.8)||3 (6.5)||0 (0)|
|T stage, n (%)||T1||15 (13.9)||8 (17.4)||7 (11.3)||0.519|
|T2||21 (19.4)||10 (21.7)||11 (17.7)|
|T3||65 (60.2)||24 (52.2)||41 (66.1)|
|Unknown||7 (6.5)||4 (8.7)||3 (4.8)|
|Grade, n (%)||G1||6 (5.6)||1 (2.2)||5 (8.1)||0.520|
|G2||61 (56.5)||25 (54.3)||36 (58.1)|
|G3||31 (28.7)||15 (32.6)||16 (25.8)|
|Unknown||10 (9.2)||5 (10.9)||5 (8.0)|
|Lymph node status, n (%)||N0||49 (45.4)||21 (45.7)||28 (45.2)||0.876|
|N1||9 (8.3)||5 (10.9)||4 (6.5)|
|N2||7 (6.5)||3 (6.5)||4 (6.5)|
|NX||43 (39.8)||17 (36.9)||26 (41.9)|
|Metastases at nephrectomy, n (%)||M0||36 (33.3)||13 (28.2)||23 (37.0)||0.358|
|M1||40 (37.0)||16 (34.7)||24 (38.7)|
|MX||32 (29.2)||17 (37.0)||15 (24.2)|
|Metastases at first line||≥3 organ sites||52 (48.1)||21 (45.6)||31 (50.0)||0.700|
|Bone metastasis||27 (25.0)||10 (21.7)||17 (27.4)||0.654|
|Liver metastasis||21 (19.4)||9 (19.5)||12 (19.3)||1.000|
|Metastases at second line||≥3 organ sites||67 (62.0)||29 (63.0)||38 (61.2)||1.000|
|Bone metastasis||34 (31.4)||16 (34.7)||18 (29.0)||0.537|
|Liver metastasis||25 (23.1)||7 (15.2)||18 (29.0)||0.110|
|Previous immunotherapy||59 (54.6)||25 (54.3)||34 (54.8)||1.000|
* The p values refer to the chi-square test except for comparisons of median age (Mann-Whitney U test).
3.2. Treatment efficacy
Table 2 provides the data on response assessment. For the first-line rTKI treatment, the objective response rate did not differ significantly by sequence group, whereas disease control rate (CR plus PR plus SD) was significantly lower for the rTKI-rTKI group (56%) than for the rTKI-EV (82%; p
|First-line rTKI agent, n (%)||Sunitinib||85 (78.7)||35 (76.0)||50 (80.6)||0.638*|
|Sorafenib||23 (21.3)||11 (23.9)||12 (19.3)|
|Response First line, n (%)||PD||20 (18.5)||12 (26.1)||8 (12.9)||0.019*|
|SD||50 (46.3)||19 (41.3)||31 (50.0)|
|PR||22 (20.4)||7 (15.2)||15 (24.1)|
|CR||5 (4.6)||0 (0)||5 (8.0)|
|NE||11 (10.2)||8 (17.4)||3 (4.8)|
|Response Second line, n (%)||PD||44 (40.7)||19 (41.3)||25 (40.3)||0.161*|
|SD||45 (41.6)||15 (32.6)||30 (48.3)|
|PR||7 (6.5)||5 (10.8)||2 (3.2)|
|NE||11 (10.2)||7 (15.2)||5 (8.1)|
|Disease control rate, n (%)||First line||77 (71.3)||26 (56.5)||51 (82.3)||0.005*|
|Second line||52 (48.1)||20 (43.5)||32 (51.6)||0.441*|
|None||31 (28.7)||9 (19.6)||22 (35.5)|
|Further treatment lines||1||43 (39.8)||20 (43.4)||23 (37.0)||0.196*|
|≥2||34 (31.5)||17 (36.9)||17 (27.4)|
* Chi-square test/Fisher exact test.
