Clinical Insights: Use of Combination Therapy for Advanced Clear-Cell Renal Cell Carcinoma

APPROXIMATELY 73,000 NEW cases of renal cell carcinoma (RCC) are expected to be diagnosed in 2019 in the United States, with up to 70% of these cases anticipated to be clear-cell subtype.^1,2

The American Cancer Society reports that based on data from 2008 through 2014, the 5-year overall survival (OS) for all types of advanced RCC (aRCC) is reported as 12%.³ Patients with a history of smoking, obesity, hypertension, chronic kidney disease, and certain genetic syndromes are at an increased risk for developing RCC. Von Hippel-Lindau syndrome, specifically, is associated with development of clear-cell subtype.⁴

Although RCC is typically found incidentally through imaging completed for other medical reasons, the key triad of symptoms that may raise the suspicion for RCC includes flank pain, hematuria, and palpable mass.⁴ In patients who receive a diagnosis of stage I through stage III disease, typical treatment approaches include active surveillance, partial or radical nephrectomy, ablative therapies, or clinical trial. Patients with stage IV disease may be candidates for a cytoreductive nephrectomy, but systemic therapy is often considered first line, especially for those with clear-cell histology and poor-risk features.⁵

Since its approval in 2006, the oral tyrosine kinase inhibitor sunitinib has remained a standard firstline therapy for treating aRCC.⁶ Sunitinib formally displaced interferon alfa in 2007 following a trial demonstrating improved progression free survival (PFS), objective response rate, and patient-reported quality of life with sunitinib 50 mg daily.⁷ In a 2015 study, nivolumab demonstrated a longer OS than everolimus in the second-line setting, and thus became the first programmed cell death receptor (PD-1) or programmed cell death ligand (PD-L1) immunotherapy agent to be approved for use in aRCC.⁸

After this introduction into the aRCC pathway, numerous studies began to assess the use of combination therapies in aRCC, including PD-1/PD-L1 with VEGF inhibition and PD-1/PD-L1 with cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibition. The use of dual immune checkpoint inhibition or combined immune checkpoint and VEGF inhibition is proposed to provide additive or synergistic activity on T-cell response and anti-tumor activity.⁹

Within a 13-month span, 3 new drug combinations were FDA approved for first-line therapy in aRCC. Two of these combinations, pembrolizumab plus axitinib and nivolumab plus ipilimumab, are now listed as preferred first-line regimens for favorable, poor, and intermediate risk status in the 2.2020 version of the National Comprehensive Cancer Network (NCCN) Kidney Cancer guidelines. The combination of axitinib plus avelumab is included in the other recommended regimens section. The guideline-driven recommendations for advanced clear-cell RCC are summarized in the Table.⁵

The combination of nivolumab plus ipilimumab was FDA approved on April 16, 2018, following the release of the results from the CheckMate 214 trial (NCT02231749). In this phase 3 trial, adult patients with previously untreated clear-cell aRCC were randomized to receive sunitinib 50 mg orally daily for 4 weeks of each 6-week cycle or nivolumab 3 mg/kg intravenous (IV) and ipilimumab IV 1 mg/kg every 3 weeks for 4 doses followed by indefinite nivolumab 3 mg/kg every 2 weeks. Among the intermediate- and poor-risk populations, the median PFS was 11.6 months (8.7-15.5) in the combination therapy group versus 8.4 months (7-10.8) in the sunitinib group (hazard ratio [HR], 0.82; P = .03). Median OS had not yet been reached in the combination group at the time of publication, but at 18 months, 75% of patients were still alive versus 60% of patients in the sunitinib group.

The most common adverse effects (AEs) of any grade reported with nivolumab plus ipilimumab included fatigue (37%), pruritus (28%), diarrhea (27%), rash (22%), and nausea (20%), whereas patients in the sunitinib group most commonly reported diarrhea (52%), fatigue (49%), palmarplantar erythrodysesthesia (43%), hypertension (40%), nausea (38%), dysgeusia (33%), stomatitis or mucosal inflammation (28%), decreased appetite (25%), hypothyroidism (25%), and vomiting (21%). Of note, 22% of the nivolumab plus ipilimumab group and 12% of the sunitinib group discontinued the study as a result of treatment-related AEs, and 35% of patients receiving the study combination required glucocorticoids for immune-related AEs.¹⁰

