Kirollos Hanna, PharmD, BCPS, BCOP; Ashley Barlow, PharmD; and Brooke Barlow, Pharm D

Renal cell carcinoma (RCC) is the ninth most common neoplasm in the United States and accounts for approximately 3.8% of all new cancer diagnoses.

 RCC originates from the kidney cortex and accounts for 85% of all renal tumors.

 The median age of diagnosis for this disease is 64 years, with a gender disparity toward men at a notable 1.7-fold increased risk of RCC development compared with females.

Older age, male sex, and African American and Hispanic ethnicities are nonmodifiable risk factors for the development of RCC, with obesity, smoking, poor diet, alcohol consumption, and hypertension identified as the leading modifiable risk factors.

The clinical presentation of RCC includes the classic triad of hematuria, flank pain, and presence of palpable masses. A minority of patients who present in the metastatic phase of disease may express bone pain, adenopathy, and pulmonary symptoms that are attributable to mediastinal masses.

 However, a majority of patients are often asymptomatic and, given the slow, progressive nature of the disease, receive a diagnosis of RCC after incidental findings through magnetic resonance imaging (MRI), a computed tomography (CT) scan, or ultrasound.

Outcomes of patients with RCC vary depending on the tumor stage, grade, extent of disease, and presence of metastasis at the time of diagnosis. The staging system most often used for RCC is the American Joint Committee on Cancer and International Union Against Cancer TNM staging system, which classifies the disease based on tumor size, nodal involvement, and presence or absence of metastasis. Patients who present with localized disease have an estimated 5-year survival rate of 92.6%.

 In patients with metastatic RCC (mRCC), clinicians should use the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model to assist in predicting survival in patients with mRCC treated with systemic chemotherapy. This prognostic tool includes the assessment of time from diagnosis to treatment, performance status, and laboratory markers. The IMDC model has been externally validated to predict outcomes and identify patients most likely to benefit from systemic chemotherapy for mRCC.

RCC’s pathogenesis is complex and multifactorial. However, recent evidence has emerged to suggest that vascular and immune components play a pivotal role, which has resulted in the availability of novel treatment options.

 Investigators have proposed that angiogenesis promotes the recruitment of endothelial cells and leads to the progression of RCC to mRCC. The discovery of this pathway has led to the integration of vascular endothelial growth factor (VEGF)-targeted agents such as bevacizumab.

PD-L1 expression is estimated to occur in up to 20% to 30% of RCC tumors. Immunomodulation with immune checkpoint inhibitors (ICIs) that block these pathways, including PD-L1 receptor inhibitors (nivolumab, pembrolizumab, atezolizumab) or CTLA-4 inhibitors (ipilimumab, tremelimumab), have become the backbone of the therapeutic landscape for RCC in combination with other first-line treatment options.

Relevant literature supports the use of these novel therapeutic treatment options, which require monitoring and may lead to toxicities. As such, pharmacists have a key role in managing patients with RCC.

Treatment Overview for Localized Renal Cell Carcinoma

Surgical excision or radical nephrectomy are effective treatment modalities in patients with localized disease (stages I-III).

 For patients with small unilateral T1a tumors or in whom the preservation of renal function is a primary issue, a partial nephrectomy is an appropriate treatment; some tumors may require a radical nephrectomy due to their location and size, and depending on surgical expertise. In contrast, active surveillance for patients with extensive comorbidities or decreased life expectancy may be appropriate to avoid the risks associated with more invasive interventions. A partial or radical nephrectomy is the standard of care for T1b tumors and has demonstrated similar outcomes.

A radical nephrectomy provides a curative approach for treating locally advanced stage II and III disease; partial nephrectomies may not resect the entirety of tumor-infiltrated tissue.

 There is no established role for adjuvant treatment following a complete nephrectomy, except in patients with stage III disease, clear cell histology, and a high risk for relapse. Numerous trials, including ASSURE and S-TRAC (NCT00326898 and NCT00375674), have evaluated the role of adjuvant sunitinib therapy. The National Comprehensive Cancer Network (NCCN) has given adjuvant sunitinib a category 2B recommendation for patients with a high risk of relapse, due to conflicting trial outcomes.