Second-line targeted therapy with either another rTKI or EV appeared to be equally efficacious with a median PFS of 4.0 mo for rTKI and 3.6 mo for EV (p
|PFS, first rTKI||8.3 (5.2–11.2)||6.6 (2.6–10.6)||10.6 (7.4–13.8)||0.058|
|7.8 (5.4–10.2)||5.5 (2.4–8.5)||10.6 (7.1–14.1)||0.009|
|10.5 (4.7–16.3)||10.5 (5.3–15.7)||13.3 (1.7–24.8)||0.019|
|PFS, second line||4.0 (2.9–5.1)||4.0 (3.2–4.9)||3.6 (1.8–5.4)||0.455|
|4.0 (2.7–5.3)||4.1 (3.4–4.8)||3.3 (2.2–4.3)||0.193|
|Sequence therapy duration||14.6 (11.4–17.9)||11.0 (6.6–15.3)||18.5 (14.2–22.8)||0.051|
|14.1 (12.5–15.7)||10.8 (6.2–15.5)||16.3 (11.7–20.9)||0.001|
|OS‡||35.5 (29.0–42.0)||29.0 (18.6–39.5)||43.0 (33.9–52.1)||0.034|
|32.7 (24.3–41.2)||22.9 (18.4–27.3)||39.9 (31.5–48.3)||0.008|
* The p values refer to the log-rank test.
Restricted to 86 patients who received the Sun-Sor (n
‡ Overall survival calculated from start of first targeted therapy.
An additional subgroup analysis of the rTKI-rTKI sequence group revealed a longer first-line PFS (10.5 vs 5.5 mo; p
For the sequential treatment groups (rTKI vs EV), no statistically significant differences were observed in the rate of grade 3 or 4 toxicities (CTCAE 3.0) or the rate of toxicity-induced treatment termination (Table 4). Most toxicity-related side effects were manageable, and permanent dose reductions were necessary in 12 patients (26%) of the rTKI group and 4 patients (6%) of the EV group (p
|Treatment termination, first-line rTKI||11 (23.9)||9 (14.5)||0.061*|
|Second line||6 (13.0)||8 (12.9)||0.773*|
|Grade 3 or 4 toxicity (second line)|
|9 (19.5)||19 (30.6)||0.397*|
|2 (4.3)||2 (3.1)||–|
|1 (2.1)||2 (3.1)||–|
|1 (2.1)||2 (3.1)||–|
* Chi-square test/Fisher exact test.
3.4. Univariate- and multivariable-adjusted Cox regression models
Table 5 depicts the univariate and multivariable Cox regression models for predictors of PFS (second-line targeted therapy) and OS from the start of sequence targeted therapy. Main characteristics such as MSKCC risk group (or missing data on MSKCC risk) and prior immunotherapy were not associated with PFS or OS. Toxicity (grade 3 or 4) of sequential therapy was a predictor of PFS (hazard ratio [HR]: 1.80; 95% CI, 1.11–2.92; p
|PFS||Univariate Cox regression||Multivariable Cox regression|
|HR (95% CI)||p value||HR (95% CI)||p value|
|Sunitinib (first rTKI)||1.71 (1.02–2.85)||0.038||1.34 (0.72–2.49)||0.352|
|Primary rTKI resistance (first rTKI)||1.86 (1.12–3.08)||0.016||1.79 (1.15–3.62)||0.015|
|Sequence rTKI-rTKI (vs rTKI-EV)||1.16 (0.78–1.74)||0.447||–||–|
|Grade 3 or 4 toxicity (second line)||1.80 (1.11–2.92)||0.017||1.63 (0.96–2.77)||0.072|
|Sunitinib (first rTKI)||2.38 (1.12–5.06)||0.023||2.84 (1.22–6.60)||0.015|
|Primary rTKI resistance (first rTKI)||4.86 (2.48–9.50)||<0.001||6.54 (3.01–14.20)||<0.001|
|Sequence rTKI-rTKI (vs rTKI-EV)||1.75 (1.03–2.96)||0.036||1.27 (0.69–2.34)||0.451|
|Grade 3 or 4 toxicity (second line)||0.79 (0.42–1.51)||0.479||–||–|
|Primary resistance (second line)||1.81 (1.03–3.19)||0.039||1.67 (0.92–3.03)||0.090|
* Overall survival since start of targeted sequence therapy.
