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Updates on the Treatment of Renal Cell Carcinoma

Renee McAlister, PharmD BCOP
Clinical Pharmacy Specialist, Melanoma and Genitourinary Malignancies
Vanderbilt University Medical Center
Nashville, TN

Renal cell carcinoma (RCC) accounts for approximately 85% of all primary renal malignancies, and up to 88% of RCC diagnoses are clear cell subtype.1,2 Less frequently encountered are the papillary, sarcomatoid, and chromophobe subtypes. RCC is the eighth most common cancer diagnosis in the United States, and it is predicted to account for 4.2% of all new cancer diagnoses and 2.4% of all cancer-related deaths in 2019.3

The Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Score and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteria are models that have been developed to assess prognosis and survival in patients with metastatic RCC (mRCC). The MSKCC Prognostic Score was developed and validated on the basis of clinical trials that studied the use of interferon for treatment of mRCC; the IMDC Criteria was developed and validated on the basis of clinical trials that studied the use of tyrosine kinase inhibitors for treatment of mRCC.4,5 The MSKCC Prognostic Score takes into account the following clinical features: interval from diagnosis to treatment of less than 1 year, Karnofsky Performance Status score less than 80%, serum lactose dehydrogenase greater than 1.5 times the upper limit of normal (ULN), corrected serum calcium greater than ULN, and serum hemoglobin less than the lower limit of normal (LLN).4 The IMDC Criteria is similar and takes into account the following clinical features: interval from diagnosis to treatment of less than 1 year, Karnofsky Performance Status score less than 80%, corrected serum calcium greater than ULN, serum hemoglobin less than LLN, neutrophil count greater than ULN, and platelet count greater than ULN.5 For both prognostic models, patients with zero clinical features are considered favorable risk, patients with 1–2 clinical features are considered intermediate risk, and patients with 3 or more clinical features are considered poor risk.4,5 The IMDC Criteria estimates 2-year overall survival (OS) to be 75% for favorable-risk patients, 53% for intermediate-risk patients, and 7% for poor-risk patients.5 The IMDC Criteria has become the standard risk stratification tool; however, some ongoing studies are still using the MSKCC Prognostic Score because they were initiated before the validation of the IMDC Criteria.

Several new drug approvals and RCC treatment guideline updates have occurred in the past 3 years, making RCC one of the most rapidly changing areas in oncology. Historically, management of non-mRCC consisted primarily of surgical or locally directed therapies.1,2 First-line management of mRCC historically consisted of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI)–directed therapies (such as pazopanib or sunitinib), which inhibit tumor growth primarily via inhibition of angiogenesis. However, on the basis of emerging data, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for treating kidney cancer were recently updated to include the option of adjuvant therapy for certain patients with non-mRCC and several new regimens for treatment of mRCC.6

Treatment Updates in the Adjuvant Setting

Several clinical trials investigating the use of adjuvant therapy for patients with high-risk stage III RCC have had results published, are awaiting final results, or are ongoing. Four studies have been published thus far: two (S-TRAC and the first arm of ASSURE) examined the use of sunitinib; one (the second arm of ASSURE), the use of sorafenib; one, the use of pazopanib (PROTECT); and one, the use of axitinib (ATLAS).7-10 Only one of these studies, S-TRAC, met its primary endpoint of disease-free survival (DFS).7

S-TRAC was a double-blind phase 3 trial that randomized 615 patients with locoregional, high-risk, clear cell RCC 1:1 to receive either sunitinib 50 mg orally daily or placebo for 4 weeks on the medication followed by 2 weeks off for 1 year.7 Patients were required to initiate treatment within 3–12 weeks of nephrectomy. The primary endpoint of DFS was 6.8 years in the sunitinib group versus 5.6 years in the placebo group (p = .03). Many patients in the sunitinib group required dose reductions (34.3%), dose interruptions (46.4%), and drug discontinuation (28.1%). Adverse events reported were similar to those in prior sunitinib studies, with the most common all-grade adverse events being diarrhea (56.9%), palmar-plantar erythrodysesthesia (50.3%), hypertension (36.9%), fatigue (36.6%), nausea (34.3%), and dysgeusia (33.7%). Overall survival (OS) data were not mature at the time of original publication, and updated results showed that median OS had not yet been reached in either group after an additional 10 months of follow-up.11 As previously mentioned, the ASSURE trial did not find an improvement in DFS with 1 year of adjuvant sunitinib; however, it is worth noting that differences in the patient population (inclusion of non-clear cell histology and inclusion of higher-risk patients) may have had an impact on the results.8 On the basis of the results of the S-TRAC trial, the U.S. Food and Drug Administration (FDA) approved sunitinib for adjuvant treatment of RCC on November 16, 2017.12

