For first- and second-line therapy, there is now a growing evidence to guide the selection of the appropriate treatment; especially as comparative studies between targeted therapies are appearing. For the third-line, the evidence is still somewhat limited as is the information on the best sequential therapy.
In first-line therapy, sunitinib and pazopanib are the treatments of choice for patients with favorable or intermediate prognostic risk features and ccRCC. Pazopanib was not inferior to sunitinib in a phase 3 study and sunitinib proved to be superior to IFN-α [
16,
18]. Both agents have comparable efficacy and should be chosen at the physician’s discretion depending on treatment tolerance and patient preference. Bevacizumab combined with IFN-α represents an effective alternative for the first-line as well, and is particularly relevant for younger patients with a favorable risk. Essential for the choice of the targeted therapy for tumors with clear cell histology is a classification according to the risk models MSKCC or IMDC. In patients with a poor risk score, temsirolimus is the one valid therapy option. In this setting, temsirolimus showed a prolonged OS compared to IFN-α. In patients with non-ccRCC and/or poor prognostic risk, temsirolimus represents the standard of care supported by phase 3 data. Alternatives include sunitinib and everolimus [
1].
Real-life data based on prospective registry data in Germany underline that the recommended guideline therapy is followed in clinical practice. Pazopanib and sunitinib are the most commonly used drugs in first-line therapy of mRCC in Germany, followed by temsirolimus; other agents like bevacizumab, IFN-α or sorafenib play a minor role according to a cancer registry for advanced RCC conducted by the clinical research organization iOMEDICO (iOMEDICO AG, Freiburg, Germany), as per April 2014 [
34]. The use of sunitinib in this indication has decreased continuously over the last 7 years, while the use of pazopanib has increased in the meantime.
In second-line therapy, it remains unclear whether TKI or mTOR inhibitors are the better choice. Therapy options after TKI failure consist of everolimus and axitinib and—with a lower level of evidence—sorafenib. Axitinib has proven efficacy and superiority in terms of PFS in comparison with sorafenib after failure of the first systemic therapy. Everolimus prolongs PFS in comparison with placebo in patients who have previously failed or are intolerant to first-line VEGFR-TKI therapy. However, neither axitinib nor everolimus demonstrated an advantage in terms of OS, and there is no direct comparison between the two substances. Not surprisingly, everolimus and axitinib are currently the most commonly used agents for second-line therapy of mRCC in Germany according the iOMEDICO cancer registry [
34].
Despite the limited number of phase 3 trials in this setting, it is widely accepted that patients who retain a good performance status may still benefit from a third line of therapy. Available therapy options are everolimus after two previous lines of TKI and sorafenib after a first-line of TKI followed by an mTOR inhibitor. The median PFS reached in the third line are comparable to that in the second-line [
33]. In current medical care of mRCC, almost half of the patients who received a second-line treatment are treated in a third-line (25 % of all patients treated with a systemic therapy) and one-fifth get a fourth-line (10 % of patients with a systemic therapy) [
34].
Sequencing in first- and second-line therapy
Seven new targeted therapies (axitinib, bevacizumab + IFN-α, everolimus, pazopanib, sorafenib, sunitinib and temsirolimus) and one checkpoint inhibitor (nivolumab) with proven efficacy have been approved since 2005 for the treatment of mRCC, and real-world data reflect their use in clinical practice. But what is the optimal sequence of these agents?
There is little evidence available on the optimum sequence of these agents in first or second-line therapy; consequently, the EAU guidelines give no firm recommendation on the best sequence for targeted therapy.
