The Evolution of Clinical Trials in Renal Cell Carcinoma: A Status Report for 2013–2016 from the ClinicalTrials.gov Website

BACKGROUND

An estimated 63,990 Americans will be diagnosed with renal cell carcinoma (RCC) and 14,400 will die of the disease in the USA in 2017 [1]. Although 63% of RCC patients present with localized, early stage disease, about 30–40% of these patients develop metastatic disease in the future [2]. About 34% patients have regionally advanced or metastatic disease at diagnosis [3].

Over the last 15 years, the treatment paradigm of advanced RCC has rapidly evolved [4]. This began with the development of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) directed therapies and has recently moved on to checkpoint inhibitors and other immunotherapeutics. Specifically, since 2005, the US Food and Drug Administration has approved 6 VEGF receptor tyrosine kinase inhibitors (TKIs), 2 mTOR inhibitors, bevacizumab and the checkpoint inhibitor nivolumab.

Given the development of a wide variety of therapeutic options for use in patients with RCC, clinical trial landscape has been evolving as well. Additionally, increasing correlative studies to identify novel markers for both prognostic and predictive purposes has expanded areas for exploration.

In 2013 we explored the ongoing clinical trials for patients with RCC registered with ClinicalTrials.gov Web site [5]. The goal of that study was to shed light on trends in clinical trials research in RCC and identify areas where more resources might be warranted. Given the advent of immune checkpoint inhibitors, other novel immunotherapeutics and various combination therapies, we conducted a second analysis of ongoing clinical trials as of May 2016 to compare with the landscape of clinical trials in 2013. Our aim was to highlight current state of therapeutic trials in RCC, highlight the evolution of trials over 3 years and identify areas that require more research efforts.

MATERIAL AND METHODS

The data for this study were collected from the ClinicalTrials.gov website. The ClinicalTrials.gov Web site was created in accordance with the mandate of the FDA Modernization Act of 1997 [6]. This act required the creation of a clinical registry that would be accessible to public, and that would report information pertaining to federally and privately funded trials testing experimental drugs. The site provides the largest database of clinical trials in the world, including almost all interventional human trials performed in the United States and 185 countries worldwide.

The advanced search option was used with the search term, “renal cell carcinoma” OR “renal cell cancer” OR “kidney carcinoma” OR “renal neoplasm” OR “kidney neoplasm”. The search was further refined to “interventional” for study type and “age ≥18”, as we had in the previously published study. The prior published study captured open studies as of Sep 24, 2013. In this study our lock out date was May 26, 2016. We excluded studies that opened after Sep 25, 2013 and closed before May 26, 2016 (Fig. 1). Basket trials with ≥7 tumors with non-RCC tumor histologies, terminated studies, studies with unknown status and pediatric studies were excluded.

Fig.1

Trial selection.

We extracted the following information: (1) clinical trial phase; (2) recruitment status; (3) stage; (4) treatment setting (surgery/adjuvant/neoadjuvant/metastatic); (5) intervention (surgery/radiation/chemotherapy/targeted therapy/immunotherapy/vaccine combinations); (6) study design (e.g. single arm/combination/parallel study); (7) name of drugs; (8) whether tissue biopsy was required; (9) histology; (10) whether biomarkers were evaluated; (11) type of sample on which biomarker testing was done; (12) randomization status; (13) control group; (14) primary outcome; (15) secondary outcome; (16) number of study sites; (17) study location; (18) study sponsor; (19) target enrollment; (20) date of trial activation and closure.

For our purposes, we defined targeted therapy according to the National Cancer Institute (NCI) definition that includes drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Immunotherapy was defined as a type of biological therapy that uses substances to stimulate or suppress the immune system.

The results were compiled and analyzed independently by the first 3 authors of this report and any questions or discrepancies in data collection or coding were resolved by the last 2 authors as a separate, third party arbiter. We summarized trial characteristics using frequencies and percentages. Statistical analysis was performed to compare data collected in 2016, with previously published data collected in 2013. Fisher’s exact test was used to determine whether significant difference existed between these two groups.

