Second perhaps only to advanced prostate cancer, the metastatic clear cell renal cell carcinoma disease space has undergone rapid and transformational change over the past fifteen years. This rapidly shifting treatment landscape was highlighted recently at the American Society of Clinical Oncology 2019 Annual Meeting:
Early years: cytokine therapy
It has been recognized for many decades that renal cell carcinoma is an immunologically active tumor. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC. Prior to 2005, treatment for metastatic RCC (mRCC) was limited to cytokine therapies (interferon-alfa and interleukin-2).
Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Based on early data suggesting a response rate between 10 to 15%5 and comparative data demonstrating a survival benefit compared to other available systemic therapies available at the time6, interferon-alfa retained utilization despite significant toxicity. Further, it was among patients with metastatic RCC receiving interferon-alfa that the Motzer prognostic criteria were derived6. In their seminal paper in the Journal of Clinical Oncology, Motzer and colleagues demonstrated that low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and short time from initial RCC diagnosis to start of interferon-alfa therapy (<1 year) could be used to risk-stratify patients with renal cell carcinoma. However, even among patients treated at a center of excellence, median overall survival was only 30 months in favorable-risk patients, 14 months in intermediate-risk patients and five months in poor-risk patients6.
Other immunologic therapies were explored including interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%)7, interleukin-2 was distinct in that durable complete responses were observed in approximately 7 to 9% of patients8. This observation led to the U.S. Food and Drug Administration (FDA) approval of high-dose IL-2 in 1992. However, IL-2 is associated with significant toxicity which has limited its widespread use.
Combinations of interferon and interleukin therapies were explored subsequently those these data demonstrated no improvement in overall survival9, with significantly increased toxicity compared to monotherapy with either agent.
A new standard: molecularly targeted agents
Based on work into the molecular biology underlying ccRCC, researchers were led to “rational targeted therapeutics” including targeting of the vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR). Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation.
Bevacizumab, a humanized monoclonal antibody against VEGF-A, was the first inhibitor of the VEGF pathway used in clinical trials. As is standard in an oncology pathway, it was first tested in patients who had progressed on the current standard of care (cytokine therapy) and subsequently tested in untreated patients. In head-to-head trials against interferon-alfa, the addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival10,11. Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.
Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. As highlighted in the Figure above, sorafenib was one the first molecularly targeted agents clinically available. However, despite FDA approval, sorafenib was quickly supplanted by sunitinib as a first-line VEGF inhibitor.
In keeping with the aforementioned oncology pipeline, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-α in a pivotal Phase III randomized trial12. Among 750 patients with previously untreated, metastatic RCC randomized, median progression-free survival was significantly longer among those who received sunitinib (11 months) than those who received interferon-alfa (5 months; hazard ratio 0.42, 95% confidence interval 0.32 to 0.54). Similar benefits were seen in the overall response rate with subsequent follow-up demonstrating a strong trend towards improved overall survival. In the pivotal trial, patients who received sunitinib had a significantly better quality of life than those who received interferon-alfa12, despite class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. On account of these data, sunitinib is widely used as a first-line treatment of RCC.
Since the approval of sunitinib and sorafenib, there has been the development and subsequent approval of a number of other tyrosine kinase inhibitors. For the most part, the goal of these agents has been to reduce the toxicity of VEGF inhibitors while retaining oncologic efficacy. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib13. Axitinib was evaluated first as second-line therapy14 and then in the first-line setting compared to sorafenib15. Among 192 patients with previously untreated ccRCC randomized to axitinib and 96 patients randomized to sorafenib, median progression-free survival was not significantly different (10.1 months and 6.5 months, respectively; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05)15. Finally, tivozanib has been compared to sorafenib among patients who had not previously received VEGF or mTOR-targeting therapies. While this study demonstrated tivozanib’s activity, it was not FDA approved and is therefore not used.
Most recently, a multikinase inhibitor, cabozantinib has been approved for the first-line treatment of mRCC. In the Phase II CABOSUN trial, cabozantinib was compared to sunitinib in the first-line treatment of patients with intermediate or poor-risk mRCC16. Assessing the primary outcome of progression-free survival, the 79 patients randomized to cabozantinib had significantly longer progression-free survival (8.2 months) compared to the 78 randomized to sunitinib (5.6 months; hazard ratio 0.66, 95% confidence interval 0.46 to 0.95). A recent update on this trial utilizing independent progression-free survival (PFS) review demonstrated comparable results (hazard ratio 0.48, 95% confidence interval 0.31 to 0.74)17. Even with an increased follow-up (median 34.5 months), no significant difference in overall survival was demonstrated (26.6 months in patients receiving cabozantinib and 21.2 months in those receiving sunitinib; hazard ratio 0.80, 95% confidence interval 0.53 to 1.21). While this appears to demonstrate a significant benefit to cabozantinib, median survival in the sunitinib arm was lower than may be expected18 which would serve to exaggerate the apparent benefit of cabozantinib.
In parallel to the development, clinical appraisal and utilization of VEGF inhibitors have come the development of mTOR inhibitors. Temsirolimus was the first mTOR inhibitor to reach clinical utility in patients with metastatic RCC. In the Global ARCC Trial, temsirolimus, interferon, and the combination were compared among 626 patients with pre-defined poor-risk metastatic RCC who had not previously received systemic therapy19. Notable compared to many trials in this disease space that have utilized progression-free survival as the primary outcome, overall survival was the primary outcome, with the study powered based on comparisons of the temsirolimus group and the combination group to the interferon-alfa group. Patients who received temsirolimus had significantly improved overall survival compared to those receiving interferon-alfa (hazard ratio 0.73, 95% confidence interval 0.58 to 0.92). Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent.
