First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape

Abstract

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.

FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy

“… 1–8 Immune checkpoint inhibitors (ICIs) in particular have revolutionized the treatment paradigm for aRCC, reflecting a fundamental shift in the approach to treating aRCC by leveraging the immune system to attack cancer cells, rather than targeting pathways underlying tumor pathogenesis, as with TKIs or mTOR inhibitors. 1 2 9 10 …”

“… 11 US Food and Drug Administration (FDA) approval was granted on the basis of results from the CheckMate 025 phase 3 clinical trial in 2015, which compared nivolumab and everolimus in the second-line and third-line settings, in which nivolumab demonstrated superiority. 1 11 12 …”

“…3 11 15 IO options currently constitute the backbone of both first-line and second-line treatments. 1 3 13 …”

“…Despite the promising efficacy of these combination treatments, disease progression is inevitable for many patients, and no standard of care exists for those who did not respond to an ICI combination in the first-line setting. 1 9 15 16 In clinical practice, the potential benefits of ICIs or ICI combinations when given beyond the first-line and second-line setting have not been fully elucidated. 9 13 When patients develop resistance or toxicity to immune checkpoint blockade in the first-line treatment of aRCC, a new challenge has emerged regarding how to optimally treat patients in the second-line and beyond in patients who have received prior IO therapy.…”

Discovery of a novel monoclonal PD-L1 antibody H1A that promotes T-cell mediated tumor killing activity in renal cell carcinoma

“…Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of patients with advanced RCC. PD-1/PD-L1 checkpoint blockade has become front-line therapy with four different treatments approved by the FDA since 2018 [1]. The high rates of disease recurrence post-surgery in patients with RCC has led to the testing of immune checkpoint inhibitors in the adjuvant setting.…”