RESULTS

A total of 263 open trials were identified on May 26, 2016, out of which 182 trials were registered after Sep 25, 2013 and 81 trials were registered before Sep 25, 2013. We excluded trials that were closed as of May 26, 2016 (n = 17). After excluding terminated studies (n = 2), studies with 7+ tumors types (n = 50), and non-RCC tumor types (n = 39), non-cancerous conditions (n = 4) and meta-analysis (n = 1), we included 165 trials open as of May 26, 2016-117 trials received after, and 48 trials received before Sep 25, 2013. This compares to the 169 trials selected in the 2013 analysis.

DISCUSSION

While the number of trials and the basic study characteristics in our follow-up survey remained largely unchanged from the 2013 survey, there were several interesting observations that were noted. Most notably, and not unexpectedly, there were more clinical trials in 2016 compared to 2013 using IT alone or in combination with other drugs (24.2% vs 10.7%, p = 0.001), and the use of TT declined (32.9% vs 47.9%, p = 0.005). IT alone was used in 16.4% of current trials, compared to 5.96% in 2013. TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). This reflects the evolving treatment paradigm in patients with metastatic RCC, and other metastatic cancers, in which IT drugs targeting the PD-1 pathway are being explored alone and in combination in various settings to maximize the efficacy of these exciting agents. We predicted this would be the case in our 2013 discussion and the current results confirm, and maybe even exceeded our expectations from that time [5].

We anticipate the focus on IT-based trials to continue to grow. One note of caution that has been expressed in both the medical and lay literature is in regards to the rational consideration of our most valuable resource used in all of these trials—our patients [7, 8]. As more and more IT-based trials come to fruition, less patients are available to populate them, creating a potential investigational deficit that could limit clinical progress. For example, combination of anti-PD1/PDL1 therapy with anti-VEGF antibody was used in 4 trials (nivolumab+bevacizumab, pembrolizumab+ziv-aflibercept and two trials atezolizumab+bevacizumab). Similarly, anti-PD1/PDL1 therapy with VEGFR TKIs were used in at least four trials and pembrolizumab+SBRT was used in two trials (Table 5). Investigators must be cognizant of this imbalance, and we as a community must strive to ensure the focus is on rational and novel combinations, concepts, and designs that may help answer important questions that will lead to better patient outcomes, and not duplicative trials that would only result in the approval of similar, and very expensive drugs. For example, it is encouraging to see other trials studying novel checkpoint inhibitors like anti CSF1R, IL-15 agonist, anti LAG3, anti CD27 and anti TIM03, and other agents like HDAC and glutaminase inhibitors. These agents are not currently used in clinical practice, and they may offer a potentially new option to patients who have exhausted standard frontline options. How trials are approved and funded may well dictate the application of these concepts.

Accordingly, we recorded a statistically significant increase in industry sponsored trials in our 2016 analysis compared to 2013. The reasons for this are likely multifactorial, but may on some level reflect the changing landscape of available funding mechanisms for oncology trials. One hypothesis to explain this would be a decrease in the amount of funding to support oncology research being dispersed by the National Cancer Institute (NCI), which is the predominant source of public funding for clinical oncology trials. However, this appears not to be the case, as publicly available reported expenses published on the NCI website [9] demonstrates slight increases in funding overall on an annual basis between 2013–2016, and this includes when broken down by funding mechanism and when considering a cumulative inflation rate of 3% over that time period. This was not looked at specifically for spending on trials focused on RCC, which may still account for part of the discrepancy. Another potential reason may be related to the increasingly expensive novel immunotherapy agents that are being tested in RCC trials today and as shown have increased in research focus. Also, given the intense competition that is inherent in trying to get similar drugs to market, pharmaceutical companies may be more willing to undertake the expense of a registration trial or large earlier stage trial in order to ensure control for eventual submission to regulatory agencies. This changing paradigm deserves monitoring and if persistent, may be ripe for further research to better determine the underlying reasons. While pharmaceutical-sponsored trials remain a necessity to support the breadth of research still needed for RCC, a dramatic shift of funding to predominantly industry-sponsored trials may have implications for the types of trials performed, favoring established drugs and combinations with existing infrastructure, and marginalizing novel concepts and compounds.

