Abstract
Objectives:
Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In an effort to better align trials, the Definition for the Assessment of Time to event Endpoints in CANcer trials (DATECAN) project published recommendations in 2015 to be used in mRCC clinical trial design. We analyzed mRCC trial criteria to determine if DATECAN’s recommendations were followed.
Materials and Methods:
We compared eligibility criteria across 29 phase 3 mRCC trials conducted between 2003 and 2019. We then evaluated endpoints used in 10 phase 3 trials activated between 2015 and 2019 to determine their compliance with DATECAN’s recommendations.
Results:
Among the 29 trials, performance status, renal function, and disease characteristics differed in terms of requirements and measures used. In terms of endpoints, the 10 trials did not entirely follow DATECAN’s recommendations. In total, 7/10 trials’ primary endpoint was progression-free survival (PFS) as recommended; 4/9 trials used PFS as an endpoint but did not publish their definition of PFS, and the 5 that did, included “death from any cause” instead of DATECAN’s recommendation of “death from kidney cancer.”
Conclusions:
Key eligibility criteria were somewhat inconsistent across the phase 3 mRCC trials studied. Endpoints in the newer trials did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and adoption of recommendations are needed to better harmonize trial design.
Keywords: cancer, kidney, eligibility, endpoints, harmonization
Randomized-controlled clinical trials are considered the “gold standard,” but performing multiple comparative trials is not always practical in a rapidly changing treatment landscape. Therefore, many clinicians rely on meta-analyses and cross-trial comparisons to understand how best to use a new drug or drug combination. Despite their convenience, cross-trial comparisons are not ideal because even trials in the same disease and patient population have different eligibility criteria and endpoints.1
Until more recently, there have been limited efforts to harmonize trial eligibility criteria in metastatic renal cell carcinoma (mRCC), leading to significant heterogeneity across trials in terms of both eligibility and endpoints. Many have also argued for eligibility criteria to be adjusted to better represent the real-world patient population. During trial recruitment, ~25% of patients will screen fail, largely due to not meeting eligiblity criteria.2 These high screen failure rates not only cost time, money, and resources but may also ultimately affect the generalizability of trial results. A recent study by Heng et al3 compared mRCC patients who were and were not trial eligible and treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. The response rate, median progression-free survival (mPFS), and median overall survival were all significantly lower in the trial-ineligible group, suggesting that trial results may not be directly generalizable to trial-ineligible patients. Few studies have analyzed the differences in eligibility criteria between trials and the suitability of specific criteria for the real-world mRCC patient population.
Efforts to improve trial design have been largely concentrated on harmonizing endpoints. In December 2015, Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN)4 published recommendations for time to event endpoints (TEE) in mRCC trials. Expert consensus pinpointed and defined 2 TEEs for mRCC: kidney cancer-specific survival (death from RCC or protocol treatment) and PFS (death from RCC or local, regional, or metastatic progression). Before DATECAN’s TEE guidelines, TEEs varied significantly across trials, and many trials did not clearly define the “starting point” and the “event of interest” for their endpoints.5 DATECAN hoped that its recommendations would become standard practice for future clinical trials, but the preliminary effectiveness and uptake of its guidelines has not previously been assessed.
The primary aim of this study was to examine eligibility criteria across phase 3 mRCC trials. The secondary aim was to assess the effectiveness of DATECAN’s efforts towards trial harmonization by comparing trial endpoints to DATECAN’s endpoint recommendations.
MATERIALS AND METHODS
We reviewed randomized trials assessing chemotherapy, immunotherapy, and targeted therapies for mRCC that included at least 100 participants. We searched ClinicalTrials.gov using the term “metastatic kidney cancer” and the filters: “phase 3 trials,” and “interventional studies.” To assess eligibility criteria across trials, we used trials that started between 2003 and 2019. To assess endpoints, we used trials that started between September 2015 and 2019.
We collected eligibility criteria and endpoints from ClinicalTrials.gov, trial protocols, and published articles from PubMed.
We also reviewed the DATECAN publications to establish endpoints suggested for mRCC trials.
