Efficacy of Cabozantinib, Nivolumab, and Ipilimumab Combination Therapy in Advanced Clear-Cell Renal-Cell Carcinoma

By: Shakhzoda Rakhimova, PharmD Candidate ℅ 2024


Renal-cell carcinoma (RCC) is a type of kidney cancer in which malignant epithelial cells are found in the lining of the renal tubules or renal cortex.1 Clear-cell renal-cell carcinoma (ccRCC) is the most common type, accounting for about 80% of all RCC cases.2  ccRCC is named aptly for its appearance: transparent tumor cells under the microscope.2 Common risk factors for RCC include obesity, analgesic abuse, hypertension, family history of RCC, and certain genetic conditions.3 The two most common genetic abnormalities associated with ccRCC are mutations of the Von Hippel–Lindau (VHL) and protein polybromo-1 (PBRM-1) genes. More specifically, decreased expression of both of these genes results in increased activity of the ccRCC tumor, and decreased expression of the VHL gene alone was associated with a decline in overall survival.4

RCC Staging

To understand the extent of the disease and determine an appropriate treatment plan, cancer is classified into stages. The staging classifications are unique to the specific type of cancer. For RCC, there are four stages, each dependent on the size of the tumor and its location. For example, stage I is when the tumor is local to the kidney and is less than or equal to 7 centimeters. Conversely, stage IV is when the tumor can be any size but has spread beyond the kidney into other organs such as the brain, liver, bones, lungs, or distant lymph nodes.5 The five-year survival rate for localized and distant RCC is 93% and 15%, respectively.6

ccRCC Clinical Presentation, Diagnosis & Treatment

The clinical presentation of renal cell carcinoma in adults includes a lump in the abdomen, blood in the urine, unexplained weight loss, loss of appetite, and anemia.3 Diagnosis consists of a physical evaluation, laboratory testing, and imaging. A physical evaluation includes examining a patient for signs of lumps in the abdominal region. Laboratory testing would include a urinalysis to examine for hematuria, and other factors such as menstruation, infection, or recent strenuous exercise should be ruled out.7 Treatment can include surgery, radiation, chemotherapy, or immunotherapy. Surgery can be an option for localized RCC and is usually followed by chemotherapy or radiation to eradicate any remaining malignant cells. Radiation utilizes high-energy rays to eliminate cancerous tumor cells. Chemotherapy can be used, though it has not had a tumor response of over 10% in clinical trials.5

Immunotherapy has been utilized at all stages, including as adjuvant therapy in post-nephrectomy or post-radiation patients, and in combination therapy for stage IV or recurrent RCC.5 Adjuvant immunotherapy can include Keytruda (pembrolizumab) or Sutent (sunitinib). Pembrolizumab is an immune checkpoint inhibitor and targets the programmed cell death protein 1 (PD-1) protein on the surface of T-cells.5 Sunitinib is a tyrosine kinase inhibitor (TKI) that targets the vascular endothelial growth factor (VEGF) to inhibit tumor growth.5 First-line treatment for metastatic ccRCC includes a combination of immunotherapies, including Cabometyx (cabozantinib) plus Opdivo (nivolumab), Yervoy (ipilimumab) plus nivolumab, or Lenvima (lenvatinib) plus pembrolizumab.8

Cabozantinib, Nivolumab, and Ipilimumab Overview

Protein kinase B (PKB or Akt) and the mammalian target of rapamycin (mTOR) are responsible for tumor cell proliferation and survival.9 Another mechanism of malignant tumor cell survival is through upregulating hypoxia-inducible factors (HIFs), which are transcription factors responsible for regulating oxygen delivery and can adjust in hypoxic conditions.10 They are also responsible for mediating factors involved in cell growth, such as transforming growth factor alpha (TGFα), platelet-derived growth factor (PDGF), and VEGF.10 mTOR can be activated by VEGF and PDGF signaling through Akt.10 Approved therapies for ccRCC include targeting VEGF receptors (VEGFRs), PDGF receptors (PDGFRs), or the mTOR/HIF pathway.10

Cabozantinib is an oral TKI that targets multiple receptors involved in tumor angiogenesis, including VEGFR.11 It is indicated for patients with advanced RCC, hepatocellular carcinoma (HCC), and metastatic thyroid cancer.12 It is also approved to be used in combination with nivolumab for RCC. The recommended dose in RCC is 60 mg as a single agent, or 40 mg when used in combination with nivolumab, once daily without food until disease progression or unacceptable toxicity is administered.12


Nivolumab is a monoclonal antibody that blocks the programmed death-receptor 1 (PD-1) receptor, allowing T-cells to attack the metastatic tumor.13 It is currently indicated for a plethora of cancers, including but not limited to RCC, non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, classical Hodgkin lymphoma, and squamous cell carcinoma of the head and neck.14 The recommended dose for advanced RCC is 240 mg every two weeks or 480 mg every four weeks when used as a single agent.14 

Ipilimumab is a monoclonal antibody that inhibits the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which allows for increased T-cell activity to be carried out. It is currently indicated for RCC, melanoma, NSCLC, colorectal cancer, HCC, malignant pleural mesothelioma, and esophageal cancer.15 The recommended dose in advanced RCC is 1 mg per kilogram intravenously over 30 minutes immediately following nivolumab 3 mg per kilogram intravenously over 30 minutes on the same day, every three weeks for four doses.15 

Previous Clinical Trials

The clinical trials leading up to the trial analyzing the efficacy of cabozantinib plus nivolumab and ipilimumab for patients with advanced ccRCC include the CABOSUN, the CheckMate 214, and the CheckMate 9ER clinical trials.