While our 2013 analysis did not capture the categories “combination vs single agent” trials and “parallel” trials, we believe that the necessity to add these designations reflects that more trials are using novel designs. The parallel trials included trials such as the “NivoPlus” study containing several arms with nivolumab combination therapies. This reflects the increasing trend to conduct large scale, early-phase trials that not only explore dose or single agent efficacy, but are designed to perform comparisons with existing standard therapies in an effort to expedite the path to approval. One contemporary example of this in the RCC space might be the trial that led to the approval of the combination of lenvatinib/everolimus for metastatic RCC [10]. This 3 arm, phase II trial compared lenvatinib to everolimus or the combination for patients with metastatic RCC refractory to one TKI. Although it included only about 50 patients per arm, it met its primary endpoint by demonstrating a PFS benefit for the combination compared to everolimus alone leading to FDA approval. This underscores the evolving perspective of the US FDA in how it evaluates drugs for regulatory approval, and encourages trial designs that can simultaneously evaluate multiple treatment modalities or endpoints in a single study. Whether this departure from the long-standing clinical trial dogma ultimately leads to more regulatory approvals and improves patient outcomes remains to be seen.

As multiple trials (ASSURE, S-TRAC, PROTECT) have failed to report an overall survival benefit of adding VEGFR TKIs in the adjuvant setting [11–13], there is a need for more trials in this perioperative space, with the goal of reducing recurrence and increasing survival in early stage kidney cancers post-nephrectomy. Surprisingly the number of trials conducted in the adjuvant/neoadjuvant setting did not differ between the two analyses (9.7% vs 10.6%). Of note, our analysis did not capture two main ongoing clinical trials conducted in the neoadjuvant/adjuvant setting – the PROSPER trial studying perioperative nivolumab and the IMmotion010 trial studying atezolizumab in adjuvant setting in high risk RCC patients.

Additionally, more studies need to be conducted in non-clear cell histologies as these tumors do not respond to the standard treatments approved for ccRCC. The number of trials including non-clear cell histologies did not differ in the two analyses (8.5% vs 10%). Most of these studies included papillary cancers (8 of 14), 1 study included chromophobe histology and 3 studies included all non-clear cell histologies.

Our study is limited by several factors. The accuracy of data reported in ClinicalTrials.gov may not be uniform across studies. As this is a U.S. based registry, a comprehensive database of all RCC trials may not be available. Separate individuals captured data in the 2013 and 2016 analysis, and the interpretation of the definition of individual characteristics may be variable. While the data in our analysis was collected by three individuals and reviewed again by a single individual, human error in data collection is a potential source of inaccuracy. Our study included 48 trials that were also present in the 2013 analysis as these trials opened before September 24, 2013 but were also open in 2016. Additionally, 31 trials that opened after September 24, 2013 were also excluded as they closed before our lock date of May 26, 2016. However, these inclusions and exclusions were made as the goal of our study was to study the landscape of all RCC trials registered as of May 26, 2016. The strength of this study is our ability to compare the spectrum of registered clinical trials across two separate time points.

Overall, our findings reflect the current changing paradigm of systemic treatment in metastatic RCC. While more immunotherapy trials are being developed in this setting, we as a community must be cautious and cognizant to continually design trials that explore new ideas and answer new questions, and not duplicate efforts by repeating trials with similar drugs without a net benefit to the patient community. There is a clear need to develop more of these trials in the adjuvant and neoadjuvant setting to see if incremental benefit can be acquired by trying immunotherapy in patients with early stage RCC. Additionally, more trials need to be conducted specifically in the perioperative space and in patients with non clear-cell histology, as they do not respond well to standard therapies for clear cell RCC.