Kidney Cancer Coverage from Every Angle

Nivolumab + Cabozantinib for Clear Cell Renal Cell Carcinoma

Posted: Thursday, June 10, 2021

The combination of nivolumab plus cabozantinib1 was approved as first-line therapy for advanced renal cell carcinoma (RCC) in January 2021.2 With multiple first-line options available for patients with metastatic kidney cancer, current clinical dilemmas center around individualized treatment selection and sequencing. 

Historically, kidney cancer has been considered one of the most difficult cancers to treat, owing to a poor prognosis and its universal resistance to cytotoxic chemotherapy, explained Robert J. Motzer, MD, the Jack and Dorothy Byrne Chair in Clinical Oncology and Kidney Cancer Section Head at Memorial Sloan Kettering Cancer Center in New York City. Responses to cytokines, such as interferon and interleukin-2, in the 1980s sparked a continued interest in exploring immunotherapy for patients with advanced clear cell RCC,3 he told JNCCN 360. [Editorial Note: About 80% of patients with kidney cancer have tumors characterized by clear cell features; the remainder are non–clear cell types.4]

Breakthroughs in Systemic Treatment for Metastatic Clear Cell Kidney Cancer

Tyrosine Kinase Inhibitors

A breakthrough in systemic therapy was realized in 2005 to 2006, when high response rates and efficacy were reported with antiangiogenic tyrosine kinase inhibitors (TKIs), such as sunitinib5 and sorafenib,6 in patients with metastatic RCC. The development and use of these agents came after researchers understood the role the Von Hippel-Lindau gene7 plays in regulating angiogenesis. The Von Hippel-Lindau gene is mutated in most patients with clear cell carcinoma, Dr. Motzer explained. Sunitinib and sorafenib were approved based on those reports,5,6 and pazopanib8 was approved a few years later. Until recently, sunitinib and pazopanib were the mainstays of first-line treatment for advanced or metastatic clear cell RCC, Dr. Motzer continued. TKI response rates were in the 30% to 50% range, and both progression-free and overall survival were prolonged with treatment.

Newer-generation TKIs include lenvatinib and cabozantinib, as well as axitinib, to a certain degree, Dr. Motzer said. Lenvatinib and cabozantinib exert their effects at multiple targets. Lenvatinib has activity at the fibroblast growth factor (FGF) receptor,9 cabozantinib is active against MET and AXL,10 and “all of these TKIs exert anti-VEGF activity,” Dr. Motzer clarified. This activity at multiple targets “may explain the greater efficacy associated with the newer-generation agents.”


The next breakthrough in systemic treatment of metastatic clear cell RCC emerged after results of the CheckMate 025 trial were reported. “The efficacy of the checkpoint inhibitor nivolumab was compared with that of everolimus in patients who had been given a TKI as first-line treatment,”11 Dr. Motzer said. Those who received second-line nivolumab benefited in terms of response, overall survival, and quality of life. “The next step was to combine immunotherapies and evaluate outcomes compared with TKIs,” he explained.

Three large phase III trials pitted the following combination regimens against sunitinib: nivolumab plus ipilimumab (CheckMate 214)12; pembrolizumab plus axitinib (KEYNOTE-426)13; and avelumab plus axitinib (JAVELIN Renal 101).14 All of these combinations improved response rates and progression-free survival, but “only the avelumab-plus-axitinib combination was not associated with improved overall survival,” Dr. Motzer said. “The first-line treatment paradigm for metastatic RCC changed from monotherapy with TKIs to combination regimens that included checkpoint inhibitors.”

The first-line treatment paradigm for metastatic RCC changed from monotherapy with TKIs to combination regimens that included checkpoint inhibitors.

Rationale for Combination Regimens

Risk Classification

The two RCC classification systems (MSKCC,15 IMDC16) are roughly interchangeable and are used prognostically and for stratification in phase III trials. In the CheckMate 214 trial of nivolumab plus ipilimumab,12,17,18 those with intermediate/poor-risk disease benefited the most compared with single-agent sunitinib. However, those patients classified as having favorable-risk disease continued to derive the most benefit (response rate, survival) from monotherapy with sunitinib.

“We think the risk groups reflect differences in underlying biology,” Dr. Motzer told JNCCN 360. “Those with favorable-risk disease may have tumors that are primarily driven by VEGF. However, patients with intermediate- or poor-risk disease may have tumors with a more inflammatory phenotype, which may respond more robustly to immunotherapies.”

