Combination Therapy Strategy in First-Line Settings for Advanced Renal Cell Carcinoma

Cancers of the kidney and renal pelvis are among the 10 most common cancers in the United States, with an estimated lifetime risk of 1.68%.^1,2 Approximately 79,000 new kidney cancer cases will be diagnosed in 2022; the majority will be diagnosed in men (50,290 cases compared with 28,710 cases in women), and an estimated 13,920 people will die from the disease.1 Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of all cases.¹ Several histological subtypes of RCC have been the described, with clear cell RCC (ccRCC) being the most common and accounting for approximately 70% of RCC cases.^3,4
At the time of initial kidney cancer diagnosis, 16% of patients present with disease that has spread to regional lymph nodes or nearby organs, 16% present with disease that has spread to distant sites, and 65% of patients present with localized disease.^5,6 Compared with patients with regional or distant disease, those with localized kidney cancer have higher survival rates (5-year relative survival rate, ≈ 93%).5 In contrast, patients with regional or distant disease have a 5-year relative survival rate of about 70% and 13%, respectively.⁵
The treatment of patients with advanced RCC is evolving rapidly, with 3 new combination regimens receiving approval by the US Food and Drug Administration (FDA) in recent years.^7-11 Systemic therapies are usually recommended following reoccurrence and for patients with unresectable tumors.¹² Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), such as sunitinib, have been part of the standard frontline treatment of advanced RCC, demonstrating longer progression-free survival (PFS) and higher response rates compared with prior standards of care.^12-14 These agents inhibit the activity of receptor tyrosine kinases that are key for tumor growth, pathologic angiogenesis, and metastasis.^13,15
As immunosuppressive pathways are also involved in tumor pathogenesis, clinical trials have evaluated the combination of TKIs with immune checkpoint inhibitors (ICIs) in advanced RCC.^7,8,16-21 After demonstrating improved overall survival (OS), PFS, and response rates over single-agent sunitinib in patients with advanced ccRCC, TKI/ICI combinations are now the recommended preferred regimens for the frontline treatment of advanced disease with clear cell histology.^7,8,12,21 This article reviews key clinical data supporting the role of these relatively new TKI/ICI combinations in the frontline setting of advanced RCC and important considerations for their use in clinical practice.

Classification and First-Line Combinations for Advanced Rcc
Prognostic risk models, such as the International Metastatic RCC Database Consortium (IMDC) criteria, help guide frontline treatment selection for patients with advanced RCC.^12,22,23 The IMDC criteria were derived from patient populations with metastatic RCC treated with VEGF-targeted therapy, and they have been validated for use as a prognostic tool across different therapy lines.^23-29 The IMDC risk calculator stratifies patients into 3 risk groups: favorable (0 risk factors), intermediate (1-2 risk factors), or poor (≥ 3 risk factors).²³ The risk group is determined by the presence of the following 6 risk factors: time from initial diagnosis to systemic therapy of less than 1 year, Karnofsky performance status less than 80%, hemoglobin level below the lower limit of the normal range, corrected serum calcium level above the upper limit of normal (ULN), neutrophil count above the ULN, and platelet count above the ULN.^23-26
Because this tool provides the corresponding estimated median survival based on population medians, it is not intended to advise individual patients or replace medical advice from a physician.^22,23 However, the IMDC model can help facilitate frontline therapy selection.²³ Certain combination regimens may be used across any IMDC risk group, whereas other regimens are only beneficial in some risk groups.^12,23,30 For instance, in a clinical trial, the combination of ipilimumab plus nivolumab provided survival benefit over sunitinib in patients with intermediate- and poor-risk advanced RCC, while no such benefit was observed in patients with favorable-risk disease.^23,30 The importance of RCC risk status in determining individual patient needs is highlighted by evidence-based guidelines, which provide treatment recommendations for patients with advanced RCC based on risk stratification.¹²
Combination regimens containing VEGFR-TKIs and ICIs play a key role in the current frontline treatment of advanced RCC.^{12,15,19,20,31,32} The VEGFR-TKI drug class exerts its antitumor activity by blocking VEGF-mediated endothelial cell survival, reducing angiogenesis and tumor proliferation, and inducing tumor cell apoptosis.^18,31,33 Additionally, VEGFR-TKIs promote T-cell function and reduce immunosuppressive cells.17,18 ICIs in this setting are monoclonal antibodies that target cell death protein 1 (PD-1).^20,32 By blocking the interaction between PD-1 and its ligands, these agents inhibit the immune response mediated by the PD-1 pathway, including the antitumor immune response, resulting in decreased tumor growth.^20,32 Thus, the combination of a VEGFR-TKI with an ICI acts on angiogenic and immunosuppressive pathways.^20,31,32

