SUMMARY
Background:
Patients undergoing resection of renal-cell carcinoma are at risk for disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered after surgery.
Methods:
In this double-blind, phase III trial, we enrolled patients at 398 centres in the United States. After nephrectomy, patients with an intermediate-high or very-high risk for recurrence were randomized to receive oral everolimus 10 mg daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival in the intention-to-treat population; secondary endpoints included overall survival and safety. This trial is registered with ClinicalTrials.gov, number NCT01120249.
Findings:
Between April 1, 2011 and September 15, 2016, a total of 775 patients were randomly assigned to receive everolimus and 770 to receive placebo. With a median follow-up of 76 months, recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% vs. 63%; stratified logrank P=0·050, stratified hazard ratio [HR], 0·85; 95% CI, 0·72 to 1·00; P= 0·051) but did not meet the pre-specified p-value for statistical significance of 0·044 Recurrence-free survival was longer with everolimus than placebo in the very-high risk group (HR, 0·79; 95% CI, 0·65 to 0·97; P= 0·022) but not in the intermediate-high risk group (HR, 0·99; 95% CI 0·73 to 1·35; P=0·96). Grade 3 or higher adverse events occurred in 46% of patients who received everolimus and 11% who received placebo.
Interpretation:
Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal-cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal-cell carcinoma after surgery.
INTRODUCTION
Recurrence rates after surgical resection for clinically localized renal-cell carcinoma (RCC) range from 2% to 40% at five years. 1 Recurrences after curative-attempt radical or partial nephrectomy most often manifest as distant metastatic disease. Despite significant advances in treating metastatic RCC, the vast majority of advanced RCC patients will eventually progress on therapy. Prevention of metastatic disease remains a priority in the curative setting of early stage RCC.
Adjuvant systemic therapy after cancer surgery is an established strategy that improves outcome for a number of malignancies including breast, colon, and lung cancer. The availability of an effective medical therapy is a prerequisite for adjuvant systemic treatment; until the early 2000’s, broadly effective systemic treatments for RCC were lacking and development of adjuvant treatments lagged behind that of other cancers. Subsequent to the advent of effective tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for metastatic RCC, numerous adjuvant trials were conducted with these agents. 2–10 Despite effectiveness in the metastatic setting, only one of five reported trials of TKI therapy and one of four reported trials of immunotherapy have reported a statistically significant, albeit modest, disease-free survival benefit when administered as adjuvant therapy. 2,3
Everolimus is a rapamycin analogue that is an effective inhibitor of the mTORC1 complex, an intracellular target that has many functions including coordination of cellular growth and proliferation relevant to RCC biology. Everolimus was approved for use in metastatic RCC in 2009 based on a placebo-controlled trial that demonstrated improved progression-free survival in the second-line setting. 11
Given the activity of everolimus in advanced RCC and its distinct mechanism of action directed towards the tumour cell itself rather than the tumour microenvironment, we hypothesized that adjuvant treatment may reduce disease recurrence after nephrectomy. We performed EVEREST, a randomized, placebo-controlled trial of everolimus after surgical resection, to our knowledge the first and only phase III adjuvant trial of a mammalian target of rapamycin (mTOR) inhibitor in renal carcinoma.
METHODS
Study design and participants
This phase III, double-blind, placebo-controlled trial was designed by investigators within the Genitourinary Committee of SWOG Cancer Research Network, an NCI-funded cooperative group and member of the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN). Patients were enrolled at 398 centres in the United States through the NCTN. Eligible patients were 18 years of age or older and had undergone a full surgical resection with negative margins (radical or partial nephrectomy) of RCC within 84 days prior to planned start of study drug. Histologic confirmation of either clear cell or non-clear cell RCC was required (collecting duct or medullary carcinomas excluded). Patients must have been considered either intermediate-high (no nodal metastases and tumour stage 1b with grade 3 or 4, tumour stage 2 with any grade, or tumour stage 3a with grade 1 or 2) or very-high risk (tumour stage 3a with grade 3 or 4, tumour stage 3b, 3c, or 4 with any grade, or nodal metastases with any tumour stage and any grade) for recurrence. These risk categories represented a modification of the UCLA Integrated Staging System and were the same categories used in ECOG’s ASSURE trial of adjuvant sunitinib, sorafenib or placebo. 4,12 Grade and stage were determined by the local site and no central pathology review was performed. Additional eligibility included absence of residual or metastatic disease on cross-sectional imaging, Zubrod performance status of 0 or 1, and no prior therapy except surgery for RCC. Exclusion criteria included chronic use of corticosteroids or other immunosuppressive agents, cirrhosis or severe hepatic impairment, or uncontrolled hyperlipidaemia, diabetes mellitus, or pulmonary disease. The protocol was approved by the institutional review boards of all participating institutions and by the NCI Central Institutional Review Board after its establishment. All patients provided written informed consent in accordance with institutional and federal guidelines.
