ReviewImmunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma
Introduction
Renal-cell carcinoma (RCC) represents approximately 90% of all renal cancers, with 85% of RCC identified as the clear-cell subtype.1 The incidence of RCC has increased by approximately 2% per year over the last 65 years.2 Strikingly, nearly one third of patients are initially diagnosed with advanced or metastatic RCC (mRCC).3, 4, 5, 6 mRCC has a variety of clinical presentations, however, and risk assessment is important, both to determine prognosis and to stratify patients for clinical drug development.
In the age of targeted therapies, risk assessment for mRCC patients was established with the International Metastatic Renal Cell Carcinoma Database (IMDC) criteria. From a multicenter cohort of 645 patients, 6 clinical factors were shown to be independently prognostic of survival on multivariable analysis: (1) anemia, (2) neutrophilia, (3) thrombocytosis, (4) hypercalcemia, (5) Karnofsky performance status < 80, and (6) < 1 year from diagnosis to first-line systemic therapy.7 Favorable risk patients had none of these factors, intermediate risk patients had 1 or 2 of these factors, and poor risk patients had more than 3 of these clinical factors. Risk stratification has now become a key part of clinical decision making, both for regulatory agencies granting indications for treatment and for clinicians selecting treatments for patients.
Over the past decade, the introduction of targeted therapies has greatly improved the outcomes of patients with mRCC.4, 5, 6 Multitargeted tyrosine kinase inhibitors (TKIs), which inhibit vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR), have been standard therapy options for patients with mRCC (Figure 1). Of these, sunitinib and pazopanib have been commonly used for first-line treatment of mRCC.8 However, in December 2017, cabozantinib was approved by the United States Food and Drug Administration (FDA) for first-line use in mRCC based on improved progression-free survival (PFS) compared to sunitinib.9 In non–clear-cell RCC, particularly papillary RCC, sunitinib still represents the preferred front-line therapy based on 2 randomized trials (Aspen and ESPN).10, 11 Finally, in patients with poor-risk RCC or chromophobe RCC, an mTOR-based strategy may have superior efficacy over vascular endothelial growth factor (VEGF) inhibition.12
Within the past 3 years, immunotherapy checkpoint inhibitors (CPIs) have significantly changed the treatment landscape for patients with mRCC. The combination of ipilimumab with nivolumab has further improved clinical outcomes and has been approved for first-line treatment of intermediate to poor risk mRCC patients.13 With a more complex understanding of cross-talk between RCC signaling pathways such as VEGF and the tumor microenvironment and tumor-infiltrating lymphocytes (TILs) in mRCC, there is a rationale for combining VEGF and immunotherapy agents (Figure 2), and early clinical trial data support these strategies (ClinicalTrials.gov NCT02420821). However, combination therapy is accompanied by increased adverse events (AEs), cost, and effects on sequencing second-line treatments. Furthermore, to date, there are no randomized data comparing combination immunotherapies to one another.
Here we discuss recent advances and controversies in first-line treatment of mRCC using anti-VEGF monotherapy, discuss immunotherapies, and address the future of combination approaches with anti-VEGF and immunotherapy.
As our basic understanding of RCC pathophysiology and its dependency on angiogenesis increased, this has translated into the successful development of VEGFR TKI monotherapy targeted agents. The von Hippel-Lindau (VHL) gene encodes an E3 ligase that cooperates in ubiquitination of hypoxia-inducible factor (HIF)-1α, targeting it for proteasome degradation. When VHL is lost or inactivated in up to 80% of sporadic cases of clear-cell carcinoma, HIF-1α overaccumulates, resulting in up-regulation of VEGF and platelet-derived growth factor (PDGF).14 With unopposed stimulation of VEGF and PDGF receptors (VEGFR and PDGFR), tumor angiogenesis, growth, and metastasis ensue.15 Initial proof-of-concept studies for targeting angiogenesis demonstrated that bevacizumab, an anti-VEGF antibody, showed notable efficacy in RCC.16, 17, 18 Since then, multiple VEGFR TKIs have been FDA approved for either first- or second-line treatment of mRCC.