Treatment Overview of Relapsed or Stage IV Renal Cell Carcinoma

Historically, interferon-α and high-dose interleukin-2 have been used as therapies for RCC, but they are now used only in selected patients due to the development of therapies with an improved efficacy and toxicity profile. Targeted therapy using tyrosine kinase inhibitors (TKIs), and/or anti-VEGF antibodies are now widely used in first- and second-line treatments. Agents targeting the mammalian target of rapamycin (mTOR) are also used in this setting. 

The FDA has approved numerous agents for the treatment of advanced RCC as frontline and subsequent therapies: sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, everolimus, bevacizumab in combination with interferon, cabozantinib, and lenvatinib-everolimus. ICIs represent a revolution in RCC treatment options, with avelumab, pembrolizumab, nivolumab, atezolizumab, and ipilimumab demonstrating efficacy and safety in combination with another agent.

Based on results from several positive studies and its tolerability, sunitinib has been listed by the NCCN Kidney Cancer Panel as a category 1 option for the first-line treatment of patients with relapsed or medically unresectable clear cell stage IV RCC with good-risk and poor- or intermediate-risk features.

As a result, numerous clinical trials have compared therapeutic options with sunitinib as the standard-of-care arm.

CheckMate 214 (NCT02231749) was an open-label, multicenter, phase 3 trial comparing nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks versus sunitinib monotherapy 50 mg, 4 weeks on and 2 weeks off in patients with advanced RCC.

 Investigators randomized 1096 patients (1:1) to nivolumab plus ipilimumab or sunitinib monotherapy; 425 and 422 treated patients, respectively, had intermediate or poor risk. The co-primary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in intermediate- and poor-risk patients.

The combination of nivolumab plus ipilimumab produced a higher ORR compared with sunitinib monotherapy (42% vs 27%, P<.001), and a higher complete response rate (CRR; 9% vs 1%, P<.001) in the intermediate- and poor-risk patients. The 18-month OS rate was 75% (95% CI, 70-78) with nivolumab plus ipilimumab and 60% with sunitinib (95% CI, 55-65). The median PFS (11.6 months vs 8.4 months; HR, 0.82; P=.03) was not statistically significant because it did not meet the prespecified 0.009 threshold. The 18-month OS in the intent-to-treat (ITT) population favored nivolumab plus ipilimumab versus sunitinib (78% vs 68%), but exploratory analyses of just the favorable-risk patients favored sunitinib (88% vs 93%).

Investigators observed treatment-related adverse events (TRAEs) in 93% of patients who received nivolumab plus ipilimumab, and in 97% of patients who received sunitinib; grade 3 or 4 events occurred in 46% and 63% of patients, respectively. TRAEs led to discontinuation in 22% and 12% of patients, respectively.

On April 19, 2019, the FDA approved pembrolizumab plus axitinib for the first-line treatment of patients with advanced RCC, based on findings from KEYNOTE-426 (NCT02853331).

 The open-label, phase 3 trial randomly assigned patients in a 1:1 ratio to receive pembrolizumab 200 mg IV every 3 weeks plus axitinib 5 mg orally twice daily, or sunitinib 50 mg orally daily for the first 4 weeks of each 6-week cycle.

 The axitinib could be increased to 7 mg, then 10 mg twice daily if safety criteria were met, and reduced to 3 mg, then 2 mg twice daily to manage toxic effects. The sunitinib dose also could also be reduced to 37.5 mg, then 25 mg once daily for the first 4 weeks of each 6-week cycle to manage toxic effects.

Eligible patients were 18 years or older and chemotherapy naive with newly diagnosed or recurrent stage IV clear cell RCC; they had a Karnofsky performance status (PS) score of 70 or more, at least 1 measurable lesion as evaluated according to RECIST 1.1 criteria, and an available tumor sample for biomarker assessment. The main efficacy end points in the study were OS and PFS.

The trial demonstrated a statistically significant improvement in OS in a prespecified interim analysis for patients on pembrolizumab plus axitinib (HR, 0.53; 95% CI, 0.38-0.74; P < .0001). With deaths reported in 18% of patients, the median OS was not reached in either arm. The 12-month OS rate was 90% in the pembrolizumab plus axitinib arm and 78% in the sunitinib arm. The median PFS was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs sunitinib (HR, 0.69; 95% CI, 0.57, 0.84; P = .0001), respectively. The ORR was 9.3% (95% CI, 54.5-63.9) in the pembrolizumab plus axitinib group, and 35.7% (95% CI, 31.1-40.4) in the sunitinib group (P < .001). Investigators observed the benefit of pembrolizumab plus axitinib across favorable-, intermediate-, and poor-risk groups and regardless of PD-L1 expression.