Randomisation and masking
Patients were randomised 1:1 to receive either everolimus or placebo using a dynamic balancing algorithm with stratification based on risk group (intermediate-high vs. very-high), histology (clear cell vs. non-clear cell) and performance status (0 vs. 1). Randomisation procedures were conducted by the SWOG Statistics and Data Management Centre and patients were randomly assigned upon study registration through the NCI OPEN web-based application.
Procedures
Everolimus 10 mg orally once daily or matching placebo was administered for 54 weeks in a double-blind fashion. Dose interruptions and dose reductions for toxicity were permitted as stipulated in the protocol. Criteria for early removal from treatment included disease recurrence or symptomatic deterioration, unacceptable toxicity, delay in protocol treatment for greater than 28 days, or patient treatment refusal and/or withdrawal of consent. To monitor for recurrence, patients underwent physical exam and scans of the chest, abdomen, and pelvis every 18 weeks for the first year, every 6 months for two years, and then annually until recurrence, death, or a maximum of 10 years after randomization.
SWOG’s Data and Safety Monitoring Committee (DSMC) oversaw the conduct of the study and was responsible for making recommendations regarding termination and/or early reporting of the study. 13 The members of the committee received confidential reports and met every 6 months.
Outcomes
The primary endpoint was recurrence-free survival, defined as the time from randomization to first documentation of renal-cell recurrence or death due to any cause. Recurrence was based on positive biopsy and/or radiographic findings as defined in the protocol for individual organ sites. Once documentation of recurrence was received at the SWOG Statistics and Data Management Centre, the patient’s treatment assignment could be unblinded to aid in subsequent treatment decision-making. Secondary endpoints included overall survival and safety as assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Additional objectives were to bank tissue and biologic specimens for future study of molecular biomarkers and to bank blood to study the relationship between steady state trough levels of everolimus and relevant side effects.
Statistical Analysis
We determined that a sample size of 1170 patients would provide 85% power to detect a 22% reduction in the hazard rate of recurrence-free survival with everolimus compared to placebo, based on the expectation that half of patients would be each enrolled in the intermediate-high and very-high risk groups and that 15% of patients would stop study treatment within the first 3 months. This would correspond to an improvement in the median recurrence-free survival from 4·9 years in the placebo group to 6·3 years in the everolimus group if the distributions were exponential. In July 2015, the statistical plan was amended, in consultation with the DSMC and approved by the NCI, to account for a higher-than-anticipated rate of early study treatment discontinuation. In order to achieve a sample size that would be feasible to accrue in a reasonable amount of time, the statistical power was reduced from 85% to 80% to detect an 18% reduction in the hazard rate of recurrence-free survival with a total sample size of 1464 eligible patients, corresponding to an improvement in median recurrence-free survival from 4·9 to 6·0 years. The study specified a stratified log rank test with a one-sided alpha level of 2·5%. Four interim analyses were to be conducted when 30%, 50%, 70%, and 90% of recurrence-free survival events had occurred in the placebo arm. Evidence suggesting early termination of the trial would be if the alternative hypothesis of improvement in recurrence-free survival in the everolimus arm was rejected at the 0·2% level, and the null hypothesis of no difference in recurrence-free survival would also be tested at the one-sided level of 0·1%. If the decision was made to continue the study to completion, the final analysis would be conducted after 804 total events, assuming the alternative hypothesis, had occurred across both arms using a stratified, one-sided log rank test with an alpha level of 2·2% (two-sided 4·4%) to account for interim testing. A stratified proportional hazards (PH) model, accounting for the three stratification factors, was used to estimate the hazard ratio and confidence interval for both recurrence-free survival and overall survival. No adjustment was made to the alpha level for overall survival assessment or subset analyses. Subset analyses based on the three stratification factors were prespecified. For the recurrence-free survival sensitivity analysis, we censored patients without an event at the date of their last disease assessment, rather than their last contact date because frequency of disease assessment in later years became less frequent. HR results of subset analyses are presented for descriptive purposes using the proportional hazards model without stratification. The subset by treatment interaction p-values are from the residual chi-square in a PH model with only subset and treatment indicators and their interaction in the model. Methods of Kaplan and Meier were used to estimate recurrence-free survival and overall survival rates at 5-years post-randomization for recurrence-free survival and overall survival.
