Meta-Analysis Characterizes Nivolumab/Ipilimumab Hyperprogression in Renal Medullary Carcinoma

A systematic review and meta-analysis was conducted to synthesize available clinical evidence on nivolumab (Opdivo) plus ipilimumab (Yervoy) in renal medullary carcinoma (RMC), with particular focus on the signal of rapid progression and hyperprogression observed in this setting and the biologic correlates that may explain it.¹ Across the analyzed evidence base, outcomes were dominated by early treatment discontinuation and limited objective benefit, underscoring an urgent need to refine patient selection and to clarify tumor-intrinsic and immune mechanisms that may contribute to paradoxical acceleration on immune checkpoint blockade.

Key clinical findings drawn from the included dataset showed that all patients experienced rapid clinical and radiographic progression, including 5 of 10 patients meeting established radiologic criteria for hyperprogression. Treatment exposure was brief, with a median of 2 infusions (range, 1-6), and efficacy outcomes were poor, with a median progression-free survival (PFS) of 1.38 months (95% CI, 1.28-1.60) and median overall survival (OS) of 8.23 months (95% CI, 3.45-not estimable [NE]). Prespecified end points such as objective response rate, duration of response, and disease control rate were NE due to the absence of confirmed responses and uniformly rapid progression.

The FDA approved nivolumab plus ipilimumab for the frontline treatment of patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC) in April 2018.² The regulatory decision was supported by data from the phase 3 CheckMate 214 (NCT02231749) trial.

To elucidate the mechanistic underpinnings of the hyperprogression phenotype, investigators performed post-hoc single-cell RNA sequencing (scRNA-seq) on immunotherapy-naive fresh tumor biopsies from 7 patients with RMC and on tissues collected immediately following progression nivolumab plus ipilimumab from 2 patients.¹ After stringent quality control, 23,880 cells were profiled and assigned to 10 major cell types using canonical marker genes. Tumor cells were detected in 7 patients and retained for downstream analyses, whereas 2 samples without identifiable tumor cells were excluded. Malignant tumor clusters were supported by inferred genome-wide copy-number variations derived from scRNA-seq data. Pathway enrichment analyses showed expected activation of inflammatory programs, including interferon gamma (IFNγ) signaling—within the T-cell compartment following checkpoint blockade, but also demonstrated significant enrichment of DNA replication and cell-cycle pathways in the tumor cell compartment, consistent with the clinically observed hyperprogression.

How was this meta-analysis designed to evaluate CAR’s prognostic performance in RCC?

This study was designed as a PRISMA-guided systematic review and meta-analysis intended to clarify the prognostic role and clinical implementability of the C-reactive protein-to-albumin ratio (CAR) in RCC.

A systematic literature search was conducted across English-language databases (PubMed, EMBASE, and the Cochrane Library) from database inception through June 25, 2025, using MeSH and title/abstract terms capturing RCC and CAR (including CRP/Alb ratio variants). In addition to the electronic strategy, reference lists of retrieved articles were manually screened to identify eligible studies not captured in the initial search.

Study selection followed a sequential screening workflow (title/abstract review followed by full-text eligibility assessment). Two independent reviewers evaluated each candidate study for inclusion, with discrepancies adjudicated by a third reviewer serving as mediator.

Eligible studies were required to measure serum CAR prior to treatment initiation; enroll adults aged at least 18 years or older; include over 20 participants; use an observational design or randomized controlled trial framework; and report or allow derivation of TP/FP/FN/TN data to support pooled evaluation of CAR’s predictive performance in RCC. Exclusion criteria removed studies with insufficient prognostic performance reporting, animal/in vitro-only designs, duplicate/unclear datasets, or non-original research formats (reviews, abstracts, editorials/commentaries, and supplementary-only materials).

The meta-analysis was structured to synthesize evidence on CAR’s prognostic significance; potential mechanistic underpinnings; and future clinical applicability. To interrogate heterogeneity and generalizability, the investigators also prespecified subgroup analyses to compare predictive performance across countries/regions and across methodological and dimensional divisions.

What adverse effects were observed across studies in the analysis?

Treatment-emergent adverse effects (TEAEs) at least possibly related to study treatment demonstrated no unexpected toxicity signals. The only related grade 4 adverse effect (AE) was hypotension in 1 patient, which also met the protocol-defined prespecified extreme toxicity criterion. Related grade 3 AEs were infrequent and included increased alanine aminotransferase levels, anemia, and pain (n = 1 each). The most commonly reported related AE was decreased neutrophil count (n = 3).

Across all TEAEs regardless of attribution, all 10 patients experienced at least one adverse effect. Grade 3 or higher adverse effects included pain (n = 2) and abdominal pain, increased alanine aminotransferase, anemia, hypotension, and pericardial tamponade (n = 1 each). The most common AEs overall were back pain (n = 4), and pain, constipation, dyspnea, decreased neutrophil count, and proteinuria (n = 3 each).

References

1. Soeung M, Yan X, Zanca C, et al. Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence. Nature Communications. 2025;16(1). doi:10.1038/s41467-025-65462-z
2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed January 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell