At a median follow-up of 3 years in the intention-to-treat (ITT) population, the 3-year DFS rate was 81% with durvalumab plus tremelimumab (n = 225) vs 73% with active monitoring (n = 340; HR, 0.65; 95% CI, 0.45-0.93; P = .0094).
“There is good evidence that that overall effect is largely driven by the effect in the higher-risk population of patients,” James Larkin, PhD, FRCP, F Med Sci, said during the presentation.
Larkin is a consultant medical oncologist at The Royal Marsden NHS Foundation Trust in London, United Kingdom (UK).
The HR for DFS outcomes favored the treatment arm in patients with higher-risk disease in the ITT population (0.52; 95% CI, 0.34-0.80; P = .0016), and DFS outcomes also favored active monitoring in patients with intermediate-risk disease in the ITT group (HR, 1.19; 95% CI, 0.61-2.32; P = .309).
DFS outcomes also favored patients with higher-risk disease and higher risk of treatment interaction (interaction HR, 0.43; 95% CI, 0.19-0.95; interaction P = .019).
What is the design of the RAMPART trial?
RAMPART was a multi-arm, multistage study that enrolled patients at least 18 years of age with confirmed RCC who were at high or intermediate risk of relapse, or had fully resected synchronous ipsilateral adrenal metastases, or had a single fully resected soft tissue metastasis.1,2 Patients needed to have a Leibovich score of 3 to 11, undergone surgery between 28 and 91 days prior to random assignment, and a World Health Organization performance status of 0 or 1.2
The trial initially enrolled 1750 patients.1 However, the sample size was affected by COVID-19 and the results of the phase 3 KEYNOTE-564 trial (NCT03142334), which showed a DFS improvement with pembrolizumab vs placebo in patients with clear cell RCC with an increased risk of recurrence following surgery. Following design modification, the new target sample size was 750 patients.
The trial was designed for patients to be randomly assigned 3:2:2 to undergo active monitoring (arm A), receive durvalumab at 1500 mg every 4 weeks for 1 year (arm B), or receive durvalumab at the same dose and schedule in combination with tremelimumab at 75 mg on day 1 and week 4 of each cycle (arm C).
The primary end point was DFS. The current analysis was pre-powered and prespecified to evaluate DFS by risk of relapse at baseline in arm A vs arm C.
In the current analysis, 565 patients from the UK, France, Spain, and Australia were randomly assigned to undergo active monitoring (n = 340) or receive durvalumab plus tremelimumab (n = 225; 207 received allocated intervention). At follow-up, 340 patients in the monitoring arm were followed up as allocated, and 156 patients in the treatment arm discontinued treatment. Overall, 340 and 225 patients in each respective arm were analyzed for the primary outcome.
What additional efficacy findings were seen with durvalumab/tremelimumab vs active monitoring in RAMPART?
Larkin noted that baseline characteristics were well balanced between the 2 studied arms. Notably, 16.2% and 15.1% of patients in the monitoring and treatment arms, respectively, had non–clear cell disease histology. Additionally, the rates of intermediate-risk, high-risk, and M1NED disease were 44.4%, 50.6%, and 5.0% in the monitoring arm vs 45.8%, 49.3%, and 4.9% in the treatment arm.
Among patients in the higher-risk population, at a median follow-up of 3 years, the 3-year DFS rate was 78% in the treatment arm (n = approximately 122) vs 61% in the monitoring arm (n = 189; HR, 0.52; 95% CI, 0.34-0.80; P = .0016). In the intermediate-risk population, at a median follow-up of 3.1 years, the 3-year DFS rates were 86% (n = 103) and 87% (n = 151), respectively (HR, 1.19; 95% CI, 0.61-2.32; P = .309).
Larkin explained that DFS outcomes favored treatment over control across all exploratory subgroups.