By December 2020, 9·5 years after study activation, three of the prespecified interim analyses had been conducted, but the number of new recurrence-free survival events was dramatically slowing, making it unlikely that we would reach the targeted number of events even with ten years of follow-up. Therefore, the statistical analysis plan was modified to conduct the fourth and final interim analysis in March 2021 regardless of the percent of expected information observed with a change in testing futility from the one-sided value of 0·1% to 2·5%. If the decision was made to continue the study, the final analysis was to be conducted in March 2022 even if the specified 804 total events had not yet occurred. This analysis plan was developed by 2 independent biostatisticians with no knowledge of or access to the study endpoint data and was approved by the DSMC and the NCI.
Although this trial was designed as a one-sided primary hypothesis, we report all p-values as two-sided for ease of interpretation. Assessment of the proportional hazards assumption was evaluated with a Kolmogorov-type supremum test that was computed on 1,000 simulated patterns (SAS PHREG procedure, version 9·4). This trial is registered with ClinicalTrials.gov, number NCT01120249.
Role of the Funding Source
The funders of this study did not have a role in its design, data collection, analysis, interpretation, or report writing, nor in the decision to submit the paper for publication. The funders did receive a copy of the final study manuscript for review.
RESULTS
Between April 1, 2011 and September 15, 2016, a total of 1545 patients were randomized, 775 to everolimus and 770 to placebo (Figure 1). 1499 patients were found to be eligible (755 everolimus and 744 placebo) and included in the intention-to-treat efficacy analysis. Of eligible patients who were assigned everolimus, 47% (355/755) discontinued treatment prior to the prescribed 54 weeks due to adverse events, refusal or other reasons unrelated to disease recurrence compared with 17% (124/744) of those assigned to placebo (Figure 1). Thirty-seven percent of patients who received everolimus underwent dose reductions as compared with 7% of patients who received placebo. The median time on study treatment was 9·3 months in the everolimus group and 12·6 months in the placebo group. Three patients (2 everolimus, 1 placebo) were unblinded to treatment assignment for emergency purposes prior to documentation of disease recurrence and 262 patients (92 everolimus, 170 placebo) were unblinded for treatment-decision making purposes after verification of disease-recurrence.
Figure 1.
Consort Diagram: Enrolment and Outcomes
* 46 patients (20 everolimus, 26 placebo) were excluded from the intention-to-treat efficacy analysis upon central eligibility review which was conducted after randomization but before data analysis. Reasons for ineligibility included: insufficient imaging/unable to rule rule-out residual or metastatic disease n =24; evidence of residual or metastatic disease n=13; not intermediate-high or very-high risk n = 5; ineligible histology n =2; other active or recent cancer n=2 † 479 patients (355 everolimus, 124 placebo) discontinued study treatment prior to 54 weeks due to reasons other than disease recurrence or death as follows (% is that of all eligible, randomized patients):
Patient characteristics were well-balanced between the two arms with the majority of patients (55%) belonging to the very-high risk group (Table 1). The majority of patients were white (91%) and male (70%), similar to other adjuvant studies. 2,4,5,10 90% underwent radical as opposed to partial nephrectomy and 17% of patients had non-clear cell tumours.
Table 1.
Characteristics of Eligible Patients at Baseline (Intent-to-Treat Population)
| Characteristic | Everolimus (N=755) |
Placebo (N=744) |
|---|---|---|
| Age - years | ||
| Median (interquartile range) | 58 (51, 66) | 58 (50, 66)) |
| Sex* | ||
| Male | 520 (69%) | 522 (70%) |
| Female | 235 (31%) | 222 (30%) |
| Performance Status | ||
| 0 | 603 (80%) | 588 (79%) |
| 1 | 152 (20%) | 156 (21%) |
| Race | ||
| White | 688 (91%) | 670 (90%) |
| Black | 34 (5%) | 27 (4%) |
| Asian | 11 (1%) | 20 (3%) |
| Other/Unknown | 22 (3%) | 27 (4%) |
| Risk Group | ||
| Intermediate High | 343 (45%) | 337 (45%) |
| Very High | 412 (55%) | 407 (55%) |
| Pathologic T Stage | ||
| pT1 | 62 (8%) | 71 (10%) |