RESULTS
In total, 48 phase 3 trials were reviewed for eligibility criteria, 29 of which were deemed eligible. Of 15 phase 3 trials evaluating endpoints, 10 were eligible (Fig. 1).
FIGURE 1.
Consort diagram of eligible trials.
Eligibility Criteria
Five eligibility criteria were assessed with our methodology. The results are summarized in Table 1.
TABLE 1.
Eligibility Criteria in mRCC Trials (n = 29)
| Trial Identifier Treatments Investigated | PS | Renal Function | Presence of CNS Metastases | Measurable Disease | Progressed on Last Treatment | Investigators |
|---|---|---|---|---|---|---|
| 1st line | ||||||
| ARCC | KPS ≥ 60% | Serum ≤ 1.5×ULN | Not permitted unless treated and stable, no corticosteroids | Required (RECIST 1.0) | NA | Hudes et al6 |
| NCT00065468 | ||||||
| Temsirolimus vs. Temsirolimus + IFN-α vs. IFN-α | ||||||
| CALGB 90206 | KPS ≥ 70% | Serum ≤ 1.5×ULN | Not permitted | Not required | NA | Rini et al7 |
| NCT00072046 | ||||||
| Bevacizumab + IFN-α vs. IFN-α | ||||||
| Sunitinib vs. IFN-α | ECOG 0–1 | NI | Not permitted | Required (RECIST 1.0) | NA | Motzer et al8 |
| NCT00083889 | ||||||
| Sunitinib vs. IFN-α−2a | ||||||
| COMPARZ | KPS ≥ 70% | CrCl ≥ 30mL/min | Not permitted unless treated and stable | Required (RECIST 1.0, CT/MRI) | NA | Motzer et al9 |
| NCT00720941 | ||||||
| Pazopanib vs. Sunitinib | ||||||
| INTORACT | KPS ≥ 70% | Serum ≤ 1.5×ULN | Not permitted | Required (RECIST 1.0, CT/MRI) | NA | Rini et al10 |
| NCT00631371 | ||||||
| Bevacizumab + Temsirolimus vs. IFN-α | ||||||
| SWITCH | ECOG 0–1 | Serum ≤ 2.0×ULN | Not permitted unless asymptomatic or stable | Required (RECIST 1.0, CT/MRI) | NA | Eichelberg et al11 |
| NCT00732914 | ||||||
| Sunitinib-sorafenib vs. Sorafenib-sunitinib | ||||||
| Cross-J-RCC | ECOG 0–1 | Serum ≤ 1.5×ULN | Not permitted unless asymptomatic, no corticosteroids | Required (RECIST 1.1) | NA | Tomita et al12 |
| NCT01481870 | ||||||
| Sorafenib-sunitinib vs. Sunitinib-sorafenib | ||||||
| CheckMate 214 | KPS ≥ 70% | Serum ≤ 1.5×ULN CrCl ≥ 40 mL/min | Not permitted | Required (RECIST 1.1) | NA | Motzer et al13 |
| NCT02231749 | ||||||
| Nivolumab + Ipilimumab vs. Sunitinib | ||||||
| SWITCH-II | KPS ≥ 70% | Serum ≤ 2.0×ULN | Not permitted unless asymptomatic or stable | Required (RECIST 1.1, CT/MRI) | NA | Retz et al14 |
| NCT01613846 | ||||||
| Sorafenib-pazopanib vs. Pazopanib-sorafenib | ||||||
| CheckMate 9ER | NI | NI | Not permitted unless treated and stable | NI | NA | Choueiri et al15 |
| NCT03141177 | ||||||
| Nivolumab + Cabozantinib vs. Sunitinib | ||||||
| KEYNOTE-679 | KPS ≥ 70% | Serum ≤ 1.5×ULN CrCl ≥ 30 mL/min | Not permitted unless inactive | Required (RECIST 1.1) | NA | Jones et al16 |
| NCT03260894 | ||||||
| Pembrolizumab + Epacadostat vs. Sunitinib or Pazopanib | ||||||
| CLEAR | KPS ≥ 70% | NI | Not permitted unless treated and stable, no corticosteroids | Required (RECIST 1.1) | NA | Grunwald et al17 |
| NCT02811861 | ||||||
| Lenvatinib + Everolimus vs. Lenvatinib + Pembrolizumab vs. Sunitinib | ||||||
| KEYNOTE-426 | KPS ≥ 70% | NI | Not permitted unless inactive | Required (RECIST 1.1) | NA | Rini et al18 |
