In the Clinic . . .
SH is a 47-year-old woman with a history of hypothyroidism and menopause who was diagnosed in March 2019 with Fuhrman grade III clear cell renal cell carcinoma (RCC), pT1b (Table 1). Her tumor was initially resected with laparoscopic right radical nephrectomy. No surveillance follow-up was performed. Her family history was notable for multiple malignancies, including gastric cancer in a sister at age 35, smoking-related lung cancer in her mother, and prostate cancer in her grandfather.
In June 2023, liver lesions were incidentally identified during laparoscopic cholecystectomy. Subsequent computed tomography (CT), fluorodeoxyglucose positron emission tomography, and magnetic resonance imaging demonstrated multiple liver metastases and a heterogeneous pancreatic body/tail mass. CT-guided liver biopsy confirmed metastatic clear cell RCC without sarcomatoid features. Laboratory evaluation showed anemia, elevated lactate dehydrogenase, normal renal and hepatic function, and normal calcium. She had an Eastern Cooperative Oncology Group performance status of 1 with mild gastrointestinal symptoms. At this point, SH was diagnosed with metastatic RCC involving the liver and pancreas, with an intermediate-risk International Metastatic RCC Database Consortium (IMDC) score based on anemia.
Given rapid progression and the need for prompt disease control, she initiated first-line nivolumab plus cabozantinib in September 2023. Imaging showed a marked response, with reduction of the liver lesion from 34 mm to 7 mm and the pancreatic lesion from 56 mm to 19 mm by September 2024, consistent with partial response by Response Evaluation Criteria in Solid Tumors. The patient did experience cabozantinib-associated diarrhea that required dose reduction and grade 2 eczematous rash, as well as grade 2 pneumonitis attributed to nivolumab, which required corticosteroid treatment.
In February 2025, SH developed progression in the lung, liver, and bone; lung biopsy confirmed metastasis of the clear cell carcinoma. A next-generation sequencing panel revealed multiple alterations, including mutations in CDKN2A and TP53, and an overall high tumor mutational burden (TMB-H; 13.3 mutations/Mb). She received second-line axitinib with partial response, followed by progression in the brain and lung in September 2025. Despite hospitalization and treatment owing to seizures and clinical deterioration, SH died in January 2026.
aRCC: Disease Overview and Epidemiology
In 2026, an estimated 80,450 new cases of kidney and renal pelvis cancers are expected to be diagnosed, making it the seventh-most common cancer diagnosis in the United States.1 Kidney cancer is more common in men than in women, with a median age at diagnosis of 65 years and 77.9% of diagnoses occurring in patients 55 years and older.
Renal cell carcinoma (RCC), the most frequently occurring kidney and renal pelvis cancer, is classified as having either clear cell histology (approximately 70%) or non-clear cell histology (including papillary RCC, chromophobe RCC, and other rare subtypes of RCC).2 Smoking, obesity, hypertension, and exposure to certain carcinogenic chemicals have been identified as risk factors for RCC. The classic triad of flank pain, gross hematuria, and palpable abdominal mass is present in fewer than 10% of patients and typically indicates advanced disease. In the current era of widespread cross-sectional imaging, the majority of RCC is detected incidentally, with incidental diagnosis rates ranging from 37% to 61%. A subset of patients present with de novo metastatic disease in the absence of localizing symptoms.3
In addition, between 6% and 9% of RCC tumors are attributed to the presence of germline cancer-causing mutations.4 The most recent revision (published in 2022) from the World Health Organization of the classification of urogenital tumors included molecular-driven groupings of RCC: SMARCB1-deficient medullary RCC, TFEB-altered RCC, ALK-rearranged RCC, and ELOC-mutated RCC.5
Compared with the overall RCC patient population, advanced RCC (aRCC), which includes metastatic disease, has a significantly lower 5-year relative survival (79.2% vs 20.3%).1 RCC is marked by a high propensity for metastasis, often occurring at multiple distant metastatic sites, the most frequent being the lung (45%), bone (30%), liver (20%), and brain (8%).6,7 Among these, bone is a particularly challenging metastatic site in aRCC and is associated with poorer clinical outcomes—reduced progression-free survival (PFS) and overall survival (OS), and increased overall burden of illness through skeletal-related events such as pathologic fractures, spinal cord or nerve root compression, and hypercalcemia.8-10
In aRCC, the duration of response (DOR)—how long tumor shrinkage or disappearance is maintained following treatment—is becoming increasingly important as a treatment outcome. The introduction of immunotherapy and targeted therapies has markedly improved the percentage of patients who achieve durable responses, with some lasting several years.