| pT2 | 147 (19%) | 158 (21%) |
| pT3 | 525 (70%) | 498 (67%) |
| pT4 | 17 (2%) | 14 (2%) |
| pTX | 4 (< 1%) | 3 (< 1%) |
| Nephrectomy | ||
| Radical | 689 (91%) | 662 (89%) |
| Partial | 66 (9%) | 82 (11%) |
| Histology | ||
| Clear Cell | 626 (83%) | 622 (84%) |
| Non-Clear Cell | 129 (17%) | 122 (16%) |
| Papillary | 57 (8%) | 52 (7%) |
| Chromophobe | 53 (7%) | 46 (6%) |
| Other | 19 (2·5%) | 24 (3·2%) |
| Pathologic LN Status | ||
| pN0 | 219 (29%) | 220 (30%) |
| pN+ (fully resected) | 58 (8%) | 57 (8%) |
| pNx (clinically N0) | 478 (51%) | 467 (63%) |
Sex was self-reported by participant
The final analysis was conducted in March 2022 with 556 recurrence-free survival events and a median follow up of 76 months. Median recurrence-free survival was not reached in either arm. The estimated 5-year recurrence-free survival was 67% for everolimus and 63% for placebo with a stratified logrank p-value=0.050. The corresponding stratified hazard ratio is 0·85 (95% CI, 0·72 to 1·00; P= 0·051), but did not meet the pre-specified p-value for statistical significance of 0·044 (Figure 2A). Whether censoring at last contact date or at last disease assessment did not impact the recurrence-free survival primary result (HR=0.85, 95% CI 0.72, 1.00, P=0.052). Lung was the most common site of recurrence, followed by lymph nodes (Table S1). In an assessment of potential stratification factor by treatment interactions, none had a p-value less than 0·15. However, in the analysis by risk group, the treatment benefit was most notable in the very-high risk group, with a hazard ratio of 0·79 (95% CI, 0·65 to 0·97; P= 0·022), but not in the intermediate-high risk group (HR 0·99, 95% CI 0·73 to 1·35; P=0·96) (P for interaction = 0·22) (Figure 3). We descriptively evaluated the homogeneity of treatment effect on recurrence-free survival across important subsets of patients based on demographics and disease characteristics as shown in Figure S1.
Figure 2.
Recurrence-Free and Overall Survival
Panel A shows the Kaplan-Meier estimates of recurrence-free survival. Panel B shows the Kaplan-Meier estimates of overall survival.
Figure 3.
Panel A shows the Kaplan-Meier estimates of recurrence-free survival for patients with very-high risk disease (tumour stage 3a with grade 3 or 4, tumour stage 3b, 3c, or 4 with any grade, or nodal metastases with any tumour stage and any grade). Panel B shows the Kaplan-Meier estimates of recurrence-free survival for patients with intermediate-high risk disease (tumour stage 1b with grade 3 or 4, tumour stage 2 with any grade, or tumour stage 3a with grade 1 or 2).
Treatment comparison of survival was a prespecified secondary objective. At the time of the final analysis, a total of 290 deaths had occurred, 139 (18·4%) in the everolimus group and 151 (20·3%) in the placebo group. Seventy-four percent of deaths were attributed to RCC (Table S2) and 19% of patients who died did not have prior documentation of RCC recurrence. Median overall survival was not reached in either arm (stratified hazard ratio for death, 0·90; 95% CI 0·71 to 1·13; P=0·36) (Figure 2B). The estimated rate of survival at 5-years was 87% in the everolimus arm and 85% in the placebo arm.
Adverse events of any grade that were attributed to treatment by the investigator occurred in 96·5% of patients who received everolimus and in 80·9% of patients who received placebo. Grade 3 or higher adverse events occurred in 46% of patients who received everolimus and 11% of those who received placebo. The most common adverse events in the everolimus arm were mucositis (65%), fatigue (56%), diarrhoea (33%) and rash (31%) and the most common laboratory abnormalities were hypertriglyceridemia (53%), hypercholesterolemia (49%), anaemia (42%) and hyperglycaemia (35%) (Table 2 and Figure S2). The most common grade 3 and higher adverse events in the everolimus arm were mucositis (14%), hypertriglyceridemia (11%), and hyperglycaemia (5%). No treatment-related deaths occurred among patients treated with everolimus.
Table 2.
Adverse events. Shown are number (%) of participants with a given type and grade of adverse event classified by treatment arm and listed by organ system in order of decreasing frequency. Excludes adverse events unlikely or not related to treatment per investigator assessment. Shown are adverse events with ≥ 10% incidence and those with ≥ 1% incidence of grade 3 or higher event.
