In our recently published Nature Communications article, “Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence”, we report the first-ever prospective clinical trial dedicated specifically to patients with RMC (NCT03274258). The results were not what we had hoped for, but they delivered a clear and practice-changing message.
Why we tested nivolumab plus ipilimumab in RMC
Before this trial, the evidence for ICT in RMC consisted of anecdotal responses and small case series, some suggesting that PD-1/PD-L1 blockade could benefit a subset of patients. At the same time, our own molecular work and that of others indicated that RMC is characterized by an inflamed tumor microenvironment and extensive immune checkpoint upregulation – features that, in other tumor types, often predict benefit from ICT.
Given the dramatic activity of nivolumab plus ipilimumab in metastatic clear cell RCC, it was rational and ethically appropriate to prospectively evaluate this combination in RMC. We therefore designed a single-arm, phase II study with objective response rate (ORR) as the primary endpoint and prespecified futility rules.
Ten patients with RMC were enrolled between 2018 and 2020. They were predominantly young, Black individuals with sickle cell trait and high-volume metastatic disease – a clinical population familiar to anyone who has treated RMC in a tertiary center.
What we observed in the clinic: hyperprogression, not benefit
The clinical signal was unambiguous. There were no confirmed objective responses. All 10 patients experienced rapid disease progression, and 5 of 10 met radiologic criteria for hyperprogression, defined using established RECIST-based rules. Median progression-free survival was only 1.38 months (95% CI 1.28–1.60), and median overall survival was 8.23 months.
In practical terms, most patients received just two doses of nivolumab plus ipilimumab before their disease escalated dramatically, often with explosive growth of existing lesions and rapid appearance of new metastases. These were not subtle changes that required central review to appreciate; they were clinically obvious to the treating team and devastating for patients and families.
For a disease with such a narrow therapeutic window, this matters. Patients with RMC often have only one or two realistic opportunities for systemic control. Spending one of those opportunities on a regimen that not only fails to help but may actually accelerate progression is not acceptable once we recognize the risk.
Beyond the clinic: dissecting the biology of hyperprogression
The second half of our study asked a simple question: why did this happen?
To address this, we performed single-cell RNA sequencing on fresh tumor biopsies obtained from RMC patients before treatment and, in two cases, at progression on nivolumab plus ipilimumab. We analyzed 23,880 cells after stringent quality control and identified tumor cells based on copy-number variation patterns inferred from the single-cell data.
Several key findings emerged:
- Combination ICT induced a robust interferon-γ (IFNγ) response in the tumor microenvironment, especially in T cells, exactly what one might expect from effective checkpoint blockade.
- However, RMC tumor cells responded to this IFNγ-rich milieu in a maladaptive way: they activated a “myeloid mimicry” transcriptional program, adopting myeloid-like features that are normally associated with immune-suppressive myeloid cells.
- This program was orchestrated by a CEBPB/p300 signaling axis, and it was tightly linked to pathways promoting proliferation and survival.
To test causality, we turned to our immunocompetent somatic-mosaic genetically engineered mouse model (SM-GEMM) of RMC. In this in vivo system, combination ICT with anti-PD1 plus anti-CTLA4 antibodies (corresponding to the same therapeutic targets as nivolumab plus ipilimumab in humans) again accelerated tumor growth and activated myeloid-affiliated transcriptional circuits in tumor cells, mirroring the patient data.
Crucially, pharmacologic inhibition of p300, a key co-activator within this axis, suppressed the myeloid mimicry program and restored sensitivity to ICT in the mouse model. This provides proof-of-principle that hyperprogression in RMC is not an unavoidable consequence of ICT, but a targetable adaptive resistance mechanism.
What does this mean for practicing urologists and oncologists?
From a clinical standpoint, the message is straightforward:
- In RMC, nivolumab plus ipilimumab should not be used outside of a clinical trial at this time. The combination was not just ineffective; in half of treated patients it was associated with radiologic hyperprogression and very short PFS.
- These data complement and help explain prior prospective reports suggesting limited benefit of ICT in RMC and highlight the danger of extrapolating immunotherapy success in clear cell RCC to biologically distinct rare subtypes.
- Whenever possible, patients with suspected or confirmed RMC should be referred early to centers with expertise in this disease and access to clinical trials. Platinum-based chemotherapy and other mechanism-guided strategies remain the current mainstays of systemic treatment.
Broader implications: hyperprogression as a tractable problem
Although RMC is rare, the concepts emerging from this work may resonate more broadly with colleagues treating other ICT-resistant cancers:
- Hyperprogression is not a vague clinical impression; it can reflect a tumor-intrinsic adaptive program triggered by immune activation.
- That program – here, myeloid mimicry via CEBPB/p300 – may be both measurable (through translational profiling) and targetable (with epigenetic or transcriptional modulators).
- Rational combination strategies, such as adding agents that block these adaptive programs to ICT, could potentially convert hyperprogression into benefit in selected settings.
A “negative” trial that moves the field forward
It is never easy to conduct a trial in which every patient progresses quickly and no one benefits clinically from the experimental regimen. But for rare, aggressive cancers like RMC, learning what does not work – and why – is essential.
By rigorously documenting hyperprogression with nivolumab plus ipilimumab and uncovering the myeloid mimicry mechanism underlying it, this first dedicated RMC trial has already had a tangible impact: sparing future patients from ineffective and potentially harmful therapy, while opening a new mechanistic avenue for drug development.
In that sense, this “negative” trial is a critical step forward in our effort to finally change the trajectory of RMC for our patients and their families.
Written by: Pavlos Msaouel, MD, PhD, Associate Professor, Genitourinary Medical Oncology & Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX
Read the Abstract