Thomas E. Hutson, DO, PharmD, FACP
EDITORIAL NOTE | Editor-in-Chief, Kidney Cancer Journal
There is a particular kind of optimism that belongs only to a field in the midst of genuine transformation — not the breathless enthusiasm of early promise, but the sober, evidence-anchored confidence that comes from watching survival curves separate and hold. That is the optimism I bring to this editorial. In 2026, renal cell carcinoma (RCC) is no longer a disease we manage; for a growing proportion of patients, it is a disease we can cure. How we arrived here, what it means, and what it demands of us next is the subject of this note.
I write this column not to summarize trial data — our dedicated meeting report in this issue does that work thoroughly — but to offer the perspective that data alone cannot: the intellectual scaffolding beneath the numbers, the biological logic that connects bench discovery to bedside reality, and the unfinished business that remains despite this year’s remarkable progress.
I. The Biology Behind the Breakthroughs
Modern RCC therapeutics did not emerge from clinical intuition alone. They are the downstream consequence of decades of foundational science — most traceable to William Kaelin Jr., Peter Ratcliffe, and Gregg Semenza’s Nobel Prize-winning work on the hypoxia-inducible factor (HIF) pathway and the tumor suppressor role of the von Hippel-Lindau (VHL) protein. The VHL gene is mutated or silenced in approximately 90% of clear cell RCC, making HIF-2α activation not a peripheral feature of the disease but its molecular signature.
The arrival of belzutifan — an orally bioavailable, highly selective HIF-2α inhibitor — transformed that molecular insight into clinical medicine. What is remarkable about belzutifan’s trajectory is not simply its efficacy in advanced disease, but the speed and completeness with which it has migrated across the disease spectrum: from hereditary VHL disease, where it first demonstrated striking activity, to metastatic ccRCC after IO therapy, and now, compellingly, into the curative-intent adjuvant setting. The 2026 data confirm that HIF-2α inhibition is not a niche strategy for a genomic subtype — it is a fundamental therapeutic principle in clear cell RCC.
Parallel to HIF-directed therapy, our understanding of the tumor immune microenvironment in RCC has matured considerably. Early conceptual models of PD-1/PD-L1 blockade in RCC assumed a relatively immunogenic tumor with checkpoint-mediated exhaustion as the dominant suppressive mechanism. We now appreciate a far more complex picture: CD8+ T cell dysfunction in RCC spans multiple states — from early dysfunction amenable to reinvigoration, to deep exhaustion that is refractory to PD-1 rescue — and the spatial architecture of tumor-infiltrating lymphocytes, myeloid cell polarization states, and the composition of the stromal compartment all modulate response and resistance to checkpoint therapy. This mechanistic refinement has direct translational implications. The combination of CTLA-4 and PD-1 blockade, as exemplified by the long-term CheckMate 214 data, likely succeeds by targeting distinct phases of immune dysfunction simultaneously. The durvalumab plus tremelimumab data from RAMPART, now with full follow-up, adds further evidence that this dual-checkpoint strategy is operationally sound across disease settings.
“We are not simply extending survival — we are uncovering the biological logic of a cure, one pathway at a time.”
At the bench, several emerging biology areas deserve the field’s sustained attention. Tumor heterogeneity in RCC — both spatial and temporal — remains a major unsolved problem. Intratumoral evolutionary dynamics, wherein subclonal populations harboring distinct genomic alterations compete and evolve under therapeutic selection pressure, underlie the clinical phenomenon of acquired resistance. Single-cell RNA sequencing studies have begun to map these evolutionary trajectories in unprecedented detail, and liquid biopsy platforms are beginning to capture this heterogeneity non-invasively. The integration of multi-region sequencing with longitudinal ctDNA monitoring is, I believe, the next great experimental frontier in RCC biology — and its clinical translation is already beginning.