| NCT02853331 | ||||||
| Pembrolizumab + Axitinib vs. Sunitinib | ||||||
| JAVELIN Renal 101 | ECOG 0–1 | CrCl ≥ 50 mL/min | Not permitted unless inactive | Required (RECIST 1.1) | NA | Motzer et al19 |
| NCT02684006 | ||||||
| Avelumab + Axitinib vs. Sunitinib | ||||||
| Bempegaldesleukin + Nivolumab | KPS ≥ 70% | NI | Not permitted unless treated and stable | Required (RECIST 1.1) | NA | Tannir et al20 |
| NCT03729245 | ||||||
| Bempegaldesleukin + Nivolumab vs. Sunitinib or Cabozantinib | ||||||
| COSMIC-313 | KPS ≥ 70% | NI | Not permitted unless inactive | Required (RECIST 1.1) | NA | Bjarnason et al21 |
| NCT03937219 | ||||||
| Cabozantinib + Nivolumab + Ipilimumab vs. Nivolumab + Ipilimumab | ||||||
| PDIGREE | KPS ≥ 70% | CrCl ≥ 30 mL/min | Not permitted unless asymptomatic and stable | Required (RECIST 1.1) | NA | Zhang et al22 |
| NCT03793166 | ||||||
| Nivolumab + Ipilimumab followed by Nivolumab alone vs. followed by Nivolumab + Cabozantinib | ||||||
| 1st or 2nd lines | ||||||
| VEG105192 | ECOG 0–1 | CrCl ≥ 30 mL/min | Not permitted | Required (RECIST 1.0) | NI | Sternberg et al23 |
| NCT00334282 | ||||||
| Pazopanib vs. Placebo | ||||||
| TIVO-1 | ECOG 0–1 | Serum ≤ 2.0×ULN | Not permitted unless treated and stable | Required (RECIST 1.0) | NI | Motzer et al24 |
| NCT01030783 | ||||||
| Tivozanib vs. Sorafenib | ||||||
| Axitinib | ECOG 0–1 | NI | Not permitted | Required (RECIST 1.0) | Radiologic PD (RECIST 1.0) | Hutson et al25 |
| NCT00920816 | ||||||
| Axitinib vs. Sorafenib | ||||||
| RENAVIV | ECOG 0–1 | NI | Not permitted unless treated and stable | Required (RECIST 1.1) | Radiologic PD (RECIST 1.0) | Aggarwal et al26 |
| NCT03592472 | ||||||
| Pazopanib ± Abexinostat | ||||||
| 2nd line | ||||||
| TARGET | ECOG 0–1 | NI | Not permitted | Required (RECIST 1.0, CT/MRI) | NI | Escudier et al27 |
| NCT00073307 | ||||||
| Sorafenib vs. Placebo | ||||||
| AXIS | ECOG 0–1 | NI | Not permitted | Required (RECIST 1.0) | Radiologic PD (RECIST 1.0) | Rini et al28 |
| NCT00678392 | ||||||
| Axitinib vs. Sorafenib | ||||||
| INTORSECT | ECOG 0–1 | Serum ≤ 2.0xULN | Not permitted | Required (RECIST 1.0) | Radiologic PD (RECIST 1.0) or clinical PD | Hutson et al29 |
| NCT00474786 | ||||||
| Sorafenib vs. Temsirolimus | ||||||
| ≥2nd line | ||||||
| RECORD-1 | KPS ≥ 70% | NI | Not permitted unless treated and stable, no corticosteroids | Required (RECIST 1.0, physical examination/CT/MRI) | Progressed on Sunitinib or Sorafenib w/in 6 mo | Motzer et al30 |
| NCT00410124 | ||||||
| Everolimus vs. Placebo | ||||||
| GOLD RCC | KPS ≥ 70% | Serum ≤ 1.5×ULN | Not permitted | Required (RECIST 1.1, CT/MRI) | Radiologic PD w/in 6 mo of last therapy | Motzer et al31 |
| NCT01223027 | ||||||
| Dovitinib vs. Sorafenib | ||||||
| METEOR | KPS ≥ 70% | Serum ≤ 2.0×ULN CrCl ≥ 30 mL/min | Not permitted unless treated and stable | Required (RECIST 1.1) | Progressed on/after VEGFR tyrosine kinase inhibitor w/in 6 mo | Choueiri et al32 |
| NCT01865747 | ||||||
| Cabozantinib vs. Everolimus | ||||||