Despite significant improvements in the efficacy of systemic treatment of mRCC patients, the best strategy of sequencing targeted therapies remains a matter of debate. Literally all patients with mRCC inevitably experience tumour progression during first-line treatment necessitating sequential therapy.
In this study we compared frequent sequence strategies. Our data support the notion that both efficacy and safety of the most frequently applied sequential targeted therapies (ie, switching rTKI agents or rTKI followed by EV) may be comparable. Interestingly, however, we observed a significant difference in OS favouring the rTKI-EV sequence option. Given the higher proportion of patients with primary (intrinsic) resistance in the rTKI-rTKI group, selection bias cannot be excluded as a reason for this observation. However, a trend towards improved survival for rTKI-EV was still present upon exclusion of cases with intrinsic rTKI resistance, indicating a potential benefit of an early change of mode of action. Results were confirmed in an analysis restricted to cases with Sun as first rTKI (ie, comparing the Sun-EV sequence and the Sun-Sor sequence).
Prospective data on the best sequential therapy among the available sequence options in mRCC are still lacking. In contrast to our observations, Vickers et al. reported that patients receiving another VEGFr-targeted therapy in the sequence setting may experience a longer PFS compared with those treated with mammalian target of rapamycin (mTOR) inhibitors . However, among the 216 patients, only 24 individuals were treated with mTOR inhibitors, and as few as 3 received EV. Apart from our study, no data exist directly comparing the use of EV and rTKI treatment after failure of first-line rTKI therapy in a relevant number of patients. A prospective phase 2 study reported a median PFS of 4.4 mo and an OS of 16 mo for Sor after failure of Sun or bevacizumab . In a recent study on sequential targeted therapy, a median second-line PFS of 4 mo was reported for 25 patients receiving EV after Sun failure . Although the PFS observed in these studies compares well with our data, OS was usually not reported for the entire sequence of treatments. In line with our study, a number of smaller retrospective trials suggested that the sequential use of Sor and Sun or vice versa may show clinical benefit in mRCC patients  and , although the only prospective single-arm trial on this sequence option indicated a low efficacy of Sor in the second-line setting . Nonetheless, sequencing VEGFr targeted therapy may be a valid treatment option. Porta et al. recently reported on a multicentre series of 189 patients treated with Sun followed by Sor and vice versa . In this study a longer median duration of sequential therapy was observed for the Sor-Sun sequence. However, the imbalance of important characteristics such as the higher proportion of previous systemic therapy (71% vs 38%) and poor risk patients (32% vs 10%) in the Sun-Sor group may account for this observation. Indeed, another study on registry data did not observe differences in PFS or OS by rTKI sequence . Due to their retrospective nature, the validity of these studies and our observations is limited. In our study, an exploratory subgroup analysis, a trend towards longer PFS and OS estimates was observed for the Sor-Sun sequence compared with the Sun-Sor sequence, but the sample size was too small, and no valid conclusions can be made. Results of ongoing prospective randomised trials comparing sequence options, such as Sun followed by EV versus vice versa (NCT00903174) or Sor versus Tem after failure of Sun (NCT 00474786), are eagerly awaited.
Our study has important limitations. The limited numbers of patients in each group underline the uncertainty of our observations. Due to the fact that some patients were treated outside our centres during first-line therapy, data on MSKCC risk group were missing in a significant number of patients. The imbalanced distribution of relevant variables, such as number of metastatic sites or histologic type and missing data on MSKCC prognostic group, may be additional sources of bias. We cannot exclude a selection bias towards good risk patients due to the relatively high proportion of cytokine-pretreated patients. A novel risk prognosis score has been introduced based on patient data from the targeted therapy era  but has not yet been validated. This score cannot be calculated in our patient population because neutrophil count is largely missing.