This distinction provided the rationale for combining a checkpoint inhibitor with a TKI, in that the regimen addresses both mechanisms (ie, VEGF and inflammation). For example, the combination of pembrolizumab plus axitinib showed greater efficacy and benefit in response rate, progression-free survival, and overall survival across all risk groups compared with sunitinib.19

Those with favorable-risk disease may have tumors that are primarily driven by VEGF. However, patients with intermediate- or poor-risk disease may have tumors with a more inflammatory phenotype, which may respond more robustly to immunotherapies.

Administration of the Combination Regimen

The efficacy data for nivolumab in trials (nivolumab plus ipilimumab; second-line nivolumab)12,17,18 were established using the every-2-week schedule of 240 mg. However, in other tumor types, a schedule of 480 mg every 4 weeks was shown to be both effective and well tolerated. Therefore, the prescribing information for nivolumab20 lists the every-2-week or 4-week schedules as being equivalent.

When cabozantinib is used as a single agent in previously treated patients, the dosage is 60 mg per day.21 “When it is part of a first-line combination with an immunotherapy,” Dr. Motzer stated, “the cabozantinib dosage is reduced to 40 mg per day.”

Ana Adriazola, DNP, RN, AGPCNP-BC, an advanced practice registered nurse with the Genitourinary Medical Oncology Unit at the MD Anderson Cancer Center, Houston, confirmed that the monthly regimen is used most often by the MD Anderson team. “We almost always start with 480 mg of nivolumab every 4 weeks. When we used the 240-mg nivolumab dose every 2 weeks in a trial with another TKI, we didn’t notice any difference aside from the inconvenience of more frequent visits for the infusions.”

According to Dr. Adriazola, the protocol calls for administering the combination regimen for 2 years, after which the nivolumab is dropped and the cabozantinib is continued. “I have one patient from the original CheckMate 9ER trial1 who has been on cabozantinib now for about 3 or 4 years,” she said.

Delaying Initiation of Systemic Therapy

Patients with RCC may present with a wide variety of clinical situations, Dr. Motzer told JNCCN 360. Some individuals have aggressive disease, with growing metastases and the development of new metastases. On the other hand, the disease appears indolent in some patients, “with slow almost imperceptible disease progression for years. In patients with asymptomatic small-volume disease, it may be wise to consider delaying initiation of systemic treatment,” he suggested.

These patients may be monitored regularly with serial imaging. “As long as there is stable disease or slow, asymptomatic disease progression, active systemic treatment may be delayed for a considerable period,” Dr. Motzer said.

Encouraging Healthy Behaviors

Dr. Adriazola generally encourages patients to keep up with healthy behaviors. However, she acknowledges the challenges inherent in dealing with patients who are facing metastatic cancer. “This population tends to lose weight and muscle mass, so we encourage good nutrition, adequate protein intake, hydration, and introduce a dietitian to the clinical team early on.”

Controlling diabetes and blood pressure may directly impact the efficacy and safety of any future cancer treatment—making conversations about controlling modifiable risk factors critical. “I’ve told patients that unless their blood pressure is controlled, we may have to underdose the cancer regimen when and if it becomes necessary,” Dr. Adriazola noted.

“I focus these ‘lifestyle’ conversations on patients who are under active surveillance [every 3–4 months] but who have not yet started systemic treatment. These patients may have small asymptomatic pancreatic metastases, which seem to be more indolent when associated with metastatic kidney cancer. Others have subcentimeter lung nodules that haven’t changed from scan to scan,” Dr. Adriazola said. “I explain that treatments may need to be initiated at some point and are associated with risk for hypertension, proteinuria, and worsening of kidney function. Being in good shape when treatment starts significantly contributes to the success of therapy.” Clinicians may want to consider a systemic regimen once localized treatments, such as surgery or radiation, fail to control disease, new metastases appear, or existing lesions grow.

Nivolumab Plus Cabozantinib: Clinical Experience

Recalling the first patients with highly symptomatic, progressive disease who had been started on the combination of nivolumab plus cabozantinib, Dr. Adriazola said, “they were ‘on fire.’” In an interview with JNCCN 360, Dr. Adriazola noted that diagnoses were mostly for de novo metastatic disease, with growing and newly appearing lesions, elevated calcium levels, and increasing day-to-day pain. “In my experience, after patients started on the nivolumab-plus-cabozantinib regimen, symptoms decreased, and the clinical picture stabilized. I can’t comment on the duration of disease control yet, but things look good after the first few scans.”