| CheckMate 025 | KPS ≥70% | Serum ≤ 1.5×ULN CrCl ≥ 40mL/min | Not permitted | Required (RECIST 1.1) | Progressed on/after last treatment w/in 6 mo | Motzer et al33 |
| NCT01668784 | ||||||
| Nivolumab vs. Everolimus | ||||||
| TIVO- | ECOG 0–1 | Serum ≤ 1.5×ULN CrCl ≥40mL/min | Not permitted unless treated and stable | Required (RECIST 1.1) | Progressed on/after 2 or 3 systemic regimens, one of which includes a VEGFR TKI | Rini et al34 |
| NCT02627963 | ||||||
| 3Tivozanib vs. Sorafenib | ||||||
CNS indicates central nervous system; CrCl, creatinine clearance; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; IFN-α, interferons α; KPS, Karnofsky Performance Score; mRCC, metastatic renal cell carcinoma; MRI, magnetic resonance imaging; NA, not applicable; NI, not indicated; PD, progressive disease; PS, performance status; RECIST, response evaluation criteria in solid tumors; ULN, upper limit of normal; VEGFR TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitor.
Performance Status (PS)
There is variation between trials using either Karnofsky Performance Status (KPS) (16/29, 57%) or Eastern Cooperative Oncology Group (ECOG) Performance Status (12/29, 43%) (Fig. 2A). Despite the difference in the mode of measurement, PS requirements were relatively consistent, within each line of treatment and across all treatments, with most trials (27/28, 96%) requiring roughly equivalent ECOG PS 0–1 and/or KPS ≥ 70%.
FIGURE 2.
Comparison of Key Eligibility Criteria Used in mRCC Trials. A. Performance status. B. Renal function. C. Brain metastases. D. Measurable disease. E. Method of disease assessment. F. Progression required for trial entry. CrCl indicates creatinine clearance; CT, computed tomography; ECOG, European Cooperative Oncology Group; KPS, Karnofsky Performance Score; MRI, magnetic resonance imaging; RECIST, response evaluation criteria in solid tumors.
Renal Function
Discrepancies in how renal function was measured and cutoffs were observed across all lines of treatment. In total, 38% (11/29) of trials did not publish their renal function requirements. Of those that published, 50% (9/18) used only serum creatinine, 22% (4/18) used only calculated creatinine clearance, and 28% (5/18) used both (Fig. 2B). Both the required serum creatinine and creatinine clearance values varied across trials.
Presence of Central Nervous System (CNS) Metastases
In total, 38% (11/29) of trials excluded patients with CNS metastases, whereas 62% (18/29) permitted CNS metastases as long as they were treated and stable, inactive, and/or asymptomatic (Fig. 2C).
Measurable Disease According to Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines
All but 1 trial (CALGB 90206) indicated that eligible patients must have measurable disease according to RECIST criteria (Fig. 2D), with variations again seen in the imaging modalities being used to assess disease.
Disease Progression
In total, 75% (9/12) of trials investigating ≥ second-line treatments indicated that eligible patients must have experienced disease progression, with variation in the definition of “progression” (Fig. 2F).