II. Biomarkers: From Aspiration to Clinical Tool
For much of the past decade, the search for predictive and prognostic biomarkers in RCC has been characterized by more negative results than positive ones. PD-L1 expression, the canonical biomarker of IO response in many tumor types, has proven unreliable in RCC — a consequence, perhaps, of the tumor’s dynamic and spatially heterogeneous immune contexture. Tumor mutational burden, central to checkpoint response prediction in microsatellite-unstable cancers, is also of limited utility in a disease where most tumors carry relatively low mutational loads.
The 2026 data from KEYNOTE-564’s ctDNA substudy therefore represents something genuinely new: a biomarker that is not merely prognostic but predictive of adjuvant treatment benefit, derived from blood rather than tissue, and actionable in real time. The finding that ctDNA-positive patients at baseline derive the greatest absolute benefit from adjuvant pembrolizumab — and that ctDNA-negative patients may achieve high event-free rates with or without treatment — transforms how we should conceptualize the adjuvant decision. It raises the possibility that pathologic staging alone, our current surrogate for recurrence risk, is an imperfect proxy for the molecular residual disease burden that actually drives outcomes.
Equally important is what ctDNA dynamics during treatment may tell us. Serial ctDNA measurement — baseline, landmark at 3 and 6 months, and surveillance post-treatment — could provide a pharmacodynamic readout of treatment effect that neither imaging nor symptom status can match. The challenge ahead is not conceptual but logistical and economic: standardizing ctDNA assay platforms, validating their performance across RCC subtypes and disease states, and establishing the clinical decision-making thresholds that would support their routine use. Academic-industry collaboration, including studies supported by assay developers and incorporated into NCI-sponsored cooperative group trials, will be essential to move from “biomarker-informed” to “biomarker-guided” practice.
Genomic Classifiers and Transcriptomic Signatures
Beyond ctDNA, the field is also moving toward tissue-based transcriptomic signatures that capture the immunophenotypic complexity of individual tumors. Gene expression profiling platforms — analogous to Oncotype DX in breast cancer or Decipher in prostate cancer — are in active development for RCC. These signatures aim to stratify patients not only by recurrence risk but by the probability of responding to specific therapeutic modalities: IO-based versus HIF-2α-directed versus VEGFR-TKI. If validated in prospective datasets, such platforms could fundamentally alter the pre-treatment assessment of newly diagnosed high-risk RCC.
The integration of imaging biomarkers — including radiomic features extracted from baseline CT and MRI, functional metabolic imaging, and novel PET tracers targeting carbonic anhydrase IX (CAIX) expression — represents a further dimension of precision that remains largely pre-clinical but is advancing rapidly. CAIX, a transcriptional target of HIF-1α, is a reliable immunohistochemical marker in ccRCC and has been explored both as a prognostic marker and as a therapeutic target in antibody-drug conjugate strategies currently in early clinical development.
III. The Regulatory and Commercial Landscape: A Year of Consequential Decisions
Clinical trial results do not exist in isolation — they enter a regulatory and commercial ecosystem that shapes how, when, and to which patients new therapies ultimately reach. The year 2026 has been a pivotal one on this front, and the decisions made in regulatory offices in Rockville, London, and Tokyo over the next 12 to 18 months will determine the near-term treatment landscape for our patients.
Belzutifan’s supplemental NDA, accepted by the FDA for priority review following the LITESPARK-011 data, is the most consequential pending approval in RCC. If granted — and the PFS data are compelling — it would establish belzutifan plus lenvatinib as the preferred second-line regimen for post-IO clear cell RCC, displacing cabozantinib monotherapy from the position it has occupied since the METEOR trial. This would represent the first time a post-IO standard has been defined by a mechanism other than VEGFR inhibition alone, and it would formalize HIF-2α blockade as an essential pillar of RCC therapeutics across disease settings.