aRCC Treatment Landscape
The treatment of first-line aRCC has evolved from a reliance on vascular endothelial growth factor (VEGF)–targeted tyrosine kinase inhibitors (TKIs) to an increasing incorporation of immunotherapy (IO)-based combinations. These combinations include both dual immune checkpoint inhibitor (ICI)–IO regimens (nivolumab plus ipilimumab) as well as IO–TKI combinations including pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, avelumab plus axitinib, and cabozantinib plus nivolumab.11-19
Approved over the past decade, these combination regimens (Figure 1) are now the standard of care in aRCC, with superior OS, PFS, and response rates compared with prior single-agent regimens. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Kidney Cancer (version 2.2026) include most of these ICI–IO and IO–TKI combination regimens as Category 1 preferred recommendations in the first-line setting for patients with either favorable or intermediate/poor-risk disease.20 One exception is the combination of avelumab plus axitinib, which carries a Category 2A other recommendation in either risk group, as it is the only first-line combination that failed to demonstrate a statistically significant OS improvement.
The choice of which combination regimen to initiate is nuanced and based on considerations such as disease risk stratification, comorbidities, toxicity profiles, and patient preferences. Additional factors include the urgency of response: in patients with high disease burden or rapidly progressive disease, IO–TKI combinations may be preferred, given their higher objective response rates (ORRs) and faster depth of response (DepOR). In contrast, IO–IO combinations may be favored when a more durable response is the primary goal and immediate tumor reduction is less critical. Furthermore, in patients with sarcomatoid differentiation, IO–IO combinations—particularly nivolumab plus ipilimumab—are generally preferred, given the robust and durable responses observed in this histological subgroup. Further, the subcutaneous formulations of the IOs nivolumab and pembrolizumab are now available and indicated for use across the same solid tumor indications approved in adults as the intravenous formulations, providing patients with a potentially more flexible and convenient alternative route of administration for their IO, particularly when combined with a TKI tablet that can be taken at home.21,22
In SH’s case, first-line cabozantinib plus nivolumab was initiated, and therefore is the focus here. This IO–TKI regimen provides an example of a combination with the potential to achieve both immune modulation and antiangiogenic activity.
Cabozantinib Plus Nivolumab as First-Line Therapy for aRCC
MOA Considerations
The TKI cabozantinib has been shown to inhibit MET, AXL, and VEGFR, tyrosine kinases overexpressed in aRCC tumor cells and important in tumor cell proliferation and metastasis, tumor angiogenesis, and immune cell regulation.14 Although its clinical significance is unknown, this inhibition may be important for the immunomodulatory properties attributed to cabozantinib. These immunomodulatory properties may attenuate tumor-induced immunosuppression, and in this way cabozantinib may increase the nivolumab-mediated antitumor response induced by immune-checkpoint inhibition (Table 2).23-36
CheckMate-9ER: Efficacy Outcomes
CheckMate-9ER was a phase 3, randomized, open-label trial designed to compare the efficacy and safety of the combination of cabozantinib plus nivolumab in a head-to-head fashion with sunitinib monotherapy.18 Patients (N=651) with previously untreated aRCC with a clear cell component were randomized to either treatment arm, stratified by IMDC risk group (favorable vs intermediate vs poor), PD-L1 tumor expression (≥1% vs <1% or indeterminate), and geographic region (United States, Canada, and Western and Northern Europe vs rest of the world). Treatment was continued until disease progression or unacceptable toxicity, and the primary analysis included a median follow-up of 18.1 months (range, 10.6-30.6 months).
