VEGFR inhibitors, mTOR inhibitors, and immune checkpoint inhibitors have been studied as adjuvant therapy for patients with RCC. However, conflicting data from phase 3 trials have left investigators unclear on what their role is.
There has been much confusion surrounding the role of adjuvant therapy for patients with renal cell carcinoma (RCC). The uncertainty remains, despite several clinical trials which investigated the approach.
Adjuvant therapy aims to reduce the recurrence risk and improve outcomes across cancer types.1 However, it is currently an unmet need for patients with RCC.
Although numerous therapeutics are available to manage patients with metastatic RCC in the first-line setting, including VEGFR inhibitors, mTOR inhibitors, and immune checkpoint inhibitors (ICIs), there are few options and little guidance available to help guide the approach to adjuvant therapy. More studies are warranted to fully understand their place in this population.
“Kidney cancer is a fascinating disease and we've made a lot of great strides recently. But for the role of adjuvant therapy, so who is at high-risk, who doesn't have any visible disease on imaging scans, should we think about giving systemic therapy to try to reduce the risk of having that cancer come back? In each new era of kidney cancer therapy, from tyrosine kinase inhibitors [TKIs], targeted therapies, immunotherapies, and now even combination therapies, we've tried these different strategies. From the targeted therapies, we did not have tremendous success,” Eric A. Singer, MD, told Targeted OncologyTM.
With TKIs in the metastatic RCC setting, investigators have begun evaluating these targeted therapies in an early setting. There have been conflicting results for disease-free survival (DFS) and no overall survival (OS) benefit has been observed.1,2 Similarly, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting have been conflicting and available data have not shown improvements in OS with ICIs in the early phase. However, there has been a positive trend for pembrolizumab (Keytruda) reported.
Still, these unfavorable results surrounding several ICIs in RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy.
In the adjuvant setting for RCC, the first agents to be heavily investigated were TKIs, like sunitinib (Sutent), which was studied the S-TRAC (NCT00375674) and ASSURE (NCT00326898) trials.
Although a number of trials have assessed the use of TKIs, only 1 provided positive data, resulting in the FDA approval of sunitinib as adjuvant treatment following nephrectomy for adult patients with high risk of recurrent RCC.
“From the targeted therapies, we didn't have tremendous success. We did have the approval of sunitinib monotherapy based on progression-free survival, but that treatment was associated with a lot of toxicity, a lot of dose reductions, and a lot of holding therapy,” said Singer, chief, Division of Urologic Oncology, director, Urologic Oncology Fellowship Program, and co-director, Genitourinary Disease-Specific Research Group at the Ohio State University Comprehensive Cancer Center, and professor, Department of Urology, Division of Bioethic at the Ohio State University College of Medicine.
Sunitinib is a multitarget TKI that inhibits VEGF. Results from the S-TRAC trial supported the regulatory decision. A total of 615 patients with locoregional, high-risk clear cell RCC (ccRCC) were enrolled in the trial and treated with sunitinib or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year.
Findings showed that among patients given sunitinib, the median DFS was 6.8 years (95% CI, 5.8-not reached) vs 5.6 years (95% CI, 3.8-6.6) among patients receiving placebo (HR, 0.76; 95% CI, 0.59-0.98; P =.03). In the sunitinib group, patients experienced a greater percentage of grade 3 (48.4%) and 4 (12.1%) adverse events (AEs) vs what was observed in the placebo group (grade 3, 15.8%; grade 4, 3.6%). However, the incidence of serious AEs was similar between the sunitinib arm (21.9%) and placebo arm (17.1%).
“For the adjuvant space. Most of those clinical trials ended up reading out negative. It was only the S-TRAC trial, which looked at adjuvant sunitinib at a high dose and actually the dose that was used in the metastatic space actually showed a progression-free survival benefit,” Chung-Han Lee, MD, PhD, a genitourinary oncologist at Memorial Sloan Kettering Cancer Center, told Targeted Oncology.
Despite the approval of sunitinib in 2017, its use has been limited, based on negative results from the phase 3, double-blind, placebo-controlled ASSURE trial which evaluated patients with completely resected, nonmetastatic, high-grade, stage T1b or greater RCC. A total of 647 patients were randomly assigned to receive sunitinib. There were 438 patients who received the full starting dose of 50 mg, and 193 (44%) patients discontinued sunitinib treatment due to toxicity issues. The remaining 191 patients had a dose reduction to 37.5 mg, which led to a lower rate of withdrawal (34%).
