Findings from phase 3 adjuvant immuno-oncology trials in renal cell carcinoma have demonstrated some benefit in disease-free survival, but questions about overall survival remain.
Findings from phase 3 adjuvant immuno-oncology trials in renal cell carcinoma (RCC) have demonstrated some benefit in disease-free survival (DFS), but questions about overall survival (OS) remain.
“About 20% to 30% of patients with localized RCC develop recurrence following nephrectomy, and these patients will proceed with focal or systemic therapy during their disease course,” said Ana M. Molina, MD, an assistant professor of medicine at Weill Cornell Medical College in New York, New York, during the 40th Annual CFS®.1 “Multiple studies have evaluated adjuvant tyrosine-kinase inhibitors [TKIs] in the high-risk setting with contrasting results,” Molina, who is also the Anne Moore, MD, Clinical Scholar in Hematology-Oncology and an assistant attending physician at NewYork-Presbyterian Hospital, continued.
The only approved TKI in the adjuvant setting is sunitinib (Sutent), based on disease-free survival (DFS) benefit in the adjuvant setting for patients at high risk.2 To explore the adjuvant space, Molina highlighted findings from these 3 trials: KEYNOTE-564 (NCT03142334),3 IMmotion010 (NCT03024996),4 and CheckMate 914 (NCT03138512).5
In this trial, patients with clear cell RCC who were at high risk for recurrence after nephrectomy, with or without metastasectomy, received either adjuvant pembrolizumab (Keytruda) at a dose of 200 mg or placebo intravenously once every 3 weeks for approximately 1 year.3
Treatment-naïve patients were either classified as intermediate-high risk or high risk, or had no evidence of disease (NED) after surgery; surgery occurred less than 12 weeks after randomization. A total of 496 patients were assigned to receive pembrolizumab and 498 received placebo.
“The majority of patients in both arms had intermediate-high–risk disease [86.1% vs 86.9%, respectively]; M1 status was 5.8% in both arms and sarcomatoid features were [nearly] equal for both arms [10.5% vs 11.8%, respectively],” Molina said.
In the primary analysis at 24.1 months, the median DFS rate was 77.3% for the treatment arm and 68.1% in the control arm (HR, 0.68; 95% CI, 0.53-0.87; P = .001). At 30.1 months, the DFS rate in the treatment arm was 78.3% compared with 67.3% in the control arm (HR, 0.63; 95% CI, 0.50-0.80; P < .0001). Based on these findings, pembrolizumab was approved in the adjuvant setting. Turning to DFS by recurrence risk subgroups, Molina said clinical benefits were observed across the intermediate-high– risk, high-risk, and M1 NED groups.
DFS by sarcomatoid status also favored the treatment arm. With sarcomatoid features absent, at 24 months, the DFS rate was 79.5% in the treatment arm vs 69.4% in the control arm (HR, 0.63; 95% CI, 0.48-0.83). With sarcomatoid features present, at 24 months, the rate was 71.8% in the treatment arm vs 52.0% in the control arm (HR, 0.54; 95% CI, 0.29-1.00).
Adverse events (AEs) were consistent across all grades in both the primary and updated analyses.
A total of 778 patients were randomly assigned 1:1 to receive either atezolizumab (Tecentriq) 1200 mg intravenously every 3 weeks or placebo for 1 year, with the primary end point of DFS and secondary end points of OS and DFS. To be eligible, patients had to have resected intermediate- to high-risk RCC or clear cell and/or a sarcomatoid component.
The majority of patients had clear cell histology in the treatment vs placebo arms (93.3% vs 91.8%, respectively). They also had similar M1 NED status (14.4% vs 13.4%, respectively) and PD-L1 expression (59.5% vs 60.6%, respectively).
Reviewing the investigator-assessed DFS, Molina noted that 2 features suggested a potential clinical benefit associated with having a sarcomatoid component and PD-L1 expression. However, OS data are still immature, she noted. Exploratory DFS by PD-L1 status also suggests the potential for improvement in clinical benefit.
Regarding safety, grade 3/4 AEs of any cause were 27.2% in the treatment arm vs 21.1% in the control arm. Treatment-related AEs were also higher in the treatment arm (14.1%) vs the control arm (4.7%). The rate of AEs leading to discontinuation of atezolizumab or placebo was higher in the treatment arm (11.5%) than in the placebo arm (2.6%).
In CheckMate 914, among the key eligibility criteria were that patients had to have undergone radical or partial nephrectomy with clear cell histology and sarcomatoid features. These patients, unlike the patients in the previous trials, did not have any evidence of distant metastases after nephrectomy.
In part A of the trial, patients were randomly assigned 1:1 to receive either nivolumab at 240 mg intravenously plus ipilimumab at 1 mg/kg intravenously (n = 405) or placebo (n = 411). The primary end point was DFS and secondary end points were OS and safety.
When reviewing the key baseline characteristics for both arms, Molina said the majority of patients had a radical nephrectomy (93% for both arms) and sarcomatoid features (5% for both arms).
The majority also had pT3 disease (78% in the treatment arm and 77% in the placebo arm).
DFS was similar for both arms. The 24-month rate was 76.4% in the treatment arm and 74.0% in the control arm (HR, 0.92; 95% CI, 0.71-1.19; P = .5347). In the subgroup analysis, more patients in the treatment arm vs the placebo arm had sarcomatoid features.
“Based on [data from] these studies, pembrolizumab demonstrated clinical benefit in DFS across various subgroups, including sarcomatoid features; however, OS data are pending,” Molina said.
“But we did not see a benefit in DFS for adjuvant atezolizumab or adjuvant nivolumab plus ipilimumab.”
Further analyses are ongoing to determine the outcome of part A. Part B, which is evaluating adjuvant nivolumab monotherapy, is ongoing.
Other ongoing phase 3 adjuvant trials include PROSPER RCC (NCT03055013), which is evaluating perioperative nivolumab, and RAMPART (NCT03288532), which is looking at observation vs durvalumab vs durvalumab plus tremelimumab (Imjudo). LITESPARK (NCT05239728), evaluating pembrolizumab plus belzutifan (Welireg), is an additional adjuvant trial.
1. Molina AM. What’s new in adjuvant therapy for RCC? Presented at: 40th Annual CFS®; November 9-11, 2022; New York, NY and Virtual. Accessed November 18, 2022. http://bit.ly/3ABdla9
2. FDA approves sunitinib malate for adjuvant treatment of renal cell carcinoma. FDA. Updated August 16, 2018. Accessed November 21, 2022. http://bit.ly/3tLJHv9
3. Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
4. Bex A, Uzzo R, Karam JA, et al. IMmotion010: efficacy and safety from the phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection. Ann Oncol. 2022;33(suppl 7):S808-S869. doi: 10.1016/annonc/annonc1089
5. Motzer RJ, Russo P, Gruenwald V, et al. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: results from the randomized, phase III CheckMate 914 trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi: 10.1016/annonc/annonc1089