The only study of an oral agent that remains unpublished is EVEREST, a phase 3 double-blind trial that randomized 1,545 high-risk patients to everolimus versus placebo for 1 year.13 Patients were required to initiate treatment within 84 days of nephrectomy. This study is closed to accrual, and results are expected in October 2021. Several studies are ongoing; all are investigating the use of immune checkpoint inhibitors in the neoadjuvant or adjuvant setting. These clinical trials are studying the use of neoadjuvant pembrolizumab, neoadjuvant durvalumab plus tremelimumab, perioperative nivolumab, adjuvant atezolizumab, and adjuvant ipilimumab plus nivolumab.14

The NCCN clinical practice guidelines for kidney cancer recommend adjuvant sunitinib (category 2B) for patients with clear cell RCC and high-risk features (tumor Stage 3 or higher, regional lymph-node metastasis, or both).6 This category-2B recommendation is based on the lack of OS benefit, the discordance between the ASSURE and S-TRAC trials, and the concern for patients having to undergo 1 year of potential sunitinib toxicity during treatment in exchange for a 1-year improvement in DFS. No other systemic therapies are recommended in the adjuvant setting at this time.

Practical considerations for a pharmacist managing a patient on sunitinib therapy include counseling on appropriate administration (4 weeks on and 2 weeks off), monitoring for drug interactions (sunitinib is a major CYP3A4 substrate), and managing common VEGF receptor (VEGFR) inhibitor adverse effects such as diarrhea, hypertension, and palmar-plantar erythrodysesthesia.15 Although sunitinib was studied at the standard dose in the S-TRAC and ASSURE trials (as well as in the various studies discussed in the next section), it is common for patients to require dose reductions of sunitinib.

Treatment Updates in the Metastatic Setting

As previously mentioned, the treatment landscape of mRCC has changed dramatically over the past several years: four new therapies have been approved by the FDA in the first-line setting alone. Given the rapidly emerging data, the NCCN clinical practice guidelines for kidney cancer have undergone several recent updates and are likely to be updated again as additional therapies gain FDA approval.

Cabozantinib
Cabozantinib is an oral VEGF receptor (VEGFR) 1/2/3 inhibitor that was initially approved by the FDA in the second-line setting for mRCC on the basis of the results of the METEOR trial.16 Cabozantinib subsequently received FDA approval in December 2017 in the first-line setting for patients with mRCC on the basis of the results of the CABOSUN trial.17

CABOSUN was an open-label phase 2 trial that randomized 157 treatment-naive patients with intermediate or poor risk (per the IMDC Criteria) clear cell mRCC 1:1 to receive cabozantinib 60 mg orally daily continuously or sunitinib 50 mg orally daily for 4 weeks on followed by 2 weeks off.18 The primary endpoint of progression-free survival (PFS) was significantly longer in the cabozantinib group compared to the sunitinib group, at 8.2 months versus 5.6 months, respectively, which was associated with a 34% reduction in the rate of disease progression or death (p= .012). A subgroup analysis showed that 36% of patients included in this study had bone metastases, and these patients in particular had improved outcomes with cabozantinib over sunitinib. The most common all-grade adverse events seen in both groups were fatigue, hypertension, diarrhea, elevations in liver function tests, and palmar-plantar erythrodysesthesia, which is consistent with prior studies of both cabozantinib and sunitinib. The rates of grade 3-4 adverse events were similar in both the cabozantinib group (67%) and sunitinib group (68%).

On the basis of the results of the CABOSUN trial, the NCCN clinical practice guidelines for kidney cancer recommend cabozantinib as a category-2A recommendation for first-line treatment of patients with intermediate- or poor-risk clear cell mRCC, because the evidence is from a phase 2 trial. Although the CABOSUN trial did not include patients with favorable-risk clear cell mRCC, the guidelines also recommend cabozantinib (category 2B) as a first-line treatment for patients in this group.6

Practical considerations for a pharmacist managing a patient on cabozantinib therapy include counseling on appropriate administration (1 hour before or 2 hours after eating); monitoring for drug interactions (cabozantinib is a major CYP3A4 substrate); and managing common VEGFR inhibitor adverse effects such as diarrhea, hypertension, and palmar-plantar erythrodysesthesia.19