What’s old is new: immunotherapy for RCC
The immunologic basis for the treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Thus, it should not be surprising that the use of checkpoint inhibitors has demonstrated benefit in patients with metastatic RCC.
First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs sunitinib20. This trial randomized 1096 patients to the combination immunotherapy approach of nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients). The majority of patients had intermediate or poor-risk disease (n=847). Overall survival was significantly improved in the overall patient population; however, stratified analyses provide more nuanced results. Among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival. In contrast, among patients with favorable-risk disease, progression-free survival and overall response rate were higher among patients who received sunitinib. Recently, Escudier and colleagues have assessed the efficacy of nivolumab and ipilimumab according to the number of IMDC risk factors21. In keeping with the previously reported differences in the comparative benefit of nivo/ipi versus sunitinib on the basis of risk category (intermediate/poor versus favorable), the authors demonstrated stable overall response rate (ORR) across increasing numbers of IMDC risk factors (from zero to six) for those who received nivolumab and ipilimumab, while the ORR in patients treated with sunitinib decreased with an increasing number of IMDC risk factors.
The next frontier: combinations of targeted therapy and immunotherapy
Shortly after the data from CheckMate214 emerged, the results of IMmotion151 were presented at GU ASCO in the spring of 2018 and subsequently published. This Phase III trial compared first-line atezolizumab + bevacizumab versus sunitinib among 915 patients with previously untreated metastatic RCC22. This regime was active with a significant benefit in progression-free survival (11.2 months versus 7.7 months; hazard ratio 0.74, 95% confidence interval 0.57 to 0.96) among the whole cohort of patients and had lower rates of significant (grade 3-4) adverse events (40% vs 54%).
Since the publication of CheckMate214 and IMmotion151, two trials have reported on combinations of checkpoint inhibitors and tyrosine kinase inhibitors: KEYNOTE-426 and JAVELIN Renal 101.
In KEYNOTE-426, 861 patients with metastatic clear cell RCC who had not previously received systemic therapy were randomized to pembrolizumab plus axitinib or sunitinib and followed for the co-primary endpoints of overall survival and progression-free survival23. Similar to CheckMate214, the majority of patients had intermediate or poor-risk disease. While median survival was not reached, patients who received pembrolizumab and axitinib had improved overall survival (hazard ratio 0.53, 95% confidence interval 0.38 to 0.74) and progression-free survival (hazard ratio 0.69, 95% confidence interval 0.57 to 0.84), as well as overall response rate. These results were consistent across subgroups of demographic characteristics, IMDC risk categories, and programmed death-ligand 1 (PD-L1) expression level. Grade 3 to 5 adverse events were somewhat more common among patients getting pembrolizumab and axitinib, though rates of discontinuation were lower.
Similarly, JAVELIN Renal 101 randomized 886 patients to avelumab and axitinib or sunitinib24. Again, the preponderance of patients had IMDC intermediate or poor-risk disease. This analysis of the primary endpoints was progression-free survival and overall survival in patients with PD-L1 positive tumors. Notably, 560 of the 886 patients had PD-L1 positive tumors. Among the PD-L1 positive subgroup, progression-free survival (hazard ratio 0.61, 95% confidence interval 0.47 to 0.79) was improved in patients receiving avelumab and axitinib compared to sunitinib while overall survival did not significantly differ (hazard ratio 0.82, 95% confidence interval 0.53 to 1.28). In the overall study population, progression-free survival was similarly improved, as compared to the PD-L1 positive population (hazard ratio 0.69, 95% confidence interval 0.56 to 0.84).
Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomycin, and platinum. Meta-analyses of these data demonstrate poor response25 and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in the modern management of advanced RCC.
Integration of treatment options for patients with metastatic ccRCC
Due to the rapid proliferation of treatment options in first-line treatment of metastatic clear cell renal cell carcinoma, there is a paucity of direct comparative data. The majority of new agents have been compared to sunitinib which was the standard of care at the time that trials were designed. Due to the lack of comparative data, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue. First, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience.
Assessing this quantitatively, we have recently performed a network meta-analysis of first-line agents in metastatic RCC26. Assessing agents which are commonly utilized in 2019, we examined 12 relevant trials. Depending on the outcome of interest (progression-free survival, overall survival, or adverse events), the preferred treatment varied. However, pembrolizumab and axitinib appeared to have a high likelihood of being preferred for oncologic outcomes.
Second, considering a panel of expert opinion, the European Association of Urology recently updated its guidelines on the treatment of renal cell carcinoma. Their recommendations are highlighted in the following figure, taken from the EAU guideline:
Notably, the most recent version of these guidelines alludes to the recently published data but have not yet integrated the role of atezolizumab plus bevacizumab, pembrolizumab plus axitinib, or avelumab plus axitinib in guideline recommendations.
Finally, we may rely on the guidance of individual clinical experience.
What about surgery?
The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma has dramatically changed with the publication of the CARMENA and SURTIME studies. The available evidence suggests that systemic therapy should be prioritized ahead of cytoreductive nephrectomy. However, there remains a role of cytoreductive nephrectomy in select patients.