| Everolimus (N=740) | Placebo (N=723) | |||
|---|---|---|---|---|
| ADVERSE EVENT | Grade 1–2 | Grade 3–4 | Grade 1–2 | Grade 3–4 |
| Gastrointestinal | ||||
| Mucositis oral | 374 (51%) | 103 (14%) | 136 (19%) | 2 (<1%) |
| Diarrhea | 231 (31%) | 11 (1%) | 101 (14%) | 5 (1%) |
| Nausea | 175 (24%) | 0 | 117 (16%) | 3 (<1%) |
| AST increased | 127 (17%) | 3 (<1%) | 53 (7%) | 2 (<1%) |
| ALT increased | 118 (16%) | 6 (1%) | 50 (7%) | 3 (<1%) |
| Abdominal pain | 55 (7%) | 7 (1%) | 27 (4%) | 0 |
| General | ||||
| Fatigue | 385 (52%) | 27 (4%) | 292 (40%) | 5 (1%) |
| Edema limbs | 106 (14%) | 3 (<1%) | 33 (5%) | 0 |
| Metabolism and Nutrition | ||||
| Hypertriglyceridemia | 310 (42%) | 85 (11%) | 226 (31%) | 13 (2%) |
| Cholesterol high | 358 (48%) | 2 (<1%) | 133 (18%) | 2 (<1%) |
| Hyperglycemia | 223 (30%) | 37 (5%) | 159 (22%) | 3 (<1%) |
| Anorexia | 111 (15%) | 4 (1%) | 34 (5%) | 0 |
| Hyponatremia | 21 (3%) | 4 (1%) | 9 (1%) | 1 (<1%) |
| Hyperkalemia | 15 (2%) | 4 (1%) | 23 (3%) | 1 (<1%) |
| Dehydration | 10 (1%) | 8 (1%) | 6 (1%) | 3 (<1%) |
| Hematologic | ||||
| Anemia | 296 (40%) | 12 (2%) | 80 (11%) | 0 |
| Lymphocyte count decreased | 70 (9%) | 5 (1%) | 20 (3%) | 1 (<1%) |
| Neutrophil count decreased | 59 (8%) | 4 (1%) | 15 (2%) | 2 (<1%) |
| Dermatologic | ||||
| Rash maculo-papular | 215 (29%) | 15 (2%) | 58 (8%) | 0 |
| Rash acneiform | 197 (27%) | 16 (2%) | 39 (5%) | 0 |
| Pruritus | 128 (17%) | 7 (1%) | 54 (7%) | 1 (<1%) |
| Dry skin | 121 (16%) | 5 (1%) | 55 (8%) | 0 |
| Renal | ||||
| Creatinine increased | 221 (30%) | 2 (<1%) | 137 (19%) | 2 (<1%) |
| Nervous System | ||||
| Headache | 133 (18%) | 2 (<1%) | 79 (11%) | 1 (<1%) |
| Vascular | ||||
| Hypertension | 88 (12%) | 31 (4%) | 73 (10%) | 20 (3%) |
| Thromboembolic event | 1 (<1%) | 4 (1%) | 0 | 0 |
| Respiratory | ||||
| Dyspnea | 106 (14%) | 6 (1%) | 40 (6%) | 1 (<1%) |
| Pneumonitis | 90 (12%) | 9 (1%) | 3 (<1%) | 0 |
| Lung infection | 10 (1%) | 5 (1%) | 2 (<1%) | 1 (<1%) |
DISCUSSION
This is the first reported study of an mTOR inhibitor as adjuvant treatment for RCC. Everolimus administered after surgery did not improve recurrence-free survival as compared to placebo. The study allowed entry of patients with a wide range of recurrence risk, from those with stage I through stage IV (pT4) cancers. Subgroup analysis by risk group stratification suggested a recurrence-free survival benefit with everolimus among patients with very-high risk disease, but no benefit among those with intermediate-high risk disease. It should be noted that both positive trials that led to the FDA adjuvant indications in the United States for sunitinib and pembrolizumab limited inclusion to higher risk patients compared with the broader population eligible for EVEREST. 2,3 Consensus recommendations currently recognize that patients at the highest risk of recurrence -- those with stage pT3–4 and/or node positive disease -- should be the focus of adjuvant studies. 14 The findings of EVEREST lend further support to these recommendations.
At the time of the final analysis, we observed only 69% of the 804 recurrence-free survival events called for by the study design under the alternative hypothesis, which assumed that recurrence-free survival followed an exponential distribution. Eighty-nine percent of the observed recurrence-free survival events occurred within the first five years after randomization. In addition to limiting enrolment to very-high risk patients, future adjuvant RCC study design may benefit from assuming a percent of patients are long-term survivors (i.e., “cured”) 15 and conducting the final analysis earlier in follow-up. It should be noted that the value of long-term surveillance imaging has not been established in RCC and declining adherence to the study surveillance schedule may have contributed to the lower-than-expected rate of recurrence-free survival events observed in EVEREST.