Data showed that there were 4 treatment-related deaths in the sunitinib group, including neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. According to investigators on the study, these findings suggest a strong rationale against the use of adjuvant sunitinib in this setting.
“It was encouraging that we got an approval, but I would say that it's a rarely used drug because of the toxicity and the recurrence-free survival benefit. It does exist, but I can't say that it's something that I recommend to patients because of that toxicity profile.”
Randomized trials are continuously evaluating the use of targeted therapy and checkpoint inhibitors in patients with RCC. However, most data have not shown adjuvant therapy to be promising in RCC in patients at high risk of relapse after surgical treatment.2
“The adjuvant space within RCC is exciting. We've now had something that's reasonably well-tolerated that has demonstrated a progression-free survival type of benefit. This is something that warrants discussion with the patients, whether they would consider doing treatment with immunotherapy for a year. But I think it's important to discuss both the benefits and the potential risks related to adjuvant therapies,” said Lee.
Investigators have continued to make strides, including with the evaluation of immuno-oncology in trials like KEYNOTE-564 (NCT03142334). In the double-blind, randomized, phase 3 KEYNOTE-564 trial, 496 patients with ccRCC at high risk of recurrence after nephrectomy, with or without removal of metastases were treated with pembrolizumab, and 498 were treated with placebo.
“We have moved the needle quite a bit and went from using targeted therapies to now having a bunch of studies looking at immunotherapies. The 1 that got the most attention was KEYNOTE-564 which looked at nearly 1000 patients using intravenous pembrolizumab vs placebo,” said Singer.
Initial results from the trial led to the approval of pembrolizumab for adults with RCC at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions in November 2021. This approval marked a milestone for the field as it provides an alternative option for sunitinib in this patient population.
Shortly after, updated efficacy and safety analysis with 30.1 months of follow-up were presented and showed that DFS was maintained among patients treated with pembrolizumab (HR, 0.63; 95% CI, 0.50-0.80; nominal P < .0001).4
Three subgroups, including intermediate-high risk, high-risk, and M1 no evidence of disease (NED) following surgery, were analyzed, and findings across the subgroups were HR, 0.68; 95% CI, 0.52-0.89; HR, 0.60; 95% CI, 0.33-1.10; and HR, 0.28; 95% CI, 0.12-0.66, respectively.
Regarding safety, grade 3 or higher AEs were seen in 32.4% of patients in the pembrolizumab arm vs 17.7% of patients in the placebo arm. Twenty percent of patients in the pembrolizumab arm had serious AEs. Treatment with pembrolizumab was discontinued in 21% of patients due to toxicity, and dose interruptions resulting from AEs were observed in 26% of patients.
While pembrolizumab has had a significant impact on DFS for patients with RCC, mature overall survival data are not yet available. Investigators are holding out hope that pembrolizumab could be a new standard of care in terms of adjuvant therapy for patients with ccRCC.
“At the initial end point and then at 30 months, seeing a reduction of about 37% likelihood of recovering and a hazard ratio of 0.63 which was statistically significant, changed and ushered in a new era of an approval for a systemic immunotherapy to be used. We continue to build on that,” added Singer.
Atezolizumab (Tecentriq) was also under investigation for adjuvant therapy in RCC. The anti-PD-L1 antibody was studied in the randomized, multicenter, double-blind, phase 3 IMmotion010 trial (NCT03024996) among patients with RCC at high risk of recurrence after resection in comparison with placebo. The approval of pembrolizumab was a landmark for designing the IMmotion010 trial, as well as the phase 3 CheckMate 914 trial (NCT03138512) of nivolumab (Opdivo) and ipilimumab (Yervoy) in RCC.5
In the IMmotion010 trial, investigators evaluated the primary end point of DFS, and OS served as a secondary end point.
Findings of the trial fell short, showing that when given post-resection, atezolizumab did not improve clinical outcomes vs placebo in patients with RCC.1 At a median follow-up of 44.7 months (interquartile range, IQR, 39.1-51.0), the median investigator-assessed DFS was 57.2 months (95% CI, 44.6-not evaluable [NE]) with atezolizumab vs 49.5 months (47.4-NE) with placebo (HR, 0.93; 95% CI, 0.75-1.15; P = 0.50). At 2 years, the DFS rates were 67% vs 65%, respectively.