Baseline characteristics were balanced across the treatment arms.18 The median age was 62 years (range, 29-90) in the cabozantinib plus nivolumab arm and was 61 years (range, 28-86) in the sunitinib arm. Most patients had a Karnofsky performance status of 90 or higher (77.6% and 73.4%, respectively), and about one-half (51.7% and 52.7%, respectively) had metastatic disease. A total of 79% of the total study population had metastatic involvement of 2 or more organs, which is nearly double that seen in the real-world aRCC population (<40%).7 The most common metastases were lung (75%), bone (23%), and liver (19%). The percentage of patients with a favorable IMDC risk score was restricted, with their enrollment limited to 22% of the study population; the remaining patients had either an intermediate (58%) or a poor (20%) IMDC risk score, representing the real-world aRCC population.37,38
PFS was the primary endpoint of the CheckMate-9ER study (Table 3).18 The primary analysis of the intention-to-treat population demonstrated a significant 49% reduction in the risk of progression or death with cabozantinib plus nivolumab compared with sunitinib (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64; P<.001). Median PFS was 16.6 months in the combination arm, which was double that reached in the sunitinib arm (8.3 months). More recently, the 5-year follow-up analysis (median follow-up of 67.6 months) demonstrated that this median PFS remained consistent (16.4 vs 8.3 months; HR, 0.58; 95% CI, 0.49-0.70).39 No formal statistical testing was conducted at the time of the updated analysis.
The ORR was doubled in the combination arm vs the sunitinib arm in the primary analysis (55.7% vs 27.1%; P<.001; Table 3).18 It remained consistent at the 5-year follow-up in both arms (55.7% vs 27.4%). Furthermore, responses with cabozantinib plus nivolumab treatment deepened with time—the complete response rate of 8.0% with cabozantinib plus nivolumab at the primary analysis increased to 13.9% at the 5-year analysis, whereas that with sunitinib was the same at both analyses (4.6%).
Cabozantinib plus nivolumab combination was associated with a significant benefit in OS vs sunitinib (HR, 0.60; 98.89% CI, 0.40-0.89; P=.001).18 Median OS was not reached in either treatment arm in the primary analysis, although an early and sustained separation of the treatment arms was evident in the Kaplan-Meier analysis. At the 5-year follow-up, median OS was 46.5 months with cabozantinib plus nivolumab compared with 35.5 months with sunitinib.39
CheckMate-9ER: Safety Outcomes
The most frequent adverse reactions of any grade reported with cabozantinib plus nivolumab vs sunitinib were diarrhea (64% vs 47%), fatigue (51% vs 50%), hepatotoxicity (44% vs 26%), palmar-plantar erythrodysesthesia (40% vs 41%), and stomatitis (37% vs 46%).18 Grade 3 or 4 adverse reactions reported with cabozantinib plus nivolumab vs sunitinib included hypertension (13% vs 14%), hepatotoxicity (11% vs 5%), fatigue (8% vs 8%), and palmar-plantar erythrodysesthesia (8% vs 8%). Discontinuations owing to adverse reactions were 19.7% in the cabozantinib plus nivolumab arm (6.6% discontinued nivolumab only, 7.5% discontinued cabozantinib only, and 5.6% discontinued both agents) vs 16.9% in the sunitinib arm.
CheckMate-9ER: Exploratory Analysis by Metastatic Site
An exploratory analysis (conducted at the 5-year follow-up) demonstrated the efficacy of cabozantinib plus nivolumab vs sunitinib across patient subgroups with different metastatic involvement (Table 3).39 In patients with liver metastasis, median PFS was 10.9 vs 6.9 months (HR, 0.55; 95% CI, 0.37-0.82) and in patients with bone metastases (who typically have a poor prognosis40), it was 13.8 months vs 5.3 months (HR, 0.43; 95% CI, 0.30-0.64).