Clinical Review of Available First-Line Combinations
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Kidney Cancer recommend the following TKI/ICI combinations as preferred frontline regimens for relapsed or stage IV ccRCC: axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab.¹² All 3 combinations have been approved by the FDA for the treatment of advanced RCC, with axitinib/pembrolizumab receiving approval in 2019, followed by cabozantinib/nivolumab in January 2021, and, most recently, lenvatinib/pembrolizumab in August 2021.^9-11 These combinations are the only preferred category 1 regimens that are indicated across all risk groups based on high-level evidence of superior efficacy and safety, resulting in uniform NCCN consensus for the recommendation.¹² For patients with intermediate- or poor-risk disease, additional preferred regimens include ipilimumab/nivolumab (category 1) and cabozantinib monotherapy (category 2A).¹²

Key Clinical Data of Frontline TKI/ICI Combinations
Axitinib Plus Pembrolizumab
Axitinib is a TKI shown to target VEGFR1, VEGFR2, and VEGFR3, which are receptor tyrosine kinases involved in pathogenic angiogenesis, tumor development, and cancer advancement.³¹ Pembrolizumab is a monoclonal antibody targeting PD-1.20 The approval for the axitinib/pembrolizumab combination in advanced RCC was based on results of the KEYNOTE-426 trial (NCT02853331).⁹ This phase 3, randomized, multicenter, open-label trial enrolled 861 patients with newly diagnosed or recurrent stage IV ccRCC who had not received prior systemic therapy.⁷ Patients were randomly assigned 1:1 to receive pembrolizumab (200 mg intravenously [IV] every 3 weeks) plus oral axitinib (5 mg twice daily) or sunitinib monotherapy.⁷
The combination of axitinib plus pembrolizumab resulted in significantly longer OS and PFS and a higher objective response rate (ORR) compared with sunitinib, as demonstrated by results from the first interim analysis.7 Axitinib plus pembrolizumab provided a 47% reduction in risk of death relative to sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P < .0001).⁷ At 12 months, the OS rate was 89.9% for the axitinib/pembrolizumab group compared with 78.3% for the sunitinib group.⁷ Median PFS was significantly longer with the combination of axitinib/pembrolizumab (15.1 months) compared with sunitinib (11.1 months), with a 31% reduction in the risk of disease progression or death with the combination (HR, 0.69; 95% CI, 0.57-0.84; P < .001).⁷ The ORR was significantly higher with axitinib/pembrolizumab compared with sunitinib (59.3% vs 35.7%, respectively; P < .001).⁷ The OS and PFS benefits with axitinib/pembrolizumab over sunitinib were observed among all subgroups examined, including all risk groups.⁷ The HR for death for the different IMDC risk groups were 0.64 (95% CI, 0.24-1.68) for favorable, 0.53 (95% CI, 0.35-0.82) for intermediate, and 0.43 (95% CI, 0.23-0.81) for poor, all favoring the combination.⁷ The HR for disease progression or death also favored the combination in all IMDC risk categories (favorable: HR, 0.81 [95% CI, 0.53-1.24]; intermediate: HR, 0.70 [95% CI, 0.54-0.91]; poor: HR, 0.58 [95% CI, 0.35-0.94]).⁷
Extended follow-up results from the KEYNOTE-426 trial after a median follow-up of 30.6 months continued to demonstrate the benefits of axitinib/pembrolizumab over sunitinib (Table 1).³⁴ Median OS was not reached with the combination, and median OS was 35.7 months with sunitinib (HR, 0.68; 95% CI, 0.55-0.85; P = .0003).34 At 24 months, OS rate was 74.4% in the axitinib/pembrolizumab group and 65.5% in the sunitinib group.34 Median PFS with axitinib/pembrolizumab was 15.4 months compared with 11.1 months with sunitinib (HR, 0.71; 95% CI, 0.60-0.84; P < .0001).³⁴
The most common adverse events (AEs) of any grade occurring in at least 20% of patients receiving axitinib/pembrolizumab included diarrhea, hypertension, fatigue, hypothyroidism, decreased appetite, palmar-plantar erythro-
dysesthesia syndrome, nausea, elevated transaminase levels, dysphonia, cough, and constipation.³⁴ Grade 3 or higher AEs observed in at least 10% of patients were hypertension and increased alanine transaminase (ALT) level for those who received axitinib/pembrolizumab and hypertension for those who received sunitinib.⁷