Unfortunately, these results were inconsistent with previously published data from the KEYNOTE-564 trial. Given the contrasting outcomes with immune checkpoint inhibitors, further studies are needed to clarify the role of immunotherapy in the adjuvant setting for RCC.4
“One of the big lessons that we had learned is that, especially in the adjuvant space, tolerability became a big issue,” said Lee.
As previously noted, nivolumab in combination with ipilimumab was studied in the double-blind, phase 3 CheckMate 914 trial. Previously in the phase 3 CheckMate 214 trial (NCT02231749), the combination demonstrated a significant benefit in OS and a manageable safety profile in the first-line setting for patients with advanced/ metastatic RCC when compared with sunitinib.1
In the CheckMate 914 trial, patients who have undergone partial or radical nephrectomy with negative surgical margins with predominantly clear cell histology, and no macroscopic residual disease or distant metastases post nephrectomy were enrolled. The study consisted of 2 parts. In part A, nivolumab plus ipilimumab was compared with placebo while part B compared 3 arms, including nivolumab plus ipilimumab vs placebo vs nivolumab alone. The primary end point was DFS.
Findings already reported from part A of the trial showed that the combination of nivolumab and ipilimumab did not lead to an improvement in DFS when used as adjuvant treatment for patients with localized RCC who have undergone full or partial removal of the kidney and who are at moderate or high risk of relapse, missing its primary end point.1
Regarding safety, grade 3 or higher treatment-related AEs were seen in 28.5% of patients given the combination vs 2.0% of those given placebo. The safety profile of nivolumab plus ipilimumab was consistent with its known profile in advanced RCC. However, there was a higher rate of discontinuation due to treatment-related AEs with the combination vs placebo.
Treated with nivolumab monotherapy is also being studied in the phase PROSPER trial (NCT03055013). Patients with have high-risk RCC of clinical stage T2 or greater or any T stage with regional lymph node involvement of any histology with plans to undergo radical or partial nephrectomy were enrolled and given either treatment with 1 dose of nivolumab prior to surgery, followed by 9 adjuvant doses spaced 4 weeks apart, or nephrectomy followed by surveillance.
Investigators evaluated the primary end point of relapse-free survival, which reported similar results between the 2 arms. OS data were not mature at the time of the last analysis; however, findings were not statistically different between arms.
Additionally, 20% of patients given nivolumab had at least 1 grade 3 or 4 AE vs 6% in the control arm.
Further, the efficacy and safety of belzutifan, a HIF-2α inhibitor, in combination with pembrolizumab vs placebo plus pembrolizumab is being studied in the LITESPARK 002 study among patients with ccRCC at intermediate–high or high risk, including M1 NED. The primary end point is DFS, and the study plans to enroll 1600 patients.
Another randomized phase 3 trial is the RAMPART study, which is assessing the anti-PD-L1 monoclonal antibody durvalumab plus the anti-CTLA-4 monoclonal antibody tremelimumab among post-surgery patients with intermediate-high-risk RCC. This study is evaluating the primary end points of DFS and OS, and the planned enrollment is 1750 patients.
“In terms of next steps, we're still looking at what's the best drug or combination therapy and refining who is going to be truly at highest risk. Not only is this going to make patients live longer, but [determining,] what are the toxicities associated with it? Can we predict which patients are at especially high-risk of the rare but serious adverse events? How do we put those two things into context to make a personalized recommendation and what's going to be the best path forward for you as an individual?” said Singer.
For patients with non-metastatic RCC, surgery remains the standard of care. However, there is a significant rate of patients who develop progression after nephrectomy at approximately 40%, showing the unmet need for adjuvant therapies in RCC with a high risk of relapse.
While VEGFR-TKIs and IO have been studied and significantly improved survival outcomes for patients with metastatic RCC in recent years, conflicting results across VEGFR-TKI randomized phase 3 trials have been observed in the adjuvant setting.
According to experts like Singer and Lee, exploring the possible reasons for these conflicting results is important to get new insights for future adjuvant trials. Overall, trials evaluating ICIs have led to significant results when used as monotherapy or in combinations in metastatic settings, and the results of trials evaluating these agents in the adjuvant setting are awaited.
“There's multiple steps in which we can move this forward. One is coming up with better predictive markers on whether people have recurrent disease. The second part that would be beneficial is to get a better sense of predicting who might respond to treatments. If we can predict even that with better accuracy, we can move the needle a bit more forward in terms of those types of treatment algorithms. The other part is our ability to predict who might develop toxicity. Working on all 3 of these fronts are going to be critical,” concluded Lee.