Endpoints
In total, 70% (7/10) of newer trials (after 2015) used the recommended PFS as their primary endpoint; of the 3 trials that did not, 2 included PFS as a secondary endpoint, and 1 did not include PFS as an endpoint at all. Only 6/9 trials using PFS as an endpoint published definitions for PFS, and their definitions did not align with DATECAN’s recommended definition. All trials included “local, regional, or metastatic progression” as a progression event, following DATECAN, but they differed by including “death due to any cause” as a progression event, whereas DATECAN’s definition limits it to “death due to RCC.”
In total, 23/29 trials used Memorial Sloan-Kettering Cancer Center (MSKCC) criteria to stratify patients into favorable, intermediate, and poor risk subgroups for data analysis. Five trials used the International Metastatic RCC Database Consortium (IMDC) risk score for stratification, and 1 trial did not publish its stratification methods.
DISCUSSION
Key eligibility criteria and endpoint definitions were somewhat inconsistent across the phase 3 mRCC trials we evaluated, suggesting a need for more consistency in trial design. Developing a uniform set of eligiblity criteria for trials studying similar disease states and treatments and ensuring these criteria are applicable to the target population will be important as new treatments continue to be evaluated developed in mRCC.
The ECOG PS and Karnofsky PS are two of the most widely used methods to assess functional status. We found variablity in which scales were being used. ECOG has fewer categories, while the KPS (which is used in both MSKCC and IMDC criteria) has more, but generally the correlation between the two is quite good. One approach to consider in the context of clinical trials is to provide both scales so physicans can use the scale with which they are the most comfortable.
Another key criterion that differed across trials was renal function. Unlike PS, it is difficult to convert between serum creatinine and creatinine clearance without patient specifics, such as age and weight. Currently, national renal organizations recommend using estimated glomerular filtration rate from the Cockcroft-Gault equation or the Modification of Diet in Renal Disease Study equation. An estimated glomerular filtration rate more accurately reflects physiological status of patients compared with a static creatinine measurement. It is a universal measurement independent of US or SI units, and would be preferable for consistency across clinical trials. As well as differing in mode of measurement, trials differed in renal function cutoffs. Differences in renal function may affect trial results; for example, patients with chronic renal dysfunction may have shorter survival.35 Thus, trials requiring better renal function may generate better results. In total, 3/4 trials requiring a higher creatinine clearance were newer immunotherapy trials, possibly because of concern that immunotherapies may cause immune-mediated renal injury.36 However, we now know that renal side effects are not that common,36 so there may be an argument for decreasing the renal function cutoffs for immunotherapy trials. Some also suggest loosening or omiting renal function criteria altogether from RCC trials if study agents are not renally metabolized, thus expanding access to clinical trials for RCC patients.35
The 29 mRCC trials also differed in whether or not they considered patients with CNS metastases as trial eligible. Over one third of the trials disallowed CNS metastases (Fig. 2C). When comparing older and newer trials, 70% (7/10) of trials started before 2009 excluded patients with CNS metastases, whereas only 20% (4/20) of trials started in 2009 or later excluded, CNS metastases. Interestingly it has been shown that patients with stable CNS metastases perform similarly to those without; and it is rare for most treatments to cause CNS side effects.37 Furthermore, CNS metastases is one of the most common reasons for cancer trial ineligibility.3 Because, ~3.5% to 17% of RCC patients develop CNS metastases, and if treated locally, do well with systemic therapy, they should ideally not be excluded from trials.38
We also observed that all but 1 trial required patients to have measurable disease according to different versions of the RECIST criteria and with different measurement techniques (Figs. 2D, E). Measurable disease is required for trials to evaluate PFS, but the difference in criteria between RECIST 1.0 and 1.1 is that 1.1 accepts patients with smaller lesions and possibly lower cancer burden. This makes it harder to compare older and newer trials because the latter accepts patients with smaller lesions and likely lower cancer burden.39,40 However, these criteria are updated over time, so there will always be such variability when comparing older and newer trials.
