Real-World evidence shows no survival advantage with contemporary first-line strategies in papillary renal cell carcinoma: A call for randomized trials

Abstract

Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC subtype, yet prospective evidence guiding first-line systemic therapy remains limited. The phase 2 PAPMET trial in molecularly unselected pRCC and the phase 3 SAVOIR trial in MET-driven pRCC demonstrated clinical benefit, but neither showed overall survival improvement and were limited by small sample size (Pal et al., Lancet 2021; Choueiri et al., JAMA Oncol 2020). In this context, as IO-based combinations have gained traction in clinical practice following promising activity in single-arm studies, we leveraged real-world data (RWD) to characterize evolving treatment patterns and associated outcomes in pRCC. Method(s): Patients with pRCC were retrospectively identified from the ConcertAI Patient360TM RCC Dataset, a US-based de-identified, human curated comprehensive real-world dataset, generated from multiple electronic medical record systems and linked with medical and pharmacy claims as well as third party date of death information. Histology was defined by ICD-O-3 codes (8260/3, 8050/2, 8050/3, 8052/2, 8052/3, 8130/2, 8130/3) and NCI System codes (C27886, C27887), excluding clear cell papillary RCC (8323/1). Among patients with metastatic disease who received first-line systemic therapy, regimens were categorized as tyrosine kinase inhibitors (TKIs), IO (monotherapy or IO/ IO), MET inhibitors (METi), mTOR inhibitors (mTORi), or IO-based combinations (IO/TKI or IO/METi). Temporal trends, demographics, and outcomes were assessed. Real-world PFS (rwPFS) and overall survival (rwOS) were estimated using Kaplan-Meier methods and compared across treatment groups. Cox models evaluated associations between treatment and survival with adjustment for clinical and demographic factors. Result(s): Of 391 patients with pRCC, 385 (98.5%) had metastatic disease, of whom 216 (55.2%) initiated first-line systemic therapy between January 1, 2016, and May 1, 2024, and were included in the analyses. Median age was 65.6 years (IQR, 56.4-76.3), and 75.6% were male. Most were treated in community settings (89.4%). Patients were primarily White (61.0%) or Black/African American (26.0%); 5.5% were Hispanic or Latino. Most were from the South (40.3%), Midwest (16.1%), or Northeast (15.6%). TKIs were the most frequently used first-line regimen (49.5%), followed by IO (21.8%), METi (15.3%), IO/ TKI or IO/METi (10.6%), and mTORi (2.8%). TKIs predominated from 2016 to 2019, after which IO and IO-based combinations became the most common first-line therapies. Median rwPFS was 5.4 months (95% CI, 4.07-7.06) for TKIs, 5.0 (2.52-6.30) for IO, 4.9 (2.95-8.93) for METi, 2.4 (1.80-12.74) for IO/TKI or IO/METi, and 2.0 (0.32-3.21) for mTORi. Median OS was 14.6 months (10.50-19.90) for TKIs, 18.7 (15.00-26.10) for IO, 14.8 (9.80-24.80) for METi, 9.3 (5.19-37.45) for IO/TKI or IO/METi, and 6.9 (0.32-11.10) for mTORi. Results were similar after adjustment for age, gender, race, geographic region, practice setting, stage at diagnosis, and ECOG. Conclusion(s): In this national RWD cohort of metastatic pRCC, a shift toward IO and IO/TKI or IO/METi combinations was observed in recent years. However, survival outcomes remained similar across treatment groups. These findings underscore the need for phase 3 randomized trials. Ongoing studies such as STELLAR-304 (NCT05678673) and SAMETA (NCT03091192) reflect the current clinical equipoise and are essential to defining optimal first-line therapy in metastatic pRCC..