First-Line Immuno-Oncology Combinations for Metastatic Clear Cell Renal Cell Carcinoma (mRCC): A Systematic Review of Phase III Clinical Trials

Abstract

BACKGROUND: The introduction of immune checkpoint inhibitors rapidly changed treatment for patients with metastatic clear cell renal cell carcinoma (mRCC). First-line treatment now includes multiple immuno-oncology (IO) combinations that were approved over a short time period and were not directly compared in randomized clinical trials. Thus, clinicians face a challenge in individualizing first-line treatment to optimize clinical outcomes. OBJECTIVE: We sought to systematically review clinical outcomes for first-line IO combinations for patients with mRCC. METHODS: Literature reporting outcomes from phase III clinical trials that evaluated first-line IO combination therapies was identified through a search of the PubMed electronic database following PRISMA guidelines. Abstracts were screened to identify manuscripts that fit the search criteria, and then, a descriptive review was performed. RESULTS: Our literature search identified 2,229 abstracts that met the initial search criteria, and then, it was narrowed to 431 abstracts using filters for “clinical trial” and a “ten year” time window. After review of the abstracts, six manuscripts were selected for data extraction and subsequent review. CONCLUSION: When compared to sunitinib, four IO combinations improved overall survival as first-line treatment, and five improved progression free survival for patients with mRCC. These IO combination therapies have unique characteristics, so clinicians should take into account patient and cancer factors to individualize treatment recommendations.

Avelumab plus Axitinib for the Treatment of Patients with End-Stage Renal Disease Undergoing Dialysis: A Retrospective Case Series and Literature Review

“…Combination therapy with an immune checkpoint inhibitor and a molecular targeted therapy is now the mainstay of treatment for patients with RCC, because of the excellent outcomes obtained in phase III clinical tri- als [1]. However, there are few data regarding the efficacy and safety of combination therapies, such as Ave plus axitinib, for patients with ESRD who are undergoing hemodialysis, because all of the key clinical trials excluded such patients [1][2][3]. Several case reports have presented the outcomes associated with combination therapies [4][5][6][7], but there have been no previous case reports of the use of Ave plus axitinib (Table 1).…”

“…A meta-analysis of the immunotherapy of various cancer types indicated that the frequency of adverse events is similar for patients with or without ESRD who are undergoing hemodialysis [8]. The characteristics of the Ave/axitinib combination might have contributed to the absence of high-grade irAEs, because the frequency of irAEs associated with Ave plus axitinib that required high-dose corticosteroid (≥40 mg/ day) has been reported to be lower (11.1%) than that associated with other combinations, such as ipilimumab (Ipi) plus nivolumab (Nivo) (29.1%) or Nivo plus cabozantinib (19.1%) [1]. However, close observation for adverse events is necessary because previous reports have suggested that there is a much higher risk of adverse events in patients with ESRD, especially if a molecular targeted agent is used [10].…”

“…A combination of an immune checkpoint inhibitor and a molecular targeted agent is now widely used for the treatment of renal cell carcinoma (RCC), following the excellent outcomes of phase III clinical trials [1]. However, the efficacy and safety of such a combination for the treatment of patients with end-stage renal disease (ESRD) remain to be characterized, because such patients are usually excluded from clinical trials [1, 2].…”