The different measurement techniques between trials also presents an obstacle to trial harmonization and cross-trial comparisons, as a physical examination, computed tomography (CT) and magnetic resonance imaging (MRI) all present different levels of specificity, sensitivity, and accuracy.41 Both RECIST 1.0 and 1.1 recommend CT as the preferred measurement technique.39,40 However, over half of the trials did not specify a measurement technique, and the rest required a mix of measurement by clinical caliper, CT and MRI, possibly leading to trials defining “measurable disease” slightly differently and threfore possibly recruiting slightly different patient populations.
Trials’ criteria for disease progression shared similar inconsistencies as criteria for measurable disease, with some using RECIST criteria, while others accepting clinical progression, and many not specifying type of progression (Fig. 2F). Mandating patients to have progressed radiologically on previous treatment presents an obstacle for mRCC patients, as sometimes, there is a gap between radiologic progression and clinical progression. Radiologic imaging can show minor increases in lesion size such that the patient is not considered to have “progressive disease” by RECIST criteria, but conversely, the patient can experience a significant increase in cancer symptoms, thus denoting clinical progression. Off-trial, those experiencing symptoms without clear radiologic progression would most likely switch to a new treatment.42 However, their trial options would be limited, as many trials require radiologic progression. Loosening trial criteria to accept patients who progress clinically on their previous treatment, such as what the INTORSECT trial has done,29 will likely provide more trial options for mRCC patients and increase trial accrual. This is the case in other cancers. For example, patients entering trials of advanced prostate cancer may have progressed radiologically, clinically, or by serum prostate specific antigen criteria (PSA). Patients who progress by PSA criteria alone can be often stratified for primary endpoint analyses.
Beyond the 5-key eligibility criteria that were analyzed in this study, other eligibility criteria, such as bone marrow function, liver function, and absence of other clinically serious medical conditions, were largely consistent across trials. Bloodwork parameters, such as hemoglobin ≥ 9.0 g/dL, neutrophils ≥ 1500/mm3, platelets ≥ 100,000/μL were similar, as was exclusion of patients with active autoimmune disease, with immunodeficiencies, or on systemic steroids, for immunotherapy trials due to the risk of immune-medidated adverse events.
As well as harmonizing eligibility criteria, endpoints must also be harmonized. None of the new trials started after September 2015 completely followed DATECAN’s recommendations for defining PFS. DATECAN’s definition of PFS included 2 events as follows: (1) “death due to RCC”; (2) “local, regional, or metastatic progression.”4 All trials followed event 2, but for event 1, all used the event “death due to any cause” instead of “death due to RCC” (Table 2). This failure to apply DATECAN’s recommendations may be due partly to the difficulty in ascertaining the exact cause of death, especially in older patients who are increasingly likely to die from conditions other than cancer or with nonspecific deterioration in health.43 As the average age of patients diagnosed with kidney cancer is 64,38 the reasons for their deaths may be challenging and both time and resource consuming to determine. For example, pulmonary embolism (PE) is a common manifestation of RCC, so if a patient dies of a PE, would a physician record it as “death due to PE” or “death due to RCC?”
TABLE 2.
Endpoints in New mRCC Trials (n = 10)
| DATECAN Definition: PFS = Death From RCC or Local, Regional, or Metastatic Progression | ||
|---|---|---|
| Trial Definition of PFS | Alignment With DATECAN | |
| JAVELIN Renal 101 NCT02684006 | PD (RECIST 1.1) or death due to any cause | No—definition includes “any cause” instead of DATECAN’s RCC or PD only |
| CLEAR NCT02811861 | No published definition | NE |
| KEYNOTE-426 NCT02853331 | PD (RECIST 1.1) or death due to any cause | No—definition includes “any cause” instead of DATECAN’s RCC or PD only |
| TIVO-3 NCT02627963 | PD (RECIST 1.1) or death due to any cause | No—definition includes “any cause” instead of DATECAN’s RCC or PD only |
| Bempegaldesleukin + Nivolumab vs. TKI NCT03729245 | PFS as secondary endpoint No published definition | No—PFS as secondary endpoint instead of primary endpoint |
| RENAVIV NCT03592472 | PD (RECIST 1.1) or death due to any cause | No—definition includes “any cause” instead of DATECAN’s RCC or PD only |
| CheckMate 9ER NCT03141177 | No published definition | NE |
| COSMIC-313 NCT03937219 | PD (RECIST 1.1) or death due to any cause | No—definition includes “any cause” instead of DATECAN’s RCC or PD only |
| KEYNOTE-679 NCT03260894 | PFS not included as an endpoint | NE |
| PDIGREE NCT03793166 | PFS as secondary endpoint PD (RECIST 1.1) or death due to any cause | No—PFS as secondary endpoint instead of primary endpoint Definition includes “any cause” instead of DATECAN’s RCC or PD only |
DATECAN indicates Definition for the Assessment of Time-to-event Endpoints in CANcer trials; mRCC, metastatic renal cell carcinoma; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; RECIST, response evaluation criteria in solid tumors.