Simultaneously, the regulatory pathway for combination adjuvant therapy is being actively charted. Pembrolizumab received FDA approval in the adjuvant RCC setting in 2021 based on KEYNOTE-564; the addition of belzutifan as a companion agent in that setting, supported by LITESPARK-022, will require a supplemental approval that accounts for the more complex toxicity profile of the combination, particularly the anemia and hypoxia management burden. How prescribers, pharmacies, and payer systems absorb a 12-month combination regimen of two novel agents in the adjuvant setting — where patients are otherwise NED and potentially curable with observation — will test the practical infrastructure of oncology practice. Shared decision-making, patient education, and proactive supportive care planning will be non-negotiable components of responsible implementation.
The Competitive Dynamics of the TKI Space
It would be intellectually incomplete to discuss the RCC treatment landscape without acknowledging the competitive pressures reshaping it. Cabozantinib, which established itself as a backbone agent in second- and later-line RCC through METEOR and subsequent combination studies, faces its most substantive challenge to date from the belzutifan-based data. Exelixis, the developer of cabozantinib, has responded with an active clinical program exploring cabozantinib in novel combinations — including the CaboNivo regimen, the phase 3 CONTACT and CABINET programs, and early exploration of zanzalintinib, a next-generation oral multi-kinase inhibitor with a differentiated safety profile. The competitive vitality of this space benefits patients: when multiple active compounds compete, the evidence base expands and combination strategies become increasingly sophisticated.
AstraZeneca’s durvalumab plus tremelimumab data from RAMPART add a new entrant to the adjuvant checkpoint conversation — one that brings a different CTLA-4 agent than ipilimumab and a different patient population enrichment strategy than KEYNOTE-564. Whether this regimen achieves regulatory approval, and in which jurisdiction first, will depend on the maturity of OS follow-up and the tolerance of regulatory agencies for DFS as a surrogate endpoint in the curative-intent setting. These conversations are active and important.
IV. Non-Clear Cell RCC and the Equity Imperative
Approximately one in five patients with RCC carries a non-clear cell histology — papillary, chromophobe, collecting duct, medullary, translocation-associated, or sarcomatoid-dedifferentiated variants — yet fewer than one in ten pivotal RCC trials have enrolled these patients in numbers sufficient to generate histology-specific efficacy estimates. This imbalance is not merely a scientific gap; it is an equity issue. The patients least likely to respond to therapies developed and validated in clear cell populations are the same patients most likely to be excluded from the trials that might define better options for them.
The 2026 data on cadonilimab plus axitinib in non-clear cell histologies are welcome precisely because they are prospective, multi-center, and histology-inclusive by design. The bispecific anti-PD-1/CTLA-4 mechanism of cadonilimab is biologically plausible across non-clear cell subtypes, many of which harbor significant inflammatory infiltrates despite the absence of VHL mutation. However, phase 1b/2 data, however promising, cannot substitute for randomized phase 3 evidence. The field should resist the temptation to extrapolate small-cohort data into guideline recommendations — and should equally resist the inertia that has delayed dedicated non-clear cell trials for too long.
The hereditary RCC syndromes — VHL disease, hereditary papillary RCC type 1 (MET mutations), Birt-Hogg-Dubé syndrome (FLCN), and succinate dehydrogenase-deficient RCC — also deserve mention in any discussion of RCC equity and diversity. These populations are small in absolute numbers but scientifically important, as they offer clean molecular contexts in which to study pathway-targeted therapy without the confounding heterogeneity of sporadic disease. Belzutifan’s success in VHL disease was the proof-of-concept that launched its broader development. The RCC field should continue to invest in the molecular characterization of rare subtypes — both because it is scientifically sound and because these patients deserve the same evidence-based standard of care as their sporadic clear cell counterparts.
V. Looking Ahead: The Unanswered Questions That Matter Most
For all that 2026 has given us, the work ahead is substantial. Let me identify the questions I believe are most consequential for the field’s next chapter.
