Second-generation adjuvant studies

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

Once considered among the least treatable of advanced malignancies due to a lack of effective systemic treatments, metastatic RCC has evolved in recent years into a disease that can be managed through effective disease stabilization. This has been made possible by an understanding of the dependence of RCC on the VEGF and mTOR pathways, targeting of which can render RCC susceptible to drug therapy. Seven agents were approved in the USA for the treatment of metastatic RCC between 2005 and 2012, representing a remarkable transformation in the approach to the disease. These new agents include four multitargeted, VEGF-R kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib), two mTOR inhibitors (temsirolimus and everolimus) as well as monoclonal anti-VEGF antibody (bevacizumab) in combination with IFN. Each of these treatments has shown progression-free survival benefit compared with either IFN, placebo, or another kinase inhibitor in randomized trials [67–77]. Overall survival benefit in these same trials has been difficult to demonstrate due to significant onor post-study crossover.

A number of large-scale, placebo-controlled, randomized trials have been initiated since 2006 to investigate the adjuvant utility of the new agents (Table 14.5) [78–83]. Five of these trials are studying VEGF-R tyrosine kinase inhibitors (TKIs), while one is investigating mTOR inhibition [84]. In early 2015, initial results became available for the ASSURE trial of sorafenib, sunitinib, or placebo. An interim analysis revealed no significant differences in disease-free or overall survival between either of the experimental arms and placebo. Median disease-free survival was 5.8 years (HR = 1.01, 97.5% CI 0.83–1.23) for sunitinib, 5.8 years (HR = 0.98, 97.5% CI 0.81–1.19) for sorafenib, and 6.0 years for placebo. While these results are disappointing, longer follow-up for mature overall survival data is needed, and the results of the remaining adjuvant studies remain eagerly anticipated. At the current time, observation remains the standard of care for managing postsurgical patients, and placebo control of ongoing adjuvant studies remains ethically valid.

Several factors make VEGF-R tyrosine kinase inhibitors (TKIs) and mTOR inhibitors attractive for use in the adjuvant setting. Foremost, the drugs have proven activity against metastatic RCC with frequent tumor regression and the ability to stabilize disease and delay progression. The oral availability of most of these agents makes them well suited for adjuvant use. While side effects including skin reactions, diarrhea, and stomatitis can hinder therapy, these adverse reactions can most often be minimized through supportive care and dose interruption. However, patients’ acceptability of side effects in the adjuvant setting may be less, and several of the current adjuvant studies have had unexpectedly high dropout rates [85] due to adverse events. Additionally, the significant activity of these drugs against metastatic disease does not guarantee effectiveness in the adjuvant setting. The very infrequent incidence of complete responses with targeted agents along with their tendency to induce disease stabilization as opposed to regression raises question as to the whether these agents can eradicate micrometastatic disease.

Table 14.5. Ongoing second-generation adjuvant trials

__Kidney Cancer_ Principles and Practice-Springer International Publishing (2015) T 14.5

Optimal duration of adjuvant therapy may develop as a question as data with targeted agents continues to emerge. With cytotoxic chemotherapy, obtaining total cell kill of micrometastatic disease with cyclical administration of chemotherapy over a defined period is a rationale and effective strategy in certain cancers [86]. As VEGF-R TKIs and mTOR inhibitors are thought to have a predominantly antiangiogenic and growth inhibitory effect as opposed to a direct cytotoxic effect, continued therapy in the adjuvant setting may be needed in order to prevent relapse. This is evidenced in metastatic disease where withdrawal of the agent usually results in subsequent disease progression. Only one of the current adjuvant trials, the UK Medical Research Council’s SORCE trial, is addressing the role of duration with the two experimental arms evaluating different lengths of sorafenib therapy (1 and 3 years) [80]. The remaining trials are investigating an empiric 1 year of treatment, with the exception of the ATLAS trial of axitinib, which has a 3-year treatment duration [83].

Appropriate lessons may be learned from use of noncytotoxic systemic adjuvants in other diseases, including hormonal therapy in breast cancer and imatinib in gastrointestinal stromal tumor (GIST). Despite a number of studies addressing the question of duration in breast cancer, the optimal length of adjuvant hormonal therapy is not known. However, studies have suggested that longer durations are more effective than shorter durations [87]. Three years of imatinib was found to be superior to 1 year in the adjuvant setting for GIST [88]. These findings may be relevant to guide adjuvant RCC therapy given the use of TKIs in both diseases. If it is eventually learned that long-term therapy with a targeted agent is necessary for optimal adjuvant effect in RCC, it will be vital to improve prognostication in order to select those patients at appropriate risk who warrant chronic therapy with its associated side effects.

The ongoing trials studying VEGF-R TKIs and mTOR inhibitors represent the largest adjuvant trials in RCC conducted to date. The number of ongoing studies and their rapid accrual are testament to the enthusiasm of urologists and oncologists in finding effective adjuvant therapy for RCC. The large sample sizes and placebocontrolled design of second-generation trials will result in data that are more robust than previous. With the results of these trials beginning to emerge, we must be considering the questions to ask in future studies. Issues such as duration of therapy and appropriate control arms will arise. Improving patient selection for adjuvant therapy will remain an ongoing challenge. Finally, the development of molecular biomarkers that can both improve risk stratification and predict benefit from specific targeted therapies is greatly needed and is the path to truly personalized adjuvant therapy for RCC.

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