A number of other factors, such as haemoglobin level, age, brain metastasis, or time from diagnosis to treatment, have an impact on PFS and OS in patients undergoing sequential rTKI treatment . In univariate analyses, significant treatment-related toxicity was associated with inferior PFS in our patients, underscoring the importance of stringent management of adverse events  and .
A better understanding of the mechanism underlying treatment resistance in mRCC patients will help optimise the treatment strategy. Evasive or acquired tumour resistance may develop via mechanisms like alternative proangiogenic signalling pathways within the tumour, recruitment of bone marrow–derived proangiogenic cells, increased protection of tumour vasculature by pericytes, and increased tumour cell invasiveness to escape oxygen and nutrient deprivation . A countermeasure to overcome acquired tumour resistance could be targeting a different signalling pathway , blocking the underlying escape signalling pathway , or rechallenging the tumour after restoration of a susceptible tumour microenvironment . Intrinsic (primary) resistance may indicate other as yet undefined pathways. The underlying mechanisms of intrinsic and acquired tumour resistance are complex, and further research is needed.
In our exploratory analysis, first-line Sun treatment was an independent predictor of inferior OS. This observation deserves further study. Sun as a potent antiangiogenic agent may indeed induce an aggressive tumour phenotype , , and , although this hypothesis awaits further confirmation in clinical and translational studies. Intrinsic resistance to first rTKI treatment was a strong independent predictor of OS in our study population. As a consequence, patients with intrinsic rTKI resistance had a low chance of clinical benefit from sequential therapy. These facts underscore that overcoming treatment resistance in mRCC patients (eg, by the development of novel targeting strategies) is key for improving survival perspectives. Upon exclusion of patients with intrinsic rTKI resistance, OS still tended to be longer in the rTKI-EV sequence group. This supports the hypothesis that an early change of mode of action may increase the efficacy of mRCC treatment. However, the switch from VEGFr-targeted therapy to mTOR inhibition may not be sufficient, and targeting of pathways not related to angiogenesis may be necessary to significantly increase treatment efficacy.
EV remains the preferred option in rTKI-resistant mRCC according to the evidence available to date. Sequential rTKI therapy with Sun or Sor may provide similar efficacy in terms of PFS and response rate. The trend towards superior OS for the rTKI-EV sequence needs further confirmation in prospective randomised trials. Results from such trials comparing different sequence options are urgently needed to better define the treatment algorithms in rTKI-resistant disease.
Study concept and design: Busch, Seidel, Grünwald, Weikert.
Acquisition of data: Busch, Seidel, Wolff, Kempkensteffen, Johannsen, Hinz, Magheli.
Analysis and interpretation of data: Busch, Seidel, Grünwald, Weikert.
Drafting of the manuscript: Busch, Seidel, Grünwald, Weikert.
Critical revision of the manuscript for important intellectual content: Busch, Seidel, Wolff, Kempkensteffen, Johannsen, Hinz, Magheli, Miller, Grünwald, Weikert.
Statistical analysis: Busch, Weikert.
Obtaining funding: None.
Administrative, technical, or material support: Weikert, Miller, Wolff, Grünwald.
Supervision: Weikert, Miller, Magheli, Kempkensteffen, Grünwald.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Manfred Johannsen has received honoraria from Pfizer Germany, Bayer Ag, Novartis Germany, Sanofi-Aventis, Wyeth Germany, Glaxo Smith Kline, and Roche Germany. He is a consultant for Novartis Germany, Glaxo Smith Kline, and Pfizer Germany. Kurt Miller is an advisor to Pfizer, Roche, and Novartis. Steffen Weikert is an advisor to Pfizer, Bayer, and Novartis. The other authors have nothing to disclose.
Funding/Support and role of the sponsor: None.
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a Department of Urology, Charité University Medicine Berlin, Berlin, Germany
b Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
Both authors contributed equally to this work.
© 2011 European Association of Urology, Published by Elsevier B.V.