Weight loss (which may be associated with treatment) might improve once effective treatment is initiated, Dr. Adriazola observed. When other symptoms, particularly pain, are relieved, patients have been shown to recover their appetite, improve their nutrition, and regain some of their vigor.

Nivolumab Plus Cabozantinib: Toxicity

The majority of agents in the TKI and PD-1 inhibitor classes have distinct and separate toxicity profiles. TKIs are often associated with hypertension, fatigue, and stomatitis. In contrast, checkpoint inhibitors are associated with immune-related side effects, such as dermatitis, hepatitis, colitis, unusual neuropathic or neurologic toxicities, or severe diabetes.

Overlapping Side Effects: Teasing Out the Culprit

“The most challenging part of giving the nivolumab-plus-cabozantinib regimen (or any combination regimen) is identifying which component may be causing a side effect,” Dr. Adriazola told JNCCN 360. Some adverse effects, such as diarrhea and hypothyroidism, overlap. In addressing overlapping side effects, Dr. Motzer pointed out that the clinical picture of immune-related colitis is quite different from TKI-associated diarrhea.

For TKI-related diarrhea versus possible colitis, “one of the fastest ways to identify the culprit is to hold the TKI for a couple of days,” Dr. Adriazola said. “Of course, this depends on the severity of diarrhea. If the situation is severe—the patient is dehydrated and losing consciousness—an emergent response is required. However, if the diarrhea is less severe, holding the TKI for about 3 days may reveal where it is coming from.”

Dr. Adriazola pointed out that cabozantinib has a long half-life, “so it may be necessary to hold the dose for 3 days. If there is a rapid improvement, then the TKI is most likely the causative agent.” Once the side effect has resolved, “we may decide to reinitiate the TKI. I explain that sometimes it is like rebooting your system,” she said. If the side effects return and are not improved with supportive measures, such as loperamide and dietary changes, she told JNCCN 360, the next step might be to modify the dosing schedule.

Some side effects are more severe when a drug is given in combination, Dr. Motzer said. For instance, “hand-foot syndrome is uncommon with axitinib as a single agent but can be troublesome when the TKI is used in combination. Liver function abnormalities also emerge sometimes with both classes of drugs,” he noted.

Managing Adverse Effects Associated With Nivolumab Plus Cabozantinib

Management of treatment-related adverse effects can be quite different, depending on which drug is the culprit. For cabozantinib, “we would hold the drug and then reduce the dose,” Dr. Motzer noted. In contrast, when liver function is affected by a checkpoint inhibitor, steroids are prescribed. “Determining the causative agent is one area that requires clinical experience with these drugs and combinations,” he told JNCCN 360.

Fatigue and weight loss are tough to manage. “If nothing works, we might try 5 days on the drug and 2 days off,” Dr. Adriazola explained. “Finally, we can reduce the dose to 20 mg of cabozantinib daily. Most often, though, patients work through these issues and stay with the full dose of TKI.”

Weight loss, fatigue, diarrhea, and hand-foot syndrome are common with this combination therapy, according to Dr. Adriazola, but there are ways to address these effects. “In my experience, weight loss appears to be somewhat more common with the nivolumab-plus-cabozantinib regimen, despite adequate caloric intake. I talk to patients about eating small, frequent meals; I encourage ‘noticing what you like’ and avoiding foods that seem to cause diarrhea,” she said. “Ironically, the increase in telehealth during the COVID-19 pandemic has increased the use of nutritional counseling for these patients. Patients sometimes do not want to stay after their visit to meet with the nutritionist. The ability to consult electronically has improved this aspect of care.”

In terms of holding one versus both drugs, Dr. Adriazola commented: “The best tip I can offer is to identify side effects as early as possible and mitigate them aggressively. Patients who go back to their communities often return in worse shape than those who are local [to MD Anderson Cancer Center] and can continue to be managed by our team. Community practitioners may not have the bandwidth to respond to every complaint, and managing patients long distance by e-mail is often frustrating and not ideal.”

Future Research Directions

Now that a single-agent TKI, such as sunitinib, has been shown to be roughly inferior to one of the combination regimens, researchers are designing the next iteration of phase III clinical trials.