RECORD-3 was the first randomized phase 2 study to prospectively compare the sequence of everolimus followed by sunitinib to the sequence of sunitinib followed by everolimus. While the most important prognostic patient characteristics were equally distributed between the arms, there was no significant difference in median combined PFS, a secondary endpoint of the study, between the sequence sunitinib–everolimus (22.2 months) and that of everolimus–sunitinib (21.7 months; HR 1.2; CI 95 % 0.9–1.6) [
35]. The censoring rates were high in both arms: 56 % for everolimus–sunitinib and 57 % for sunitinib–everolimus; mainly because of patients who did not cross over to a second-line therapy within the protocol study period. Patients who never received a per-protocol second-line therapy were also censored. Although the censoring could have impacted the Kaplan–Meier and HR estimates, the combined median PFS of 22.2 months was an endpoint that had not been established previously in a prospective trial, and will serve as a benchmark for future trials in sequential therapy. The results of the study confirmed first-line sunitinib followed by everolimus at progression as one possible sequence for the treatment of mRCC.
Another trial examining sequential therapy was SWITCH-I, a randomized phase 3 study, which evaluated the efficacy and safety of sorafenib followed by sunitinib versus sunitinib followed by sorafenib. Based on retrospective data, it was hypothesized that sorafenib–sunitinib might be a statistically superior sequence; however, there was no significant difference in total PFS between both arms. The median total PFS was 12.5 months in the sorafenib–sunitinib arm and 14.9 months in the sunitinib–sorafenib arm (HR 1.01; CI 95 % < 1.27;
p = 0.54) [
36]. The OS analysis of the SWITCH-I study showed no superiority of either of the two sequences (median OS 31.5 months for sorafenib–sunitinib vs. 30.2 months for sunitinib–sorafenib; HR 1.00; CI 95 % < 1.3) [
36]. A direct comparison of the combined PFS in the RECORD-3 and the total PFS in the SWITCH study is statistically not valid due to different trial settings and different methodology of the endpoints. The AE profiles differed between the individual study medications of both trials, but were generally consistent with previously reported safety profiles for these agents in patients with mRCC [
37]. Preliminary results of the RECORD-3 study demonstrated that rates of grade 3 and 4 AEs were higher with a first-line TKI—in this case sunitinib—than with a second-line TKI [
35]. This finding seems to be consistent with the results of the SWITCH-I study, and with previous data, showing that grade 3 and 4 AEs tend to decrease in the course of TKI therapy [
36,
38].
In summary, treatment options for mRCC have expanded enormously, since the introduction of targeted therapies, and have significantly extended the survival of mRCC patients—OS can be prolonged by up to 32 months by sequencing different approved targeted drugs [
20,
23,
39]—but the availability of numerous alternative therapies creates a challenge how to select the optimal treatment protocol.
The molecular biology underlying cancer growth and control is a field of considerable ongoing research. In mRCC, the research has concentrated on TKI and mTOR inhibitors, which have improved patient survival in general, but with a limited prognosis. Therapeutics, which yield a longer lasting response, are warranted, especially those who would provoke long-term response or complete remission as observed with non-specific immunotherapy with the cytokines Il-2 and IFN-α. Another exploratory way for the future to stimulate the immune system is the vaccination with tumor-associated peptides (TUMAP), which aims at activating specific T lymphocytes against tumor tissues. The vaccine approach will need further exploration as latest data of peptide vaccination in the combination with sunitinib in mRCC as a first-line treatment has failed [
40,
41].
Recently, a deeper understanding of the underlying immunology of T cell activation led to the development of immune checkpoint inhibitors. These are monoclonal antibodies, which inhibit the PD-1 (CD279) and CTLA-4 (CD152) axis, thereby releasing the inhibition of T cell activation [
42]. This approach has shown excellent results with other tumor entities (melanoma, lung cancer) with a subgroup of patients experiencing long-term complete or partial remissions. Phase 3 results in RCC were presented and published for the first time in September 2015. Based on this data, nivolumab will probably drive the second- and third-line treatment of mRCC after failure of a VEGF-targeted therapy [
43]. Cabozantinib also shows a promising efficacy in patients that had progressed under TKI. The final results of the OS data remain to be seen, but it seems that a survival benefit yet unequaled in second-line therapy could be achieved [
43].