Cabozantinib Plus Nivolumab
Cabozantinib is a TKI that blocks the activity of several receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, MET, AXL, RET, and ROS1, all of which are involved in oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.¹⁵ Nivolumab is a PD-1–blocking monoclonal antibody.32 The approval of the combination of cabozantinib and nivolumab in advanced RCC was based on findings from the CheckMate 9ER trial (NCT03141177).10 This open-label, phase 3 trial enrolled 651 patients with untreated, advanced ccRCC and randomly assigned them 1:1 to receive nivolumab (240 mg IV every 2 weeks) plus oral cabozantinib 40 mg once daily (n = 323) or sunitinib monotherapy (n = 328).⁸
Compared with sunitinib, cabozantinib/nivolumab treatment resulted in significantly longer PFS, improved OS, and higher likelihood of response.8 Median PFS was 16.6 months in the cabozantinib/nivolumab group vs 8.3 months in the sunitinib group (HR, 0.51; 95% CI, 0.41-0.64; P < .001).⁸ The likelihood of OS at 12 months was 85.7% in the cabozantinib/nivolumab group compared with 75.6% in the sunitinib group (HR for death, 0.60; 98.89% CI, 0.40-0.89; P = .001).⁸ Median OS was not reached in either treatment arm.8 Confirmed ORR was 55.7% in the cabozantinib/nivolumab group and 27.1% in the sunitinib group (P < .001).8 Consistent benefits in PFS, OS, and ORR were observed across subgroups with the combination of cabozantinib/nivolumab.8 The HR for disease progression or death favored the combination in all IMDC risk categories.⁸
Any-grade AEs occurring in at least 20% of patients receiving cabozantinib plus nivolumab included diarrhea, palmar-plantar erythrodysesthesia syndrome, hypertension, hypothyroidism, fatigue, increased ALT level, decreased appetite, nausea, dysgeusia, asthenia, rash, and mucosal inflammation.⁸ The only grade 3 or higher AE that occurred in at least 10% of patients in either treatment arm was hypertension, which was observed with similar frequency in both arms.8
The final OS analysis of the CheckMate 9ER trial demonstrated sustained benefits with the combination of cabozantinib/nivolumab compared with sunitinib.³⁵ After a median follow-up of 32.9 months, median OS was 37.7 months in the cabozantinib/nivolumab group compared with 34.3 months in the sunitinib group, representing a considerable improvement in OS with the combination (HR, 0.70; 95% CI, 0.55-0.90; P = .0043).³⁵ The combination also led to sustained PFS and ORR benefits over sunitinib with extended follow up.35 In an exploratory post hoc analysis, more patients had a 30% or higher reduction from baseline with cabozantinib/nivolumab compared with sunitinib in target lesions involving the kidneys (45% vs 30%,
respectively), bone (56% vs 20%), lymph nodes (74% vs 48%), liver (48% vs 33%), and lungs (76% vs 46%).³⁵

Lenvatinib Plus Pembrolizumab
Lenvatinib is a multikinase inhibitor that inhibits the activities of VEGFR1, VEGFR2, and VEGFR3, as well as several other kinases involved in pathogenic angiogenesis, tumor growth, and cancer progression, such as FGF receptors (FGFR1, -2, -3, and -4), PGFRA, KIT, and RET.19 This agent has also been shown to concurrently inhibit the phosphorylation of FRS2α.¹⁹ In mouse tumor models, the combination of lenvatinib with an anti–PD-1 antibody resulted in increased activated cytotoxic T cells and greater antitumor activity compared with either agent alone.¹⁹
The combination of lenvatinib plus pembrolizumab was approved in advanced RCC based on results from the CLEAR (KEYNOTE-581) trial (NCT02811861), a multicenter, open-label, phase 3, randomized study.^11,21 This trial enrolled 1069 patients with previously untreated, advanced ccRCC and assigned them in a 1:1:1 ratio to receive oral lenvatinib (20 mg once daily) plus pembrolizumab (200 mg IV every 3 weeks), lenvatinib plus everolimus, or sunitinib, with results from the lenvatinib/pembrolizumab and sunitinib monotherapy groups being the efficacy population supporting the approval.^11,21
Patients who received lenvatinib/pembrolizumab experienced a median PFS more than double that of patients who received sunitinib, with a median PFS of 23.9 months for patients treated with lenvatinib/pembrolizumab vs a median PFS of 9.2 months for those treated with sunitinib (HR for disease progression or death, 0.39; 95% CI, 0.32-0.49; P < .001).²¹ The PFS benefit of the combination of lenvatinib/pembrolizumab over sunitinib was consistent across subgroups, including the IMDC risk groups.²¹
The combination of lenvatinib/pembrolizumab also demonstrated superiority in OS and ORR compared with sunitinib (Table 3).^19,21 While median OS was not reached with any treatment, the combination of lenvatinib/pembrolizumab led to significantly longer survival compared with sunitinib (HR for death, 0.66; 95% CI, 0.49-0.88; P = .005).²¹ The confirmed ORR with lenvatinib/pembrolizumab was 71% compared with an ORR of 36.1% with sunitinib (P < .0001).^19,21
Any-grade AEs occurring in at least 20% of patients receiving lenvatinib/pembrolizumab included fatigue, gastrointestinal symptoms, musculoskeletal pain, hypothyroidism, hypertension, hemorrhagic events, decreased appetite, rash, palmar-plantar erythrodysesthesia syndrome, dysphonia, proteinuria, acute kidney injury, weight loss, hepatoxicity, and headache.19 The only grade 3 or higher AE observed in at least 10% of patients in either treatment arm was hypertension, which was observed in 27.6% of patients in the lenvatinib/pembrolizumab group and in 18.8% of patients in the sunitinib group.²¹