Nevertheless, consistent endpoint and eligibility criteria are critical to interpreting study results. We found that 28/29 trials published the criteria they used to stratify patients into prognostic subgroups for analysis, with 23 trials using MSKCC criteria and 5 newer trials (CheckMate 9ER, COSMIC-313, KEYNOTE-679, PDIGREE, and TIVO-3) using the IMDC risk score. When analyzing trial results using MSKCC subgroups, the older trials of angiogenesis inhibitors showed less differences CNS metastases between MSKCC subgroups, whereas the newer immunotherapy trials revealed that the immunotherapy treatments may be more efficacious in the intermediate/poor risk subgroups.13 Because of this difference in efficacy between MSKCC subgroups in immunotherapy trials, studies with higher proportions of intermediate/poor risk patients may generate better results; however, because studies stratify and report their population composition consistently, readers can take that into account when comparing results across trials. In the more recent trials of immunotherapy plus angiogenesis inhibitors, the impact of MSKCC subgroups may be slightly less given that both the KEYNOTE 426 trial and the JAVELIN Renal 101 trial no difference in outcomes according to the MSKCC subgroups.18,19 Regardless, adhering to consistent patient stratification and reporting will continue to be integral to facilitating interpretation of study results.
As we look ahead, ensuring harmonization across trials in both trial eligibility criteria and key endpoints may help to significantly expedite drug development and our fundamental understanding of this disease.
Footnotes
The authors declare no conflicts of interest.
REFERENCES
- 1.Lee CK, Lord SJ, Stockler MR, et al. Historical cross-trial comparisons for competing treatments in advanced breast cancer—an empirical analysis of bias. Eur J Cancer. 2010;46: 541–548. [DOI] [PubMed] [Google Scholar]
- 2.Wong SE, North SA, Sweeney CJ, et al. Screen failure rates in contemporary randomized clinical phase I/III therapeutic trials in genitourinary malignancies. Clin Genitourin Cancer. 2017;16: e233–e242. [DOI] [PubMed] [Google Scholar]
- 3.Heng DYC, Choueiri TK, Rini BI, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol. 2014;25:149–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kramar A, Negrier S, Sylvester R, et al. Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project. Ann Oncol. 2015;26: 2392–2398. [DOI] [PubMed] [Google Scholar]
- 5.Mathoulin-Pelissier S, Gourgou-Bourgade S, Bonnetain F, et al. Survival end point reporting in randomized cancer clinical trials: a review of major journals. J Clin Oncol. 2008;26:3721–3726. [DOI] [PubMed] [Google Scholar]
- 6.Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281. [DOI] [PubMed] [Google Scholar]
- 7.Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa mono-therapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28:2137–2143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–124. [DOI] [PubMed] [Google Scholar]
- 9.Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–731. [DOI] [PubMed] [Google Scholar]
- 10.Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32:752–759. [DOI] [PubMed] [Google Scholar]
- 11.Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: a randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer. Eur Urol. 2015;68:837–847. [DOI] [PubMed] [Google Scholar]
- 12.Tomita Y, Naito S, Sassa N, et al. Sunitinib versus sorafenib as first-line therapy followed by sorafenib and sunitinib for patients with metastatic renal cell carcinoma (RCC) with clear cell histology: a multicenter randomized trial, CROSS-J-RCC. J Clin Oncol. 2017;35:469.28052707 [Google Scholar]
- 13.Motzer RJ, Tannir NM, Mcdermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–1290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Retz M, Bedke J, Bögemann M, et al. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019;107:37–45. [DOI] [PubMed] [Google Scholar]
- 15.Choueiri TK, Apolo AB, Powles T, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36(suppl): TPS4598. [Google Scholar]