Grade 3–4 adverse events occurred in 46% of patients receiving everolimus, less that what has been reported in adjuvant TKI studies, which have ranged from 49 to 72%, but greater than published studies of adjuvant checkpoint inhibitors. 2–7,10 Adverse events were consistent with the known safety profile of everolimus and included frequent stomatitis, metabolic side effects, and anaemia. It should be noted that EVEREST predated the common use of prophylactic dexamethasone mouthwash which has been reported to reduce the risk of stomatitis with everolimus treatment. 16 A significant proportion of patients (37%) discontinued everolimus early due to adverse events. This discontinuation rate mirrors what has been reported in adjuvant RCC trials with oral TKIs, which have reported discontinuation rates of 23 – 44%,2,4–7 and adherence to oral adjuvant therapies remains problematic across multiple cancer types. 17 Despite 37% of patients discontinuing everolimus prior to the prescribed 54 weeks of study treatment, we observed a non-significant difference in recurrence-free survival; shorter adjuvant treatment than the empiric 1-year used by most trials may be sufficient and should be addressed in future adjuvant RCC studies.
No overall survival advantage has thus far been detected with adjuvant everolimus in this trial, similar to all other adjuvant trials reported to date. Overall survival has been a secondary endpoint of all recent adjuvant RCC trials and these studies may not be adequately powered to detect modest survival differences. Given continued improvement in outcome for metastatic RCC patients, detection of an overall survival benefit from adjuvant therapy may be delayed and continued survival follow-up for adjuvant studies is imperative. While the FDA accepted disease-free survival as primary endpoint for the adjuvant indications for both sunitinib and pembrolizumab in the United States, it remains unknown whether early adjuvant treatment imparts a survival advantage over treatment at the time of development of metastatic disease. 2,3 In conclusion, up to one year of adjuvant everolimus did not improve recurrence-free survival in the overall study population. Multiple placebo-controlled, phase III trials have now been conducted with both tyrosine kinase inhibitors and checkpoint immunotherapy agents, with only one study among each of these classes of agents reporting positive results. The results of EVEREST warrant consideration of further study of mTOR inhibition in the adjuvant treatment of very-high risk RCC. Patient selection and future studies for adjuvant therapy should be limited to those at highest risk for RCC disease recurrence and could employ recurrence models derived from recent adjuvant trial data. 18
Supplementary Material
PANEL:
RESEARCH IN CONTEXT
Evidence before this study
We searched PubMed for randomized clinical trials published through January 2023 using terms “adjuvant” AND “renal cell carcinoma,” “RCC,” or “kidney cancer.” At the time this study was initiated in 2011, multiple randomized, adjuvant studies of cytokines, autologous tumour vaccines, and various chemotherapeutic and hormonal strategies had been published for renal-cell carcinoma (RCC), but none had demonstrated effectiveness and surveillance alone was standard of care after surgery. With the advent of vascular endothelial growth factor receptor (VEGFR) inhibitors for advanced RCC, new placebo-controlled, adjuvant studies were launched beginning with the ASSURE trial in 2006 which investigated a year of adjuvant sorafenib or sunitinib. In addition to VEGF pathway-targeted therapies, 2 mammalian target of rapamycin (mTOR) inhibitors had been approved for treatment of advanced RCC at the time of study design. In a placebo-controlled, phase III trial enrolling patients with advanced renal cancer whose cancer had progressed on sorafenib and/or sunitinib, everolimus demonstrated a progression-free survival benefit (HR 0·30, 95% CI 0·22 to 0·40; P<0.0001). Given the activity of everolimus in the metastatic setting, we designed the current study to test its efficacy as adjuvant therapy. The study design was based on that of ASSURE, which had completed enrolment prior to initiation of our study, and we selected identical risk populations based on the UCLA international staging system. Other ongoing adjuvant trials at the time of study initiation included trials investigating sorafenib, sunitinb, and pazopanib and subsequent studies would include a trial of axitinib and later trials of pembrolizumab and other checkpoint inhibitor therapies.
Added value of this study
This is the first and only adjuvant, phase III trial of an mTOR inhibitor for renal-cell carcinoma. While the overall study did not reach statistical significance, improvement in recurrence-free survival with everolimus was observed in the subset of patients at very-high risk of recurrence. These findings lend support to current recommendations for use of adjuvant therapy in patients at highest risk of recurrence after surgery.
Implications of all the available evidence
Despite multiple adjuvant studies in RCC, only one study of a VEGFR inhibitor (sunitinib) and one of a checkpoint inhibitor (pembrolizumab) have reported improvement in recurrence-free survival, while negative results have been reported in other studies using in-class agents. Longer follow-up is needed to determine if overall survival is impacted by adjuvant use of these therapies. Pembrolizumab is currently in use as an adjuvant therapy based on the results of the Keynote-564 trial and has set a new disease-free survival benchmark for adjuvant therapy. While the results of EVEREST do not support the use of everlolimus as adjuvant therapy, the recurrence-free survival benefit suggested in the very-high risk subset warrants consideration of further study in this group of patients.