Quality of Life and Safety Considerations for the Use of First-Line RCC
Combination Regimens
Impact on Health-Related Quality of Life
The impact of TKI/ICI combinations on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) of patients with advanced RCC has been described in subsequent analyses of phase 3 trials.^36-38 In the KEYNOTE-426 trial, PROs were measured using the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index–Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), and European Quality of Life (EuroQoL) EQ-5D-3L.³⁶ Overall, the combination of axitinib/pembrolizumab had minimal or no impact across PRO measures when compared with sunitinib.36 No meaningful differences in least squares mean (LSM) scores between treatment arms were noted at week 30 for FKSI-DRS, QLQ-C30 Global Health Status/Quality of Life (GHS/QoL), and EQ-5D visual analog rating scale (VAS) scores.³⁶
In the CheckMate 9ER trial, HRQOL was measured using the 19-item FKSI-19, and global health status was measured using the EQ-5D-3L.37 Treatment with cabozantinib plus nivolumab maintained or improved HRQOL, functioning, and disease-related symptoms (DRS) compared with sunitinib.37 Specifically, cabozantinib/nivolumab demonstrated stable scores for FKSI-19 (total), FKSI-19 functional well-being, and EQ-5D-3L UK utility index and improved scores for FKSI-19 DRS version 1, FKSI-19 DRS physical scale, and EQ-5D-3L VAS.37 In comparison, patients treated with sunitinib experienced a deterioration in health status as noted by a decline from baseline in scores across all assessment instruments.³⁷ Cabozantinib plus nivolumab was consistently favored over sunitinib on LSM change in FKSI-19 and EQ-5D-3L scores, with nominally significant differences demonstrated between treatment arms at most points of time until week 115 (P < .01 for all).³⁷ In the CLEAR trial, HRQOL was assessed as one of the secondary end points using the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L instruments.38 Similar or modest improvements in HRQOL and DRS mean scores were observed for patients treated with lenvatinib/pembrolizumab compared with patients treated with sunitinib.38 Physical functioning, fatigue, dyspnea, and constipation in the EORTC-QLQ-C30 scales favored lenvatinib/pembrolizumab over sunitinib (P = .02, .044, .032, and .033, respectively) to a nominally significant extent, while sunitinib was not favored over lenvatinib/pembrolizumab in any of the scales.³⁸ Time to first deterioration in EORTC QLQ-C30 scales for physical functioning, dyspnea, and appetite loss and in EQ-5D-3L VAS results favored lenvatinib/pembrolizumab over sunitinib (P = .034, .023, .028, and .041, respectively) to a nominally significant extent.³⁸
A systematic review and network meta-analysis comparing immunotherapy-based combinations for the frontline treatment of advanced RCC included analyses on PROs.³⁹ All 3 key trials involving TKI/ICI combinations were included in the analysis.³⁹ In treatment ranking analysis of the EQ-5D, the lenvatinib/pembrolizumab combination had the highest likelihood of being the preferred treatment, followed by the cabozantinib/nivolumab combination.³⁹ In regards to FKSI scores, the combination of cabozantinib/nivolumab had a higher likelihood than the lenvatinib/pembrolizumab combination of being the preferred treatment, while sunitinib had the lowest likelihood.³⁹ Of note, FKSI data on the axitinib/pembrolizumab combination were not available at the time of this analysis.⁴⁰