The most common adverse reactions in more than 20% of patients who received pembrolizumab plus axitinib were diarrhea, fatigue or asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis or mucosal inflammation, dysphonia, rash, cough, and constipation. Grade 3 or greater AEs of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group, and in 70.6% in the sunitinib group. Grade 3 or greater hepatotoxicity occurred in 20% of patients and resulted in permanent discontinuation of pembrolizumab or axitinib in 13% of patients.

Pembrolizumab plus axitinib, as a front-line option, is a category 2A recommendation for patients with favorable-risk disease, and category 1 for those with intermediate- or poor-risk disease.2 It is also a 2A recommendation as a subsequent treatment option.

Based on results from the JAVELIN Renal 101 (NCT02684006), the FDA approved avelumab in combination with axitinib for the first-line treatment of patients with advanced RCC on May 14, 2019.13 The randomized, multicenter, open-label trial evaluated the role of avelumab plus axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression.

 Eligible patients were 18 years or older and had previously untreated advanced RCC with a clear cell component and at least 1 measurable lesion according to RECIST 1.1 criteria. In addition, they had an Eastern Cooperative Oncology Group PS score of 0 or 1, a fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function. Patients were randomized to receive either avelumab 10 mg/kg IV every 2 weeks plus axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off until disease progression or unacceptable toxicity. Dose escalations and reductions of axitinib and dose reductions of sunitinib were permitted. The main efficacy end points were PFS and OS in patients whose tumors were PD-L1 positive.

Among the 560 patients with PD-L1–positive tumors (63.2%), the median PFS was 13.8 months with avelumab plus axitinib, compared with 7.2 months with sunitinib (HR, 0.61; 95% CI, 0.47-0.79; P < .001). In the overall population, the median PFS was 13.8 months compared with 8.4 months (HR, 0.69; 95% CI, 0.56-0.84; P < .001). At 19 months, the median OS data were immature, with 27% deaths in the ITT population. TRAEs occurred in 99.5% of patients in the avelumab plus axitinib group, and in 99.3% of patients in the sunitinib group; grade 3 or greater TRAEs were observed in 71.2% and 71.5% of patients in the respective groups.

Avelumab plus axitinib, as a front-line option, is a category 2A treatment for patients with favorable risk and intermediate or poor risk.

 It is also a category 3 recommendation as a subsequent treatment option.

CheckMate 9ER (NCT03141177) is an open-label, randomized, multinational phase 3 trial evaluating patients with previously untreated advanced or metastatic RCC.

 Investigators randomized a total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% had PD-L1 ≥ 1%) to nivolumab plus cabozantinib (n = 323) vs sunitinib (n = 328). The primary end point is PFS, and secondary end points include OS and ORR.

Nivolumab in combination with cabozantinib reduced the risk of death by 40% vs sunitinib (HR, 0.60; 98.89% CI, 0.40-0.89; P = .0010); median OS was not reached in either arm. The median PFS was doubled compared with those receiving sunitinib alone, at 16.6 months vs 8.3 months, respectively (HR, 0.51; 95% CI, 0.41-0.64; P < .0001). The ORR was 56% vs 27% and the CRR was 8% vs 5%, respectively. The investigators observed a longer duration of response with the combination, with a median duration of 20.2 months vs 11.5 months, respectively. All these key efficacy results were consistent across the prespecified IMDC risk and PD-L1 subgroups.

The incidence of TRAEs, including any grade and high grade, was slightly higher for nivolumab in combination with cabozantinib vs sunitinib (97% vs 93% for any grade; 61% vs 51% for grade 3 and higher), with a low rate of discontinuations (6% for nivolumab only, 7% for cabozantinib only, and 3% for nivolumab plus cabozantinib vs 9% for sunitinib). Patients treated with nivolumab in combination with cabozantinib reported a significantly better health-related quality of life than those treated with sunitinib at most time points.