The COSMIC-313 study ( identifier NCT03937219) compares the combination of nivolumab, ipilimumab, and cabozantinib with nivolumab plus ipilimumab alone in patients with intermediate/poor-risk disease. COSMIC-313 is a global trial with completed enrollment. “However, a regimen such as nivolumab plus cabozantinib, which is effective in patients with any-risk category of disease, could ostensibly make a good comparator in any first-line phase III trial for patients with metastatic RCC. Moving forward, some combination of immunotherapy plus TKI will probably be the standard therapy arm of phase III trials,” Dr. Motzer said.


Results from the CLEAR trial (NCT02811861) were reported at the 2021 Genitourinary Cancers Symposium22 and published in The New England Journal of Medicine.23 There were three treatment arms: pembrolizumab plus lenvatinib; everolimus plus lenvatinib; and sunitinib. Both lenvatinib-containing arms improved response rate and progression-free survival, but pembrolizumab plus lenvatinib also improved overall survival. “The TKI plus immunotherapy combination was the clear winner,” Dr. Motzer stated. Approval of pembrolizumab plus lenvatinib is expected soon; in the interim, it has been added to the most recent version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer.24 

The TKI plus immunotherapy combination was the clear winner.

CONTACT-03 Trial

With suitable candidates for first-line regimens, Dr. Motzer said the area of greatest need is in patients with advanced or metastatic RCC that progressed on first-line immunotherapy. The CONTACT-03 trial (NCT04338269) will compare atezolizumab plus cabozantinib versus cabozantinib in patients whose disease progressed during or after treatment with an immune checkpoint inhibitor.

Another trial (NCT04586231) will explore a role for the hypoxia inducible factor (HIF)-2 alpha inhibitor belzutifan (MK-6482). Cabozantinib will be compared with the combination of lenvatinib and belzutifan in patients previously treated for clear cell RCC.

Exploring Immunotherapy in the Adjuvant Setting

According to Dr. Motzer, another area of need for further trials is in adjuvant treatment for patients with high-risk, completely resected RCC. The CheckMate 914 trial (NCT03138512) is underway to evaluate the combination of nivolumab plus ipilimumab versus nivolumab versus placebo in this setting.

A Modern Clinical Dilemma

With several available options, selecting the most suitable first-line regimen for a patient with advanced or metastatic clear cell RCC requires nuanced decision-making.

“Currently, most patients with advanced or metastatic clear cell RCC receive a regimen that includes immunotherapy in the first line,” Dr. Motzer explained. “There are two broad categories of regimens to consider: a double immunotherapy combination, such as nivolumab plus ipilimumab, or a TKI plus immunotherapy, such as pembrolizumab or avelumab plus axitinib or nivolumab plus cabozantinib. And, we expect that pembrolizumab plus lenvatinib will join these approved options soon.”

Dr. Adriazola pointed out that patients who are less symptomatic might be started on nivolumab plus ipilimumab. This is because a TKI such as cabozantinib might be reserved for subsequent therapy when disease progression occurs.

Treatment with a single-agent TKI might be considered for patients with a variant histology (non–clear cell, such as papillary) or for an individual with a specific issue, such as a history of alcohol abuse, Dr. Adriazola told JNCCN 360. Additionally, “some patients may prefer a single-agent TKI, perhaps because of not wanting to travel for infusions of the checkpoint inhibitor every 2 or every 4 weeks.”

Efficacy/Durability: Treatment Goals

Efficacy and durability are essential in first-line treatment. “With nivolumab plus ipilimumab, the data are the most mature, and we can see there are patients who derive benefit for a long time,” Dr. Motzer told JNCCN 360. “In contrast, the regimen of avelumab plus axitinib did not show a clear benefit for overall survival, so that wouldn’t be a top option. Durability is extremely important because our goal is a sustained response over time. Moreover, I believe that in some cases, we may be able to talk about ‘cure.’”

Although the initial results from the CheckMate 9ER trial1 were reported at a median of about 18 months, Dr. Motzer said that most patients had not discontinued treatment with nivolumab plus cabozantinib yet. “As data mature, it is likely that patients will be able to continue this combination regimen for about 18 months or longer.”


The other side of the equation is the safety profile. “Certain regimens, which are associated with certain adverse effects, may be more appropriate for specific populations,” Dr. Motzer explained.