ACKNOWLEDGMENTS
Funded by NIH/NCI/NCTN awards U10CA180888, U10CA180819, U10CA180820, U10CA180821, UG1CA233163, UG1CA233160, UG1CA233191, UG1CA233178, UG1CA233340; in part by Novartis Pharmaceuticals Corporation; and in part by a grant from The Hope Foundation through the SWOG Trial Support (STrS) program. This manuscript is dedicated to the memory of Nicholas J. Vogelzang, MD -- physician, researcher, mentor, colleague -- and in recognition of his significant contributions to this study
Funding:
NIH/NCI/NCTN awards U10CA180888, U10CA180819, U10CA180820, U10CA180821, UG1CA233163, UG1CA233160, UG1CA233191, UG1CA233178, UG1CA233340; in part by Novartis Pharmaceuticals Corporation; and in part by a grant from The Hope Foundation (SWOG Trial Support (STrS) program).
Footnotes
DECLARATION OF INTERESTS
CWR reports research funding from Ayala, Bristol Myers Squibb, Daiichi-Sankyo, Deciphera, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, Xynomic, Bayer, OSI, PF Argentum IP Holdings LLC, Rain Therapeutics, Shasqi; consulting fees from Synox, Daiichi-Sankyo, AVEO, Exelixis, Astra-Zeneca, Bristol Myers Squibb; and payment for expert testimony from Pfizer, GSK, Boehringer Ingelheim. EIH reports research funding from Astellas Pharma, Arvinas, AstraZeneca, BioXcel Therapeutics, Bristol Myers Squibb, Calibr, Calithera Biosciencs Inc., Caris Life Sciences, Corcept Therapeutics, Corvis Pharmaceuticals, Daiichi Sankyo Inc., Eisai, Exelixis, Five Prime Therapeutics, Fortis Therapeutics, GlaxoSmithKline, Gilead Sciences Inc., Harpoon Therapeutics, Hoffman-LaRoche, Infinity Pharmaceuticals, iTeos Therapeutics, Janssen Research & Development LLC, Merck Sharp & Dohme, Merck, Mirati Therapeutics, Modra Pharmaceuticals, Oncolys BioPharma, Peloton Therapeutics Inc., Pfizer, Pharmacyclics LLC, POINT Biopharma, Seattle Genetics; consulting fees from Astellas Pharma; honoraria from Bayer, Sanofi, Seattle Genetics; support for attending meetings and/or travel from Astellas Pharma, Caris Life Sciences, Sanofi, Seattle Genetics; participation on a data safety monitoring board or advisory board from Astellas Pharma, AstraZeneca, Bayer, Sanofi, Janssen Research & Development LLC; leadership or fiduciary role for Zero End of Cancer, Michigan American Cancer Society; MS reports grants or contracts from Advaxis, Harpoon, Bristol Myers Squibb, Genocea, Bellicum, Xencor, Exelixis, Seattle Genetics; consulting fees from Janssen, Exelixis, Bristol Myers Squibb, Xencor; and data safety monitoring board or advisory board participation for AstraZeneca. ASA reports consulting fees from Bristol Myers Squibb, Pfizer, AstraZeneca; data safety monitoring board or advisory board participation for Eisai; and research grants paid from Merck, Bristol Myers Squibb, V Foundation, AstraZeneca, and NCCN. SKP reports support for attending meetings and/or travel from Ipsen, CRISPR therapeutics; IP reports consulting fees from Nouscom, Iovance, Nektar, and Regeneron. JIC reports grants or contracts from Merck, Bristol Myers Squibb, Aveo, Instil Bio, Hookipa, Castle Biosciences. TKC reports support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH and others); Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA; equity interest in Tempest, Pionyr, Osel, Precede Bio, CureResponse; committee participation in NCCN, NCI GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan; grant funding from Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942–16) and Program 5P30CA006516–56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI; NA reports research funding from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Tracon; consulting fees from Eisai, Seattle Genetics, EMD Serono, Janssen, Exelixis, Bayer, Astellas, Astra Zeneca, Immunomedics, Bristol Myers Squibb, Aveo, Genentech, Merck, Lilly, Gilead, Foundation Medicine. RGU reports leadership or fiduciary role for Haymarket Media, Genentech, Merck; NBH reports grants or contracts from DOD KCRC Clinical Consortium Award; consulting fees from Merck, Eisai, Bristol Myers Squibb, Aveo, Exelixis; participation in a data safety monitoring board or advisory board for Roche; leadership or fiduciary role for NIH GU Steering Committee, ECOG-ACRIN GU co-chair. UV reports grants or contracts from Merck, Bristol Myers Squibb; consulting fees from Bayer, Exelixis, Merck, Gilead, Bristol Myers Squibb, Alekermes; honoraria from Sanofi, Bayer, Exelixis; leadership or fiduciary role for Michigan Society of Hematology/Oncology. IMT reports National Cancer Institute and SWOG funding for SWOG GU Committee Chair. All other authors declare no competing interests.