Ipilimumab and Nivolumab
Nivolumab, a programmed cell death-1 (PD-1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, are immune checkpoint inhibitors that work to upregulate T-cell activation and restore antitumor immune response.20 Nivolumab was initially approved as a single agent in the second-line setting for mRCC in November 2015.21 The next approval for immunotherapy use in mRCC was not given until April 2018, when ipilimumab plus nivolumab was the first immunotherapy regimen approved by the FDA for first-line treatment of mRCC on the basis of the results of CheckMate 214.22

CheckMate 214 was an open-label phase 3 trial that randomized 1,096 treatment-naive patients with clear cell mRCC (all IMDC risk groups) 1:1 to receive either ipilimumab 1 mg/kg plus nivolumab 3 mg/kg intravenously (IV) every 3 weeks for four doses followed by nivolumab 3 mg/kg IV every 2 weeks, or sunitinib 50 mg orally daily for 4 weeks on followed by 2 weeks off.23 The coprimary endpoints were OS, objective response rate (ORR), and PFS in the subgroup of patients with intermediate- or poor-risk disease (n = 847). The median OS was not reached in the ipilimumab plus nivolumab (I+N) group, versus 26 months in the sunitinib group (p < .001). The ORR was 42% in the I+N group versus 27% in the sunitinib group (p < .001), which included 40 complete responses (CR) in the I+N group and 5 CR in the sunitinib group. The median PFS was 11.6 months in the I+N group and 8.4 months in the sunitinib group (p = .03; not significant, because the alpha level was set at 0.009 for PFS). All-grade adverse events occurred in similar numbers in each group, but the I+N group had fewer grade 3–4 adverse events (46% in the I+N group vs. 63% in the sunitinib group). The most common grade 3–4 adverse events in the I+N group were elevated lipase level (10%), fatigue (4%), and diarrhea (4%). The most common grade 3–4 adverse events in the sunitinib group were hypertension (16%), palmar-plantar erythrodysesthesia (9%), fatigue (9%), thrombocytopenia (5%), and diarrhea (5%). In addition to these clinical outcomes, a health-related quality of life (HRQoL) study showed more favorable HRQoL with the combination of I+N compared to sunitinib for patients with intermediate or poor risk.24 Despite the benefit noted with I+N for the intermediate- and poor-risk groups, the same clinical outcomes were not seen in the exploratory subgroup of patients with favorable risk.23 The OS, ORR, and PFS were significantly greater in the sunitinib group versus the I+N group, although more CR were seen in the I+N group versus the sunitinib group.

The NCCN clinical practice guidelines for kidney cancer recommend I+N as a first-line preferred recommendation (category 1) for patients with intermediate- or poor-risk clear cell mRCC and as a nonpreferred first-line recommendation (category 2A) for patients with favorable-risk clear cell mRCC.6 This regimen is a category-2A recommendation for favorable-risk patients despite the negative results of the CheckMate 214 trial because of results of the phase 1 CheckMate 016 study. CheckMate 016 did not report outcomes based on risk stratification but did report favorable outcomes for all patients included (favorable, intermediate, and poor risk).25 The guidelines also list I+N as a preferred regimen for subsequent therapy for clear cell mRCC because the CheckMate 016 study also included patients who had received one prior line of therapy.6

Practical considerations for a pharmacist managing a patient on I+N include monitoring for and counseling patients on signs and symptoms of immune-related adverse events such as colitis (new diarrhea), pneumonitis (new shortness of breath), dermatitis (new rash), hepatitis (elevations in liver enzymes), arthritis (new joint aches), and adrenal insufficiency or hypophysitis (new fatigue or headache that won’t go away).20 Patients may also be given immunotherapy information cards to keep in their wallet or purse in the event that an adverse event takes them to an emergency room or urgent care center.