Immune related adverse effects (irAEs) are dose independent, can affect nearly every organ system, emerge at any time, and warrant active treatment with steroids to resolve. With combination ICI therapy, irAEs are more prevalent within the first 12 weeks and reduce in frequency and severity once maintenance nivolumab is started.

 Although management of irAEs varies based on organ involvement, corticosteroids generally remain the main treatment strategy for grade 2 or greater nonendocrine-related irAEs. Steroid doses are based on the severity grading and the duration is based on clinical response. For patients with an endocrine-related irAE, treatment is focused on hormone supplementation. For example, those who experience hypothyroidism should be treated with levothyroxine supplementation. For any grade 4 immunotherapy toxicity, with the exception of endocrinopathies managed with hormone replacement therapy, ICIs should be permanently discontinued.

Patients should be counseled on the high potential for irAEs with treatment and informed about the importance of communicating new AEs as these toxicities can be life threatening if not acted upon urgently (FIGURE). To enhance awareness among medical providers caring for patients on ICI therapy, patients can use a wallet card in the event they need to seek emergency care. Pharmacists can increase the safety of corticosteroid use for irAE management by identifying patients at high risk of steroid-related AEs (preexisting diabetes, osteoporosis, gastrointestinal ulcers, duration of use, etc) and recommending prophylactic supportive care strategies. Patients on long-term steroids (prednisone 20 mg/day>2 weeks [or equivalent]) are at risk of pneumocystis jirovecii pneumonia and should be considered for prophylaxis with trimethoprim-sulfa-methoxazole. Other supportive care considerations include initiating gastrointestinal prophylaxis with a proton pump inhibitor or histamine 2 receptor antagonist, dosing in the morning to minimize insomnia, and optimizing glucose control for patients with diabetes.

COMMON ADVERSE EVENTS OF IMMUNOTHERAPY AND VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS

The principles of VEGF-TKI AE management are centered around knowledge of the on-target and off-target related toxicities. The most common toxicities seen with VEGF-TKIs are hypertension, skin toxicity, diarrhea, nausea, anorexia, and fatigue.18 Patients with baseline cardiovascular conditions or hypertension should receive appropriate antihypertensives to control these conditions and clinicians should anticipate needing to escalate therapy when initiating a VEGFTKI.

 If hypertension remains uncontrolled despite maximum medical therapy, a lower dose should be considered. 

Hand-foot syndrome (or palmar-plantar erythrodysesthesia) can be a painful, debilitating skin toxicity that emerges on the patient’s palms and soles at the initiation of treatment. As preventive measures, pharmacists can encourage patients to apply urea-based creams and emollients to keep skin hydrated and use protective footwear and hand wear when performing activities that could expose these areas to damage.

Anorexia, which presents as dramatic weight loss, can be caused by loss of appetite, treatment-related nausea, taste alterations, or diarrhea. This toxicity is most profound with cabozantinib, with grade 1 to 2 events occurring in 44% of patients and grade 3 in 2%.

 Weight loss can occur and, overall, this toxicity may significantly impact a patient’s quality of life.

Dose reductions or switching among agents may be an option, but unfortunately, supportive care techniques are seldom effective. Some clinicians opt to adjust the dosage schedule rather than the individual dose, including having patients take a “weekend holiday” off therapy. Serious toxicities that would warrant permanent discontinuation include gastrointestinal perforation or fistula formation, grade 3 to 4 hepatotoxicity, nephrotic syndrome, hemorrhage, thromboembolisms, or any grade 3 to 4 toxicity that does not resolve with maximum supportive care measures.

Clinicians should encourage patients to call for early support to ensure the timely intervention of supportive care measures. In addition, clinicians should try adjusting the dose and schedule of 1 therapy before switching agents, to allow patients to stay on active therapy for longer periods and achieve a longer clinical benefit. Pharmacists should ensure patients are counseled to withhold VEGF-TKI around upcoming surgeries. Given the antiangiogenic effect of these oral TKIs, holding these agents at least 1 week before any scheduled major surgery is generally recommended. Re-initiation of treatment can begin once full wound healing has occurred.

With the advent of novel TKI and ICI combination therapies for RCC, the recognition and management of overlapping toxicities between both classes represents a substantial therapeutic dilemma. irAEs are a distinct entity that respond solely to treatment with steroids to hamper the immune response, whereas TKI-related toxicities respond best to dose reductions, treatment interruptions, and traditional supportive care.