Sequencing and De-escalation
We have established that combination therapies outperform monotherapies in multiple disease settings — but we have been slower to ask whether all patients need the full combination, and for how long. The clinical benefit of adjuvant pembrolizumab plus belzutifan over pembrolizumab alone is real, but it comes with significantly higher toxicity. As ctDNA and other biomarkers mature, the most important clinical trial design question of the next decade may be: can we identify the patients for whom adjuvant monotherapy — or even observation — is sufficient, and reserve combination regimens for those with the highest molecular residual disease burden? De-escalation trials, which remain counterintuitive in an era of expanding combination data, are both scientifically necessary and ethically obligated.
Resistance Biology and Re-challenge Strategies
Virtually every patient who achieves a response to current IO-based or HIF-directed therapy will eventually experience disease progression. The mechanisms of acquired resistance — both to checkpoint blockade and to belzutifan — are not yet well characterized in clinical samples. We need prospective biopsy programs at progression, integrated with whole-exome sequencing, transcriptomics, and single-cell profiling, to map the resistance landscape and identify therapeutic vulnerabilities at relapse. Re-challenge strategies — rechallenge with prior IO therapy, sequential HIF-2α inhibition following progression on a HIF-2α inhibitor, or novel combinations targeting resistance mechanisms — require evidence, not extrapolation.
Bone Metastasis as a Disease State
The RADICAL trial has opened a door that should not be closed again. Bone metastases in RCC represent a clinically distinct entity with unique biology — the skeletal microenvironment actively modulates tumor cell behavior, promotes osteolysis, and creates an immune-suppressive niche that systemic IO therapy penetrates poorly. Dedicated clinical programs in bone-metastatic RCC, exploring both bone-directed agents (radium-223, denosumab, novel RANKL pathway inhibitors) and systemic combinations optimized for the osseous tumor microenvironment, are long overdue. RADICAL has provided the safety and preliminary efficacy foundation; phase 3 infrastructure should be prioritized.
The Global Dimension
RCC is a global disease, but its evidence base is not. The cadonilimab data, generated by investigator groups in China, reflect a growing international contribution to the RCC evidence base — one that the field should welcome and build upon. At the same time, we must be attentive to the regulatory and access disparities that mean the same approvals achieved in the United States or European Union may take years to reach patients in South Asia, Sub-Saharan Africa, or Latin America. The Kidney Cancer Journal is committed to amplifying research from underrepresented regions and to reflecting, in its editorial content, the full global community of oncologists caring for RCC patients.
A Personal Note
I have been treating patients with kidney cancer for more than two decades. I was present when IL-2 was the only systemic option for metastatic disease — a therapy with real but narrow benefit and formidable toxicity. I watched sunitinib and sorafenib transform the field in the mid-2000s, and I have witnessed, in real time, the extraordinary evolution of the IO era from a promising hypothesis to a curative reality for a meaningful subset of our patients.
What I observe in 2026 is not merely incremental progress. It is the beginning of a coherent, mechanistically grounded therapeutic architecture — one in which we understand not just which drugs work, but why, for whom, and in what sequence. The convergence of HIF-2α biology, precision immunology, and liquid biopsy-guided patient selection gives me more reason for optimism today than at any previous point in my career.
But optimism without urgency is complacency. There remain patients for whom we have no effective second-line option after IO and VEGFR-TKI failure. There remain non-clear cell subtypes for which we have no FDA-approved first-line regimen. There remain underserved global populations who will not have access to belzutifan for years after it becomes standard in the United States. These realities are our responsibility — and they will define the ethical seriousness with which this journal continues to pursue its mission: to translate the science of kidney cancer into the practice of better, more equitable care.
The architecture of a cure is being built. The work of building it belongs to all of us.
Editor-in-Chief, Kidney Cancer Journal
Director of Research, Urologic Oncology, Baylor University Medical Center
Dallas, Texas, USA
Disclosures: The Editor-in-Chief has served as a consultant or advisory board member for Pfizer, Exelixis, Merck, AstraZeneca, and Bristol Myers Squibb. No commercial entity had editorial input into the content of this note.