Management of Adverse Events Associated with TKI/ICI Combinations
Treatment-related AEs (TRAEs) can impact HRQOL and treatment duration.^7,21,36 Compared with sunitinib monotherapy, TKI/ICI combinations more likely may to lead to grade 3 or 4 TRAEs.39,40 In treatment ranking analysis from the network meta-analysis described previously, the combination of lenvatinib/pembrolizumab had the highest likelihood of being associated with TRAEs of grade 3 or 4 severity, followed by the cabozantinib/nivolumab combination.³⁹ Axitinib/pembrolizumab had the lowest odds for this outcome among the 3 combinations but still greater odds than did sunitinib monotherapy.³⁹
Some of the most common any-grade and grade 3 or higher AEs occurring with greater frequency among patients with advanced RCC treated with TKI/ICI combinations compared with those treated with sunitinib include diarrhea, hepatoxicity, and endocrinopathies.^7,8,21 In phase 3 trials, grade 3 or higher treatment-related diarrhea occurred in 9.1% of patients treated with axitinib/pembrolizumab, 6.9% of those treated with cabozantinib/nivolumab, and 9.7% of those who received lenvatinib/pembrolizumab.^8,21 The incidence of grade 3 or higher treatment-related diarrhea among patients who received sunitinib was around 4% in each trial.^7,8,21 Any-grade elevations in liver transaminase levels were more common among those treated with axitinib/pembrolizumab (26%-27%) or cabozantinib/nivolumab (25%-28%) compared with those treated with lenvatinib/pembrolizumab (< 10%).^7,8
The management of toxicities associated with TKI/ICI combinations may require dose modification of 1 or both drugs.^{15,19,20,31,32} In phase 3 trials, a substantial number of patients receiving the TKI/ICI combination required dose modifications due to AEs while still demonstrating improved survival and response rates over those receiving sunitinib monotherapy.7,8,21,35 In the KEYNOTE-426 and CheckMate 9ER trials, discontinuation of either study drug due to any-grade TRAE occurred in about 26% to 27% of patients in the TKI/ICI combination groups and 10% of patients in the sunitinib groups.^7,35 In the CLEAR trial, any-grade AEs led to discontinuation of any study drug in 37% of patients in the lenvatinib/pembrolizumab group and 14% of patients in the sunitinib group.²¹ Additionally, TKI dose reduction due to AEs occurred in about 69% of patients receiving lenvatinib and 50% of patients receiving sunitinib.²¹
Recommendations for dose modifications (which may involve dose interruption, reduction, or permanent discontinuation depending on the AE severity) as well as monitoring recommendations are provided in the prescribing information for each agent.^{15,19,20,31,32} When dosage reduction is indicated, the dose of axitinib can be reduced from the initial 5 mg twice daily to 3 mg twice daily and again to 2 mg twice daily if additional dose reduction is needed.³¹ For cabozantinib, the initial dose of 40 mg daily can be reduced to 20 mg daily and then again to 20 mg every other day if second dosage reduction is needed.¹⁵ The recommended initial dose for lenvatinib in this setting is 20 mg once daily, which can be reduced to 14 mg once daily if needed for AEs and subsequently to 10 mg once daily and 8 mg once daily if second and third dosage reductions, respectively, are needed.¹⁹
Use of anti–PD-1 antibodies can lead to immune-related AEs, which may involve any organ system at any time after starting treatment, and some can be life-threatening.^20,32 Patients receiving pembrolizumab or nivolumab should be closely monitored for the early identification and management of potential immune-related AEs.^20,32 Depending on the type and severity of the AE, interruption or permanent discontinuation of the ICI as well as administration of immunosuppressive therapy may be needed.^20,32 Dose reductions for pembrolizumab or nivolumab are not recommended.^20,32

Conclusions
The advanced RCC treatment landscape continues to evolve, with 3 relatively new TKI/ICI combination regimens receiving FDA approval in the frontline setting in recent years.^9-11 These therapeutic regimens incorporate agents that target angiogenic and immunosuppressive pathways and block the tyrosine kinase activity of VEGFR, a key driver of RCC pathogenesis.^{15,16,19,20,31,32,41,42} NCCN guidelines recommend these combination regimens as the preferred frontline treatments for patients with advanced ccRCC across all IMDC risk groups based on high-level evidence of superior efficacy and safety.¹² Importantly, these regimens have demonstrated substantially longer OS and PFS when compared with sunitinib in phase 3 trials in this patient population.^7,8,21 Patients who received lenvatinib/pembrolizumab experienced a median PFS nearly double that of patients who received sunitinib.²¹ Despite encouraging efficacy and QOL data, it is important to monitor the potential for toxicity with each of these agents. Moreover, ongoing studies will likely continue to elucidate not only their efficacy and safety profiles but also their role in the broader treatment spectrum for advanced RCC.

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