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Contributor Information
Christopher W. Ryan, Oregon Health and Science University Knight Cancer Institute, Portland OR.
Catherine M. Tangen, SWOG Statistics and Data Management Center, Seattle, WA.
Elisabeth I. Heath, Karmanos Cancer Institute, Wayne State University, Detroit, MI.
Mark N. Stein, Columbia University, New York, NY
Maxwell V. Meng, UC San Francisco Diller Comprehensive Cancer Center, San Francisco, CA.
Ajjai Shivaram Alva, University of Michigan Rogel Cancer Center, Ann Arbor, MI.
Sumanta K. Pal, City of Hope Comprehensive Cancer Center.
Igor Puzanov, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
Joseph I Clark, Loyola University Medical Center, Chicago, IL.
Toni K. Choueiri, Dana Farber Cancer Institute, Boston MA.
Neeraj Agarwal, Huntsman Cancer Institute, Salt Lake City, UT.
Robert G. Uzzo, Fox Chase Comprehensive Cancer Center, Philadelphia, PA.
Naomi B. Haas, Abramson Comprehensive Cancer Center, University of Pennsylvania, Philadelphia, PA.
Timothy W. Synold, City of Hope Comprehensive Cancer Center.
Melissa Plets, SWOG Statistics and Data Management Center, Seattle, WA
Ulka N. Vaishampayan, University of Michigan Rogel Cancer Center, Ann Arbor, MI.
Brian M. Shuch, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
Ian M Thompson, Jr., Christus Santa Rosa Health System, San Antonio, TX,.
Primo N. Lara, Jr., University of California Davis Comprehensive Cancer Center, Sacramento, CA.
DATA SHARING
Access to de-identified participant data will be available from the NCI’s NCTN/NCORP Data Archive after publication of this manuscript at https://nctn-data-archive.nci.nih.gov/. Other data requests as well as study-related documents such as study protocol and informed consent form will be granted according to the merit of a written application assessed by the SWOG GU Committee and SWOG Executive Committee. SWOG, as part of the NCI’s National Clinical Trials Network, adheres to their policy of making clinical trial data available per request.
REFERENCES
- 1.Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol 2015; 16(6): 676–85. [DOI] [PubMed] [Google Scholar]
- 2.Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016; 375(23): 2246–54. [DOI] [PubMed] [Google Scholar]
- 3.Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021; 385(8): 683–94. [DOI] [PubMed] [Google Scholar]
- 4.Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016; 387(10032): 2008–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Motzer RJ, Haas NB, Donskov F, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol 2017; 35(35): 3916–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol 2018; 29(12): 2371–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Eisen T, Frangou E, Oza B, et al. Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. J Clin Oncol 2020; 38(34): 4064–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Allaf M Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol 2022; 33 (suppl_7): S808–S69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Motzer RJ, Russo P, Grunwald V, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet 2023; 401(10379): 821–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2022; 400(10358): 1103–16. [DOI] [PubMed] [Google Scholar]
- 11.Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372(9637): 449–56. [DOI] [PubMed] [Google Scholar]
- 12.Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19(6): 1649–57. [DOI] [PubMed] [Google Scholar]
- 13.SWOG Data and Safety Monitoring Policy. https://www.swog.org/sites/default/files/docs/2017-10/Policy21.pdf (accessed February 27,2023).
- 14.Agrawal S, Haas NB, Bagheri M, et al. Eligibility and Radiologic Assessment for Adjuvant Clinical Trials in Kidney Cancer. JAMA Oncol 2020; 6(1): 133–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Othus M, Barlogie B, Leblanc ML, Crowley JJ. Cure models as a useful statistical tool for analyzing survival. Clin Cancer Res 2012; 18(14): 3731–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 2017; 18(5): 654–62. [DOI] [PubMed] [Google Scholar]
- 17.Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 2011; 126(2): 529–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Correa AF, Jegede OA, Haas NB, et al. Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma. Eur Urol 2021; 80(1): 20–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Access to de-identified participant data will be available from the NCI’s NCTN/NCORP Data Archive after publication of this manuscript at https://nctn-data-archive.nci.nih.gov/. Other data requests as well as study-related documents such as study protocol and informed consent form will be granted according to the merit of a written application assessed by the SWOG GU Committee and SWOG Executive Committee. SWOG, as part of the NCI’s National Clinical Trials Network, adheres to their policy of making clinical trial data available per request.