Comorbidities in individual patients may direct treatment selection. For example, “a patient with relatively uncontrollable hypertension should not take a TKI,” Dr. Motzer noted. “For that person, a regimen of nivolumab plus ipilimumab makes more sense. In contrast, a patient with a history of active rheumatoid arthritis should be treated with something that has a lower incidence of autoimmune disorders. I might still consider an immune checkpoint inhibitor plus a TKI or a TKI as a single agent,” he continued.

Provider Comfort Level

A significant third factor is the prescribing physician’s comfort level and the established practice pattern with the component agents and/or the combination regimen. “The pembrolizumab-plus-axitinib combination was approved first, and many oncology teams have longer clinical experience with it. There needs to be some rationale to switch to something else,” Dr. Motzer said.

Confirming Dr. Motzer’s observation, Dr. Adriazola explained: “At first, we used pembrolizumab plus axitinib in the first line and were reluctant to switch to nivolumab plus cabozantinib because of concerns regarding what to use on disease progression. In other words, we may want to keep cabozantinib in reserve for second-line or subsequent therapy. However, when we were able to compare the responses of patients on the two regimens, it became clear that patients who received nivolumab plus cabozantinib had much better and faster improvement of symptoms, relative to those who received pembrolizumab plus axitinib.”

Other Considerations

Nivolumab plus cabozantinib is a relatively easy-to-administer regimen, according to Dr. Motzer. “Cabozantinib is given at 40 mg daily when it is part of the combination regimen. If side effects warrant a reduction, you can go down to 20 mg daily,” he said.

Finally, in the real world, cost drives practice. When third-party insurers review multiple but similar-looking options, they will look for the most cost-effective treatment,” Dr. Motzer concluded.


Robert J. Motzer, MD, has received clinical research support/data safety monitoring board from Bristol Myers Squibb, Eisai, Exelixis, Genentech, Merck & Co., and Pfizer and has served on a scientific advisory board, as a consultant, or an expert witness for AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Genentech, Merck & Co., Pfizer, and Roche Laboratories.

Ana Adriazola, DNP, RN, AGPCNP-BC, reported no conflicts of interest.


  1. Choueiri TK, Powlest T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol 2020;31(suppl 4):6960_PR.
  2. U.S. Food and Drug Administration. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Available at Accessed April 20, 2021.
  3. Koneru R, Hotte SJ. Role of cytokine therapy for renal cell carcinoma in the era of targeted agents. Curr Oncol 2009;16 (suppl 1):S40–S44.
  4. Cheng L, Zhang S, MacLennan GT, et al. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnoses, and prognosis of renal epithelial neoplasms. Human Pathol 2009;40:10–29.
  5. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–124.
  6. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal cell carcinoma. N Engl J Med 2007;356:125–134.
  7. Arjumand W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma. Tumor Biol 2012;33:9–16.
  8. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061–1068.
  9. Massari F, Ciccarese C, Santoni M, et al. Targeting fibroblast growth factor receptor (FGFR) pathway in renal cell carcinoma. Exp Rev Anticancer Ther 2015;15:1367–1369.
  10. Grüllich C. Cabozantinib: multi-kinase inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res 2018;211:67–75.
  11. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–1813.
  12. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–1290.
  13. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–1127.
  14. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–1115.
  15. Memorial Sloan-Kettering Cancer Center (MSKCC/Motzer) Score for Metastatic Renal Cell Carcinoma (RCC). Available at Accessed April 20, 2021.
  16. IMDC (International Metastatic RCC Database Consortium) Risk Model for Metastatic Renal Cell Carcinoma. Available at Accessed April 20, 2021.
  17. Tannir NM, McDermott DF, Escudier B, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. J Clin Oncol 2019;38(suppl):609.
  18. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol 2019;20:1370–1385.
  19. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma: updated analysis of KEYNOTE-426. J Clin Oncol 2020;38(suppl):5001.
  20. Nivolumab (Opdivo). FDA prescribing information. Available at Accessed April 20, 2021.
  21. Cabozantinib (Cabometyx). FDA prescribing information. Available at Accessed May 11, 2021.
  22. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib plus pembrolizumab or everolimus versus sunitinib monotherapy as a first-line treatment for patients with advanced renal cell carcinoma (CLEAR study). J Clin Oncol 2021;39(suppl):269.
  23. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289–1300.
  24. Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 4.2021—April 19, 2021. To view the most recent version of these guidelines, visit

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