The CABOSUN clinical trial was a randomized, open-label, phase II, multicentered trial comparing cabozantinib with standard-of-care sunitinib in patients with advanced RCC which resulted in cabozantinib demonstrating a significant clinical benefit in progression-free survival and overall response over sunitinib.16 This trial led to the Food and Drug Administration’s (FDA’s) approval of cabozantinib as the first-line treatment in advanced RCC in 2017.17

The CheckMate 214 clinical trial was a randomized, open-label, phase III trial comparing nivolumab plus ipilimumab to sunitinib monotherapy, which resulted in the combination of nivolumab and ipilimumab showing an increase in overall survival.18 This study led to the 2018 FDA approval of the combination therapy of nivolumab and ipilumumab as first-line treatment for RCC.19

The CheckMate 9ER was a randomized, open-label, phase III trial comparing nivolumab plus cabozantinib combination to sunitinib monotherapy and resulted in the combination therapy showing an increase in progression-free survival and overall survival.20 This trial led to the 2021 FDA approval of the combination of cabozantinib and nivolumab as first-line therapy for advanced RCC.21

COSMIC-313 Trial: Efficacy of Cabozantinib Plus Nivolumab and Ipilimumab

The COSMIC-313 trial was a randomized, double-blind, placebo-controlled, phase III clinical trial analyzing the efficacy of cabozantinib plus nivolumab and ipilimumab for patients with advanced ccRCC, conducted by Choueiri et al. Between June 2019 and March 2021, 855 participants from the United States, Canada, Europe, Australia, New Zealand, Latin America, and Asia underwent randomization, which was the intention-to-treat (ITT) population.22 The experimental group contained 428 patients while the control group contained 427. Those in the experimental group received cabozantinib 40 mg while those in the control group received a placebo. In addition, both groups received nivolumab 3 mg per kilogram of body weight and ipilimumab 1 mg per kilogram intravenously every three weeks for four cycles, followed by nivolumab maintenance therapy 480 mg every four weeks for up to 2 years.22 The first 550 patients who had undergone randomization were included in the progression-free survival (PFS) population.22

Patients 18 years or older with confirmed advanced or metastatic renal-cell carcinoma with a clear-cell component, an International Metastatic Database Consortium (IMDC) risk score of intermediate or poor, a Karnofsky performance-status score of 70 or greater, and a PD-L1-positive tumor cell were deemed eligible for the trial.22 Patients were excluded if they had received previous systemic anticancer therapy for advanced renal-cell carcinoma (one previous systemic adjuvant therapy was allowed, except for combination regimens with PD-L1 and CTLA4 inhibitors). Exclusion criteria also included brain metastases or cranial epidural disease (unless the disease was adequately treated and stable), ​​autoimmune diseases, or use of immunosuppressive medications (>10 mg of prednisone or equivalent per day) within 14 days before randomization.22 Baseline characteristics of participants were well balanced between the experimental and control groups, with the average participant being a white male around 60 years old with an intermediate IMDC risk.22

The primary endpoint of this study was progression-free survival in the PFS population, and the secondary endpoint was overall survival in the ITT population. Additional endpoints included objective tumor response, duration of response, and safety.22 The Kaplan-Meier method was used to estimate the primary endpoint and duration of response confidence intervals. The Clopper-Pearson method was used to calculate the two-sided confidence intervals for each group’s point estimate of response. The Cox proportional hazard model was used to estimate the hazard ratios with 95% confidence intervals. The objective tumor response was done by assessing computer tomography (CT) or magnetic resonance imaging (MRI) scans performed at baseline, week ten, then every eight weeks through week fifty, and then every twelve weeks.22

It was determined that the 249th event of disease progression or death would provide a hazard ratio of 0.66 with 90% power in the experimental group compared to the control group, as assessed with a two-sided log-rank test at a significance level of 0.05.22 The PFS benefit was shown in the experimental group except for those with an IMDC risk score of poor.22 It was estimated that 433 deaths in the ITT population would provide a hazard ratio of 0.73 with 90% power in the experimental group compared to the control group.22 Investigators of the study deemed that data from the trial is not mature enough to assess the secondary endpoint.

In the PFS population, objective tumor response was observed in 43% [95% confidence interval (CI), 37 to 49] of patients in the experimental group and 36% (95% CI, 30 to 42) of patients in the control group. 3% of patients in both groups had a complete response to the assigned regimen.22 A grade 3 or 4 adverse event occurred in 79% (337 out of 426) of the patients in the experimental group and 56% (236 out of 424) in the control group.22

Adverse events that occurred more in the experimental group than in the control group included increased alanine aminotransferase (27% vs. 6%), increased aspartate aminotransferase level (20% vs. 5%), and hypertension (10% vs. 3%), respectively. Death that was related to the trial regimen and occurred within 100 days before the last dose of the trial regimen was observed in 5 participants in the experimental group and 4 participants in the control group.22


The clinical trial concluded that a triplet regimen of cabozantinib plus nivolumab and ipilimumab in treatment-naive patients with advanced renal carcinoma with intermediate prognostic risk provides longer PFS.22 Overall survival outcomes could not be concluded as results are still ongoing. Though this triplet therapy did show statistically significant outcomes, it also resulted in a higher incidence of adverse events. At this time, further evaluation with a larger group and longer trial duration is needed to determine whether it should be included in the guidelines for advanced ccRCC. 

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