CheckMate-9ER: Exploratory Analysis of Quality of Life
An exploratory analysis (conducted at the primary analysis) focused on quality of life (QOL) using the Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19) questionnaire.18 In the cabozantinib plus nivolumab arm, the mean FKSI-19 score was numerically maintained near baseline for more than 1.5 years, whereas in the sunitinib arm it deteriorated below baseline (in some cases over 3 points [considered a meaningful difference in QOL]) over the same time period. A disease-related symptoms subscale of the FKSI-19 showed an improvement above baseline in the cabozantinib plus nivolumab arm but a decrease below baseline in the sunitinib arm.
Durability of Response With Cabozantinib Plus Nivolumab in aRCC
A post hoc analysis, using data from the final 5-year follow-up of the CheckMate-9ER study (median follow-up, 67.6 months), was conducted to characterize DepOR in patients treated with cabozantinib plus nivolumab.41 DepOR, defined as the best percentage reduction from baseline in sum of diameters of target lesions, has been linked with improved efficacy outcomes and may be an early indicator of durable efficacy in patients receiving ICI-based regimens or targeted therapies.42-45
Among the 293 patients alive at a 6-month post-randomization landmark, 45 (15%) had achieved a complete response. Three subgroups of patients with partial responses were defined according to best percentage reduction in sum of diameters of target lesions—PR1: at least 80% (27 patients [9%]), PR2: at least 60% to less than 80% (38 patients [13%]), and PR3: less than 60% (70 patients [24%]). The median time to response was 2.8 to 2.9 months. Responses were observed even in patients with baseline characteristics associated with poor prognosis in aRCC, including poor IMDC prognostic risk score, sarcomatoid features, 2 or more metastatic sites, and liver metastases.
The response in patients with a complete response was durable (Table 4), as the median DOR was not yet reached at the time of analysis.41 Among those with a partial response, the median DOR lengthened with greater tumor reduction, increasing from 10.8 months in the PR3 subgroup to 21.7 months in the PR2 subgroup and 22.1 months in the PR1 subgroup. Importantly, durable responses were maintained after patients discontinued treatment.
Greater DepOR was associated with prolonged PFS (Figure 2).41 This was most apparent in patients with a complete response, among whom the median PFS was not reached. In patients with a partial response, the median PFS lengthened with greater tumor reduction; median PFS was 9.4 months, 18.9 months, and 18.8 months in the PR3, PR2, and PR1 subgroups, respectively. By comparison, in patients with stable disease, the median PFS was 5.9 months.
Similar trends were observed with OS, which was lengthened with greater DepOR (Figure 2).41 The median OS was not reached in those with a complete response, and in patients with a partial response increased from 41.9 months in the PR3 subgroup to 63.2 months in the PR2 subgroup and 51.6 months in the PR1 subgroup.
The median duration of cabozantinib plus nivolumab treatment was prolonged among those patients who achieved a response as compared with patients with stable disease or progressive disease.41 Even with this longer treatment exposure, patients with a response did not experience markedly higher rates of treatment-related adverse events (Table 5) compared with patients who did not experience a response (any grade: 99% vs 100%, respectively; grade 3 or 4: 72% vs 67%, respectively). In responding patients, the most frequently reported grade 3 or 4 treatment-related adverse events were similar to those in the overall population, and included hypertension (13%), diarrhea (9%), hyponatremia (8%), and palmar-plantar erythrodysesthesia syndrome (8%).
These post hoc exploratory analyses are descriptive in nature. No statistical procedure was employed. Results should be considered hypothesis-generating.