Pembrolizumab and Axitinib
Axitinib, an oral VEGFR 1/2/3 inhibitor, was previously approved for second-line treatment of mRCC on the basis of the results of the AXIS trial.26 Pembrolizumab is a PD-1 inhibitor that gained its first indication for mRCC as a first-line treatment in combination with axitinib.27 The combination of a VEGFR inhibitor and immunotherapy is believed to have a synergistic effect. It is thought that anti-angiogenic agents such as axitinib can also stimulate the immune system and that immunotherapy agents such as pembrolizumab can also have anti-angiogenic properties.28 Pembrolizumab plus axitinib was the first immunotherapy/VEGFR inhibitor combination to achieve FDA approval. The approval of the combination in April 2019 was based on the results of KEYNOTE-426.27

KEYNOTE-426 was an open-label phase 3 trial that randomized 861 treatment-naive, clear cell mRCC patients (all IMDC risk groups) 1:1 to receive pembrolizumab 200 mg IV every 3 weeks plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally daily for 4 weeks on followed by 2 weeks off.29 The first primary endpoint, median OS, was not reached in either group. However, the 12-month OS was 89.9% in the pembrolizumab plus axitinib (P+A) group versus 78.3% in the sunitinib group (p < .0001). The second primary endpoint, PFS, was longer in the P+A group, at 15.1 months versus 1.1 months in the sunitinib group (p < .001). The ORR rate was 59.3% in the P+A group versus 35.7% in the sunitinib group (p < .001), including 25 CR in the P+A group versus 8 CR in the sunitinib group. The benefit of P+A was observed in all risk groups. All-grade adverse events occurred in similar numbers in each group; however, grade 3–4 adverse events occurred more frequently in the P+A group (75.8%) versus the sunitinib group (70.6%). The most common grade 3–4 adverse events seen in the P+A group include hypertension (22.1%), elevated alanine aminotransferase (13.3%), diarrhea (9.1%), and elevated aspartate aminotransferase (7%). The most common grade 3–4 adverse events seen in the sunitinib group include hypertension (19.3%), decreased platelet count (7.3%), decreased neutrophil count (6.8%), and fatigue (6.6%).

The NCCN clinical practice guidelines for kidney cancer recommend P+A as a first-line preferred recommendation (category 2A) for favorable-risk patients with mRCC and as a first-line preferred recommendation (category 1) for intermediate- and poor-risk patients with mRCC.6 Although the KEYNOTE-426 study did not include patients who had received prior therapy, the guidelines also list the combination as an option for subsequent therapy.

Practical considerations for a pharmacist managing patients on P+A include monitoring for and counseling patients on the signs and symptoms of immune-related adverse events as described above; counseling on appropriate administration of axitinib (twice daily with or without food); detailing the difference in diarrhea seen with immunotherapy versus axitinib (axitinib diarrhea will typically respond to antidiarrhea agents such as loperamide); and managing common VEGFR-inhibitor adverse effects such as diarrhea, hypertension, and palmar-plantar erythrodysesthesia.30,31

Avelumab and Axitinib
Avelumab is a programmed death-ligand 1 (PD-L1) inhibitor that functions in the local tumor environment to upregulate T-cell activation and restore antitumor immune response.32 Avelumab gained its first indication for mRCC as a first-line treatment in combination with axitinib in May 2019 on the basis of the results of the JAVELIN Renal 101 trial.33

JAVELIN Renal 101 was an open-label phase 3 trial that randomized 886 treatment-naive, clear cell mRCC patients (all IMDC risk groups) 1:1 to receive 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 on followed by 2 weeks off.34 The coprimary endpoints were PFS and OS in patients with PD-L1-positive disease (n = 560). The median PFS for patients with PD-L1-positive disease was 13.8 months in the avelumab plus axitinib (A+A) group versus 7.2 months in the sunitinib group (p < .001). PFS in the overall population was similar, at 13.8 months for the A+A group versus 8.4 months for the sunitinib group (p < .001). OS data were not mature at the time of publication. The ORR for patients with PD-L1-positive disease was 55.2% for the A+A group versus 25.5% for the sunitinib group, which includes 12 CR in the A+A group and 6 CR in the sunitinib group. Both all-grade and grade 3–4 adverse events occurred in similar numbers in each group. The most common grade 3–4 adverse events that occurred in the A+A group include hypertension (25.6%), diarrhea (6.7%), elevated alanine aminotransferase level (6%), and palmar-plantar erythrodysesthesia (5.8%). The most common grade 3–4 adverse events that occurred in the sunitinib group include hypertension (17.1%), anemia (8.2%), neutropenia (8.0%), and thrombocytopenia (6.2%).

The NCCN clinical practice guidelines for kidney cancer have recently been updated to reflect this newest FDA approval.6 The combination of avelumab plus axitinib was added as a first-line nonpreferred recommendation (category 2A) for treatment of favorable-, intermediate-, and poor-risk clear cell mRCC. It is also included as a category-3 recommendation for subsequent therapy for patients with clear cell mRCC.