The median duration of treatment was 10.9 months (range, 0-13.3). Patients in the treatment arm received a median of 8 durvalumab infusions (range, 0-13) and a median of 2 tremelimumab infusions (range, 0-2). In total, 23% of patients in the treatment arm completed treatment per protocol: 24% of patients received 13 durvalumab infusions, and 73% of patients received both planned tremelimumab infusions.
What were key safety and QOL findings from the RAMPART trial?
Any-grade, any-cause adverse effects (AEs) were reported in 97% of patients in the treatment arm vs 63% of those in the monitoring arm. Grade 3 or higher any-cause AEs were observed in 40% and 8% of patients, respectively. Any-grade, any-cause serious AEs were seen in 34% and 6% of patients, respectively. Four percent of patients in each arm died; 2 deaths in the treatment arm were deemed treatment related.
In the treatment arm specifically, any-grade, any-cause AEs were immune related (66%), durvalumab related (89%), and tremelimumab related (79%). Grade 3 or higher any-grade, any-cause AEs were immune related (30%), durvalumab related (39%), and tremelimumab related (35%). Any-grade, any-cause serious AEs were durvalumab related (25%) and tremelimumab related (24%). Treatment discontinuation was due to durvalumab or tremelimumab in 29% and 14% of patients, respectively. Corticosteroid use was reported in 36% of patients in the treatment arm.
The most common grade 3 or higher AEs were diarrhea/colitis (treatment arm, 23%; monitoring arm, 0%), amylase/lipase level increase (12%; 1%), transaminitis (12%; 0%), renal impairment (6%; 1%), hypertension (6%; 2%), dyspnea (5%; 1%), adrenal insufficiency (4%; 0%), pulmonary embolism (4%; 1%), pruritus (4%; 0%), anemia (3%; 1%), hypophysitis (3%; 0%), myocarditis (3%; 0%), coronavirus infection (3%; 0%), and hyperglycemia (3%; 0%). Grade 5 AEs included craniocerebral injury in the monitoring arm and myocarditis in the treatment arm.
The trial’s optional quality of life (QOL) substudy was conducted in participating English-speaking countries. Patients completed the EORTC Core QOL questionnaire at baseline after random assignment, at week 16, and at month 15. This substudy demonstrated no statistically significant or clinically meaningful difference in overall health and QOL from baseline to month 15. Among 77 patients in the monitoring arm and 59 patients in the treatment arm who were included in the analysis, the mean difference in overall health and QOL over this time frame was 1.0 (95% CI, –4.6 to 6.5; P = .7324).
“The safety findings are consistent with the known profiles of durvalumab and tremelimumab,” Larkin concluded. “The results of the durvalumab vs active monitoring comparison—that’s arm B vs arm A—are expected in 2026 depending on how quickly rates accrue.”
Disclosures: Larkin reported receiving honoraria from Roche, Novartis, iOnctura, BMS, Pfizer, Incyte, Dynavax, CRUK, GSK, Eisai, Merck, touchIME, and touchExperts; performing consultancy roles with Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, and Apple Tree; receiving speaker fees from BMS, Pfizer, Incyte, Roche, Pierre Fabre, AstraZeneca, Novartis, EUSA Pharma, MSD, Ervaxx, Merck, GSK, Ipsen, Aptitude, Eisai, Calithera, Ultimovacs, and Seagen; receiving institutional research support from BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo, and Iovance; receiving grants from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, and Pharmacyclics.
References
- Larkin J, Powles TB, Frangou E, et al. First results from RAMPART: an international phase III randomised-controlled trial of adjuvant durvalumab monotherapy or combined with tremelimumab for resected primary renal cell carcinoma (RCC) led by MRC CTU at UCL. Presented at: 2025 ESMO Congress; October 17-25, 2025; Berlin, Germany. Abstract LBA93.
- Renal adjuvant multiple arm randomised trial (RAMPART). ClinicalTrials.gov. Updated September 7, 2020. Accessed November 6, 2025. https://www.clinicaltrials.gov/study/NCT03288532