The combination of pembrolizumab plus axitinib was approved by the FDA on April 19, 2019, following the release of the results from the phase 3 KEYNOTE 426 trial [NCT02853331]. This trial included adult patients with previously untreated clear-cell aRCC. Patients were randomized to either sunitinib 50 mg by mouth daily for 4 weeks of each 6-week cycle or pembrolizumab 200 mg IV every 3 weeks plus axitinib 5 mg by mouth twice daily. Median PFS was reported as 15.1 months (12.6-17.7) versus 11.1 months (8.7-12.5) in the combination and sunitinib groups, respectively (HR, 0.69; P <.001). The OS end point has not yet been reached in either group, but at 18 months, 82.3% of patients in the pembrolizumab plus axitinib group were still alive versus 72.1% of patients in the sunitinib group.

The most common AEs reported by the combination group included diarrhea (54%), hypertension (44.5%), fatigue (38.5%), hypothyroidism (35.4%), decreased appetite (29.6%), palmar-plantar erythrodysesthesia (28%), nausea (27.7%), transaminitis (27%), and dysphonia (25%). The incidence of AEs for patients taking sunitinib was similar to that reported in CheckMate 214. Approximately one-third of patients receiving the combination therapy discontinued at least 1 agent because of AEs.¹¹

Of note, the combination of avelumab plus axitinib was approved by the FDA on May 14, 2019, following the release of the results from the JAVELIN Renal 101 trial [NCT02684006]. This study compared sunitinib 50 mg by mouth daily for 4 weeks of each 6-week cycle with avelumab 10 mg/kg IV every 2 weeks plus axitinib 5 mg by mouth twice daily in adult patients with untreated clear-cell aRCC. The study reported a median PFS of 13.8 months (11.1-not estimated) versus 8.4 months (6.9-11.1) in the combination and sunitinib groups, respectively (HR, 0.69; P <.001). After 11.6 and 10.7 months of follow-up for each respective group, deaths from any cause were reported as 14.3% and 16.9%. Patients receiving the study combination of avelumab plus axitinib experienced increased rates of diarrhea, hypertension, hypothyroidism, and dysphonia in comparison to the sunitinib group. Interestingly, only 8% of patients discontinued avelumab plus axitinib, whereas 13% of patients receiving sunitinib discontinued therapy because of AEs. Approximately 11% of patients in the combination group received glucocorticoids for immune-related AEs.¹²

In summary, pembrolizumab plus axitinib and nivolumab plus ipilimumab are 2 of the new FDA approved combination therapies considered preferred first-line treatment approaches for clear-cell aRCC, with avelumab plus axitinib also included as a consideration. It is imperative for pharmacists to be aware of these newer combination-therapy options and to be especially mindful of the potential for overlapping or additive toxicities that may arise from dual immunotherapy or the combination of immunotherapy and a VEGF inhibitor. These AEs may range from cutaneous changes, such as palmar-plantar erythrodysesthesia, to gastrointestinal issues, such as diarrhea, or to endocrine concerns such as hypothyroidism, in addition to others mentioned previously in each respective trial. The mechanism for these effects varies between different agents, and pharmacists should be prepared to help elucidate the cause and assist in guiding therapy when toxicities arise.

REFERENCES

• PDQ Adult Treatment Editorial Board. Renal Cell Cancer Treatment (PDQ®): Health Professional Version.; 2002. http://www.ncbi.nlm.nih.gov/pubmed/26389256. Accessed November 2, 2019.
• Jonasch E, Gao J, Rathmell WK. Renal cell carcinoma. BMJ. 2014;349(nov10 11):g4797-g4797. doi:10.1136/bmj.g4797
• Survival Rates for Kidney Cancer. https://www.cancer.org/content/cancer/en/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html. Accessed November 6, 2019.
• Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3(1):17009. doi:10.1038/nrdp.2017.9
• National Comprehensive Cancer Network. Kidney cancer (Version 2.2020). Accessed November 5, 2019.
• Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. Longo DL, ed. N Engl J Med. 2017;376(4):354-366. doi:10.1056/NEJMra1601333
• Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2007;356(2):115-124. doi:10.1056/NEJMoa065044
• Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665
• George S, Rini BI, Hammers HJ. Emerging Role of Combination Immunotherapy in the First-line Treatment of Advanced Renal Cell Carcinoma. JAMA Oncol. 2019;5(3):411. doi:10.1001/jamaoncol.2018.4604
• Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
• Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 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. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047