- 16.US National Library of Medicine. Pembrolizumab (MK-3475) plus epacadostat vs standard of care in mRCC (KEYNOTE-679/ECHO-302) ClinicalTrialsgov. Bethesda, MD: U.S. National Library of Medicine; 2019. [Google Scholar]
- 17.Grünwald V, Powles T, Choueiri TK, et al. Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. Future Oncol. 2019;15:929–941. [DOI] [PubMed] [Google Scholar]
- 18.Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–1127. [DOI] [PubMed] [Google Scholar]
- 19.Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–1115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Tannir NM, Agarwal N, Pal SK, et al. A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator’s choice) in patients with previously untreated advanced renal cell carcinoma. J Clin Oncol. 2019;37(suppl):TPS4595. [Google Scholar]
- 21.US National Library of Medicine. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313) ClinicalTrialsgov. Bethesda, MD: U.S. National Library of Medicine; 2019. [Google Scholar]
- 22.Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: An adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2019;37(suppl):TPS4596. [Google Scholar]
- 23.Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomized, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;29:1287–1296. [DOI] [PubMed] [Google Scholar]
- 24.Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31:3791–3799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol. 2013;14:1287–1294. [DOI] [PubMed] [Google Scholar]
- 26.Aggarwal RR, Thomas S, Hauke RJ, et al. RENAVIV: a randomized phase III, double-bline, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma. J Clin Oncol. 2019;37 (suppl):TPS681. [Google Scholar]
- 27.Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134. [DOI] [PubMed] [Google Scholar]
- 28.Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931–1939. [DOI] [PubMed] [Google Scholar]
- 29.Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:760–767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet. 2008;372:449–456. [DOI] [PubMed] [Google Scholar]
- 31.Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomized phase 3 trial. Lancet Oncol. 2014;15:286–296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373:1814–1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–1813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2019;21:95–104. [DOI] [PubMed] [Google Scholar]
- 35.Agrawal S, Haas NB, Bagheri M, et al. Eligibility and radiologic assessment for adjuvant clinical trials in kidney cancer. JAMA Oncol. 2019;6:133–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Izzedine H, Mateus C, Boutros C, et al. Renal effects of immune checkpoint inhibitors. Nephrol Dial Transplant. 2017;32: 936–942. [DOI] [PubMed] [Google Scholar]
- 37.Zhang Q, Zhang X, Yan H, et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016; 7:648–654. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Bassanelli M, Viterbo A, Roberto M, et al. Multimodality treatment of brain metastases from renal cell carcinoma in the era of targeted therapy. Ther Adv Med Oncol. 2016;8:450–459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–216. [DOI] [PubMed] [Google Scholar]
- 40.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. [DOI] [PubMed] [Google Scholar]
- 41.Reuther G, Mutschler W. Detection of local recurrent disease in musculoskeletal tumors: magnetic resonance imaging versus computed tomography. Skeletal Radiol. 1990;19:85–90. [DOI] [PubMed] [Google Scholar]
- 42.Figlin RA and Tannir NM Defining disease progression in renal cell carcinoma. 2016. Available at: www.onclive.com/peer-exchange-archive/advanced-renal-cell-carcinoma/renal-cell-carcinoma-progression. Accessed July 30, 2019.
- 43.Lund JL, Harlan LC, Yabroff KR, et al. Should cause of death from the death certificate be used to examine cancer-specific survival? A study of patients with distant stage disease. Cancer Invest. 2010;28: 758–764. [DOI] [PMC free article] [PubMed] [Google Scholar]