 Knowledge of the pharmacokinetics, onset, and clinical presentation of the toxicities between TKI and ICI agents can help pharmacists decipher the causative agent and the recommended approach in management. For example, with the combination of pembrolizumab and axitinib, up to 54.3% of patients experience diarrhea, an AE that both agents can cause.

 However, axitinib’s pharmacokinetics are advantageous in this setting as the drug’s half-life of 2 to 5 hours would allow for a quick washout period to resolve any toxicities.

Therefore, 1 strategy would be to hold axitinib for 2 to 3 days; if the diarrhea resolves, the toxicity can likely be attributed to axitinib, in which case the pharmacist can follow the recommended dose modifications for management. If symptoms progress or are unchanged, the clinical picture is more consistent with an irAE and the pharmacist can refer to existing guidelines, such as those of the American Society of Clinical Oncology, Society for Immunotherapy of Cancer, and National Comprehensive Cancer Network, to facilitate assessment and management.

 Another consideration when deciding between combination therapy options with either ICI or ICI plus TKI is that ICI combinations in clinical trials resulted in a lower incidence of grade 3 or greater AEs (47%) compared with ICI plus TKI, such as pembrolizumab-axitinib and avelumab-axitinib (76% and 71%, respectively).

Choosing optimal therapy for patients with RCC should be based on the strength of the literature, maturity of the data, and patient status and preference. Clinicians should note guideline recommendations when choosing appropriate therapy for patients. With the record growth of immunotherapies, selecting preferred treatment modalities is increasingly difficult. It is likely that, with further research and upon data maturation, immunotherapies will continue to change the standards of care for the treatment of RCC. 

, is an oncology pharmacy manager at M Health Fairview and an assistant professor at Mayo Clinic College of Medicine in Rochester, Minnesota.

, is a PGY2 oncology resident at The University of Texas MD Anderson Cancer Center in Houston, Texas.

, is a PGY2 critical care resident at the University of Kentucky HealthCare in Lexington, Kentucky.

Padala SA, Barsouk A, Thandra KC, et al. Epidemiology of renal cell carcinoma. 

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2021. Accessed November 29, 2020. https://www.nccn.org/professionals/physician_gls/pdf /kidney.pdf

Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. 

. 2013;14(2):141-148. doi:10.1016/S1470-2045(12)70559-4

Deleuze A, Saout J, Dugay F, et al. Immunotherapy in renal cell carcinoma: the future is now. 

. 2020;21(7):2532. doi:10.3390/ijms21072532

Simmons MN, Weight CJ, Gill IS. Laparoscopic radical versus partial nephrectomy for tumors > 4 cm: intermediate-term oncologic and functional outcomes. 

. 2009;73(5):1077-1082. doi:10.1016/j.urology.2008.11.059

Peycelon M, Hupertan V, Comperat E, et al. Long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. 

2009;181(1):35-41. doi:10.1016/j.juro.2008.09.025

Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. 

 2016;375(23):2246-2254. doi:10.1056/NEJMoa1611406

Motzer RJ, Ravaud A, Patard JJ, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. 

2018;73(1):62-68. doi:10.1016/j.eururo.2017.09.00

Smaldone MC, Fung C, Uzzo RG, Haas NB. Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma. 

. 2011;25(4):765-791. doi:10.1016/j.hoc.2011.06.002

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo controlled, randomised, phase 3 trial. 

. 2016;387(10032):2008-2016. doi:10.1016/S0140-6736(16)00559-6

Motzer RJ, Haas NB, Donskov F, et al; PROTECT Investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. 

. 2017;35(35):3916-3923. doi:10.1200/JCO.2017.73.5324

Motzer RJ, Tannir NM, McDermott DF, et al; CHECKMATE 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated March 10, 2021. Accessed November 29, 2020. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm

Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047

Choueiri TK, Powles 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. 

. 2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257

NCCN. Clinical Practice Guidelines in Oncology. Management of immunotherapy-related toxicities, version 1.2021. Accessed November 29, 2020. nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf

Naglieri E. Management of toxicity in patients treated with tyrosine kinase inhibitors (TKI). 

. 2008;6(14):42-45. doi:10.1016/j.ejcsup.2008.06.012

Articles

Immunotherapies will continue to change standards of care for treatment of RCC. 