Practical considerations for a pharmacist managing patients on A+A are the same as those for P+A, listed above.31,32

Atezolizumab and Bevacizumab
Bevacizumab is a monoclonal antibody that binds to VEGF to inhibit the binding of VEGF to VEGF receptors. Bevacizumab was initially approved in combination with interferon-alfa for the treatment of mRCC on the basis of results of the AVOREN trial.35,36 Atezolizumab is a PD-L1 inhibitor that does not yet have an indication for mRCC. This combination has not yet been approved by the FDA; however, the results of the IMmotion151 trial were recently published, which suggests that the combination may obtain FDA approval in the near future.

IMmotion151 was an open-label phase 3 trial that randomized 915 treatment-naive, clear cell or sarcomatoid mRCC (all MSKCC risk groups) 1:1 to atezolizumab 1,200 mg plus bevacizumab 15 mg/kg IV once every 3 weeks or sunitinib 50 mg orally daily for 4 weeks on followed by 2 weeks off.37 The coprimary endpoints were investigator-assessed PFS for PD-L1-positive disease (n = 362) and OS in the intention-to-treat (ITT) population. The primary endpoint of PFS in PD-L1-positive disease was improved in the atezolizumab plus bevacizumab (A+B) group at 11.2 months versus 7.7 months in the sunitinib group (p = .0217). Median OS data in the ITT population were not fully mature at publication; however, 43% of patients in the A+B group and 42% of patients in the sunitinib group had died at the data cutoff for the second OS interim analysis (hazard ratio = 0.93). The ORR for the ITT population was 37% in the A+B group versus 33% in the sunitinib group, which includes 24 CR in the A+B group and 10 CR in the sunitinib group. All-grade adverse events occurred in 91% of patients in the A+B group and in 96% of patients in the sunitinib group. Grade 3–4 adverse events occurred in 40% of patients in the A+B group and in 54% of patients in the sunitinib group. The most common grade 3–4 adverse events in the A+B group were hypertension (14%) and proteinuria (3%). The most common grade 3–4 adverse events in the sunitinib group were hypertension (17%), fatigue (5%), diarrhea (4%), and anemia (4%).

The FDA has yet to approve the combination of atezolizumab plus bevacizumab for the treatment of mRCC; therefore, it is not listed as a treatment option in the NCCN clinical practice guidelines for kidney cancer.6 However, if this regimen obtains FDA approval, it is expected that it will also be included as a first-line (and possibly subsequent-line) treatment option for clear cell mRCC.

Practical considerations for a pharmacist managing patients on atezolizumab plus bevacizumab are similar to those detailed above for other immunotherapy plus VEGF inhibitor combinations.35,38 Patients should also be counseled on the signs and symptoms of bleeding and the potential for delayed wound healing with bevacizumab and should be monitored closely for development of proteinuria. Patients receiving bevacizumab should also be monitored closely for infusion reactions.

Conclusion

The treatment landscape for renal cell carcinoma has changed greatly over the past several years. Per the NCCN clinical practice guidelines for kidney cancer, first-line treatment for favorable-risk patients now includes axitinib plus pembrolizumab (preferred, category 2A), ipilimumab plus nivolumab (category 2A), avelumab plus axitinib (category 2A), and cabozantinib (category 2B).6 First-line treatment for intermediate- and poor-risk patients now includes ipilimumab plus nivolumab (preferred, category 1), axitinib plus pembrolizumab (preferred, category 1), cabozantinib (preferred, category 2A), and avelumab plus axitinib (category 2A). Pazopanib and sunitinib are still listed as first-line regimens for both favorable-risk (preferred, category 2A) and intermediate- and poor-risk (category 2A) patients. For subsequent therapy, additions include ipilimumab plus nivolumab (preferred, category 2A), pembrolizumab plus axitinib (category 2A), and axitinib plus avelumab (category 3). It is likely that the guidelines will be updated again if atezolizumab plus bevacizumab obtains FDA approval.

In clinical practice, first-line therapies are chosen on the basis of risk stratification, the perceived ability of a patient to tolerate each option (combination versus single-agent therapy), schedule of administration (avelumab is given every 2 weeks, atezolizumab and pembrolizumab are given every 3 weeks, and nivolumab can be given every 4 weeks after the initial ipilimumab/nivolumab combination), and other factors such as drug cost and the patient’s ability to receive funding assistance.6 Subsequent lines of therapy are chosen after similar factors, in addition to the prior lines of therapy a patient has already received, have been weighed.

References

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