For this review, we summarize the first-line VEGF TKI data of sorafenib, sunitinib, pazopanib, and cabozantinib (Table 1).12, 19, 20, 21, 22, 23, 24
Section snippets
Immuno-oncology Therapies for mRCC
Despite the clinical benefit of first-line antiangiogenesis therapy, tumor resistance often develops within the first year of treatment, underscoring a need for therapies that produce more durable responses with (ideally) less toxicity.25 Historically, RCC has been known to be immunogenic and immunoresponsive, with low levels (5%-8%) of durable complete responses to high-dose interleukin (IL)-2.26, 27 Durable complete responses are rare (1%) with VEGF-targeted strategies alone in mRCC.13, 22
Conclusion
RCC is a common malignancy with increasing prevalence, and a large number of patients present with disease in advanced stages. With a better understanding of the molecular mechanisms underlying RCC, the arsenal of treatment options for mRCC has rapidly evolved, from anti-VEGF therapy with pazopanib and sunitinib, newer VEGF/MET/AXL targeting therapy with cabozantinib, the addition of immunotherapy with first nivolumab and then combination nivolumab plus ipilimumab, and likely in the near future
Disclosure
A.J.A. has received funding (to Duke) from Medivation/Astellas, Bayer, Dendreon, Janssen, Active Biotech, Sanofi-Aventis, Gilead, Novartis, and Pfizer; consulting/speaking with Dendreon and Sanofi Aventis; and consulting with Medivation/Astellas and Janssen. D.J.G. has received research funding (to Duke) from Acerta, Astellas, Bayer, Bristol-Myers Squibb, Dendreon, Exelixis, Innocrin, Janssen, Novartis, Pfizer; consulting and speaking with Bayer, Exelixis, Sanofi; and consulting with Astellas,
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Cited by (30)
Protein kinase inhibitors in the management of clear cell renal cell carcinoma metastatic to the iris
2023, Journal Francais d'OphtalmologieThe association between antibiotic use and survival in renal cell carcinoma patients treated with immunotherapy: a multi-center study
2021, Current Problems in CancerCitation Excerpt :While the patients used ATBs in the month before (-1) or after (+1) the initiation of nivolumab (13 patients, 14% of the cohort) had impaired OS (p = 0.004), the OS difference did not reach statistical significance in patients who used ATBs between 1 and 3 months before or after immunotherapy compared to patients who were not treated with ATBs (P = 0.130) (Fig. 1). RCC is a deadly disease with limited treatment options, but the therapeutic armamentarium has significantly expanded since the entry of immunotherapy into treatment algorithms.19,20 In the first landmark study about immunotherapy in mRCC, nivolumab was compared to everolimus and demonstrated improved OS in second-line treatment (25 vs 19.6 months).
Immunotherapy for metastatic renal cell carcinoma: A brief history, current trends, and future directions
2021, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Over the last 15 years, a total of 9 antiangiogenics have been approved as first- or second-line mRCC treatments. Compared to cytokine immunotherapy, antiangiogenic regimens have superior PFS and ORR but inferior CRR [16]. As targeted antiangiogenics were incorporated into treatment algorithms, mRCC median overall survival increased from ∼12 months to 30 months [24].
Median time to progression with TKI-based therapy after failure of immuno-oncology therapy in metastatic kidney cancer: A systematic review and meta-analysis
2021, European Journal of CancerCitation Excerpt :Despite IO benefits, most IO treated patients will ultimately receive subsequent TKI-based therapy based on guideline recommendations [4]. However, the debate about the optimal TKI agent after the previous IO is still ongoing [5–11]. Unfortunately, non-inferiority comparative phase III trials have not yet examined TKI alternatives after IO-based therapy, and it is unlikely that such studies will ever be completed with sufficient power.
Immune-based combinations for the treatment of metastatic renal cell carcinoma: a meta-analysis of randomised clinical trials
2021, European Journal of Cancer
M.K.L. and K.A.B. contributed equally to this work as first authors.