Cabozantinib Plus Nivolumab: Dosing and Administration in aRCC
In patients with previously untreated aRCC, the recommended starting dosage of cabozantinib is 40 mg once daily by mouth (single tablet dose), continued until disease progression or unacceptable toxicity (Table 6).14 It is combined with nivolumab, which may be administered either intravenously (240 mg every 2 weeks or 480 mg every 4 weeks) or subcutaneously (600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks). Both formulations of nivolumab are administered for up to 2 years or until disease progression or unacceptable toxicity.
In the event of intolerable grade 2 adverse reactions, any grade 3 or 4 adverse reactions, or any-grade osteonecrosis of the jaw, it is recommended to withhold cabozantinib.14 In some cases, prolonged exposure to cabozantinib plus nivolumab may result in chronic grade 2 toxicities that require a dose reduction for management. Following resolution or improvement of the adverse reaction, cabozantinib is restarted at a reduced dosage (20 mg once daily for the first reduction; 20 mg once every other day for the second reduction). Two cabozantinib tablets are available: a 40 mg tablet and a 20 mg tablet.
Back to the Clinic . . .
This patient case reflects several clinically recognizable trajectories in the management of aRCC. First, the patient experienced relapse approximately 3 years after nephrectomy, which is consistent with the known biology of RCC, where recurrence may occur even after a prolonged disease-free interval. This reinforces the importance of regular surveillance with imaging after nephrectomy, even in patients with initially localized disease.46
At relapse, the patient presented with visceral metastatic disease involving the liver and pancreas, a setting in which rapid disease control is clinically important. The decision to initiate first-line cabozantinib plus nivolumab was made because of the need for prompt tumor shrinkage, as was demonstrated in the CheckMate-9ER study, which showed a rapid median time to response of 2.8 months with this regimen. SH’s initial response was deep and relatively rapid, with an approximately 80% reduction in target lesions, consistent with the activity expected from an IO–TKI combination.
There are also relevant mechanism of action considerations supporting cabozantinib in this setting. In addition to VEGFR inhibition, cabozantinib targets MET and AXL, pathways implicated in tumor invasiveness, metastatic progression, and resistance biology. These mechanisms may be particularly relevant in patients with aggressive or visceral metastatic phenotypes, including liver involvement.47
The dosing approach was consistent with standard practice. Nivolumab was administered at 480 mg every 4 weeks, which may be more convenient than every-2-week dosing, and cabozantinib was initiated at 40 mg daily. Subsequent dose reduction to cabozantinib 20 mg daily because of diarrhea was consistent with guideline-based toxicity management and the prescribing information. Importantly, the patient maintained a meaningful response despite dose reduction, illustrating that dose modification can preserve treatment exposure without necessarily compromising disease control.48
The durability of response was clinically meaningful, and was in line with what was expected from this combination. The patient remained on cabozantinib plus nivolumab for approximately 16 months before disease progression, which aligns with the typical PFS time frame observed in the CheckMate-9ER study (median PFS, 16.6 months with this regimen). Although the patient achieved a deep partial response, the development of acquired resistance after 1 to 2 years thus reflects a common treatment outcome.
Overall, this case highlights several practical lessons for clinical care. First-line IO–TKI therapy can produce rapid and substantial responses in patients with visceral metastatic aRCC, including liver and pancreatic disease.49 Toxicity management is essential to maintain treatment exposure and optimize benefit. The case also demonstrates that subsequent VEGFR TKIs, such as axitinib, may retain activity after prior cabozantinib-based therapy. Finally, the later development of brain metastases underscores the growing importance of central nervous system surveillance as patients live longer and receive multiple lines of therapy.
Disclosures
Dr Barata has received fees from: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Caris Life Sciences, Dendreon, Eisai, EMD Serono, ESSA Pharma, Exelixis, Guardant Health, Ipsen, Janssen, Merck, Merus, Myovant, Novartis, OncLive, Pfizer, Seattle Genetics, Targeted Oncology, and UroToday; and has share options in: Luminate Medical.
Dr Macharashvili has no disclosures to report.
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