Perioperative pembrolizumab added to MDT improves RFS in oligometastatic RCC

Adding perioperative pembrolizumab (Keytruda) to metastasis-directed therapy (MDT) significantly prolonged relapse-free survival (RFS) compared with MDT alone in patients with oligometastatic clear cell renal cell carcinoma (ccRCC). The findings come from the randomized phase 2 PE-PE trial (NCT05578664), presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.¹

At a median follow-up of 17.5 months, median RFS was 25.4 months in the pembrolizumab arm vs 11.0 months in the MDT-alone arm (HR, 0.47; 95% CI, 0.24 to 0.92; P = .024).

“Although patients with oligometastatic RCC can be treated with anti-PD1-based combinations, most receive local therapy as the first option,” explained presenting author Roberto Iacovelli, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, during the presentation at ESMO. “Two trials in the past failed to demonstrate any benefit from postoperative VEGFR-TKI [therapy]. The PE-PE trial aimed to evaluate whether perioperative pembrolizumab can reduce the risk of relapse in patients with oligometastatic RCC eligible for metastasis-directed therapy.”

Trial design and population

PE-PE is an investigator-initiated, open-label, multicenter trial conducted in Italy. Investigators enrolled 85 patients who were randomly assigned 2:1 to pembrolizumab (n = 56) or MDT alone (n = 29). In the pembrolizumab arm, patients received 1 cycle of pembrolizumab 400 mg intravenously 3 weeks before MDT, followed by 8 cycles every 6 weeks. MDT consisted of surgery and/or stereotactic ablative radiotherapy (SABR) at investigator discretion.

Patients were eligible for enrollment if they had RCC with clear cell histology, a previous nephrectomy, an ECOG performance status of 0 or 1, no brain metastases, and no previous systemic therapy for RCC. The investigators applied trial-specific criteria for oligometastatic disease. New metastases had to appear within 5 years of nephrectomy or of a previous metastasectomy. Up to 3 lesions were allowed, or 2 if bone was involved. Each lesion had to measure 3 cm or less, with the sum of diameters no greater than 5 cm.

The primary end point was RFS. Secondary end points included distant RFS, overall survival (OS), and safety.SABR was the most common form of MDT in both arms, used in 75.9% of patients in the pembrolizumab + MDT arm and 72.4% of patients in the MDT alone arm.

The median age was 64 years in each arm. Most patients had International Metastatic RCC Database Consortium (IMDC) favorable-risk disease (77.8%, pembrolizumab + MDT and 75.9%, MDT alone). More than 85% of patients in each arm were randomly assigned more than 1 year after nephrectomy.

Efficacy

Relapse events occurred in 19 patients in the pembrolizumab arm and 16 in the MDT-alone arm. The median RFS was 25.4 months in the pembrolizumab plus MDT arm vs 11.0 months in the MDT alone arm(HR, 0.47; 95% CI, 0.24 to 0.92; P = .024).

Prespecified exploratory subgroup analyses by sex, age, type of MDT, and number of lesions all had point estimates favoring pembrolizumab, with HRs ranging from 0.34 to 0.62. Confidence intervals crossed 1 in every subgroup except patients treated with SABR (HR, 0.47; 95% CI, 0.22 to 0.97).

Median distant RFS was 25.4 months with pembrolizumab plus MDT vs 11.5 months with MDT alone.

“It’s important to note here that 94% of patients progress in a different site [from] where they receive the metastasis-directed therapy,” Iacovelli said during the presentation.

OS was immature at the time of data report. Each arm had 1 death, translating to a 24-month OS of 97.8% in the pembrolizumab plus MDT arm and 96.2% in the MDT alone arm.

Safety

Any adverse event occurred in 80.4% of patients receiving pembrolizumab plus MDT and 20.7% of those receiving MDT alone. Grade 3 or higher adverse events occurred in 7.1% and 3.4% of patients, respectively.

Pembrolizumab-related adverse events occurred in 58.9% of patients in the treatment arm. Two of these (3.6%) were grade 3 or higher, consisting of 1 case of hyperglycemia and 1 case of diarrhea. The most common adverse events with pembrolizumab were hypothyroidism (23.2%), fatigue (17.9%), and diarrhea (16.1%). Pneumonitis occurred in 8.9% of patients, and none of these events were high grade.

SABR-related adverse events occurred in 5.4% of patients in the pembrolizumab arm and 6.9% of patients in the MDT-alone arm, with none grade 3 or higher. No surgery-related adverse events were reported in either arm.

Patients received a median of 6.6 pembrolizumab cycles, and 44.6% completed all 9 cycles. Treatment was stopped early because of disease progression in 17.9% of patients, patient decision or withdrawal in 10.7%, and adverse events in 7.1%.

“Despite the low disease burden and the long interval from previous nephrectomy, patients with oligometastatic RCC included in PE-PE trial and treated with metastasis-directed therapy alone continued to have a poor prognosis, with more than 50% experiencing disease progression within 1 year, and this may justify the inclusion of a medical treatment,” Iacovelli concluded during the presentation. “PE-PE trial is the first to show that perioperative and adjuvant pembrolizumab increases relapse-free survival in patients with oligometastatic RCC eligible for definitive therapy—surgery or SABR—within 5 years from previous nephrectomy or metastasectomy.”

REFERENCE
1. Iacovelli R, Volta AD, Bimbatti D, et al. PErioperative PEmbrolizumab (P) plus metastasis-directed therapy (MDT) versus MDT alone in patients (pts) with oligometastatic renal cell carcinoma (omRCC): The randomized phase II PE-PE trial. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract LBA88. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/LBA88.html.pdf