Given the variability in disease aggressiveness and the lack of highly predictive biomarkers in renal cell carcinoma (RCC), nothing resembling a “one size fits all” treatment approach has emerged for this disease.

Instead, research has sought to uncover optimal strategies for the various subsets of RCC, with careful consideration of each patient’s unique profile.

Front-line Immunotherapy Regimens in Sarcomatoid RCC
Several recent regulatory approvals have transformed the treatment of first-line metastatic RCC. Data had been lacking, however, on first-line therapy in sarcomatoid variants of RCC, a relatively rare, often more aggressive, and clinically challenging subset of this disease.

Three high-profile front-line metastatic trials of patients with sarcomatoid histology were presented at this year’s American Society of Clinical Oncology (ASCO) meeting, each of which showed significantly prolonged progression-free survival when compared with sunitinib. The trials compared sunitinib with three separate immunotherapy-containing regimens: axitinib plus pembrolizumab, atezolizumab plus bevacizumab, and ipilimumab plus nivolumab.

These results suggest that checkpoint inhibitor–containing regimens, either together or in combination with a tyrosine kinase inhibitor (TKI), are the preferred first-line option for patients with sarcomatoid variants of RCC.

Another Strike Against TKIs in the Adjuvant Setting
A number of recent studies have examined vascular endothelial growth factor TKIs in the adjuvant or “no evidence of disease” setting, including the ASSURE, S-TRAC, and PROTECT trials. The lone positive study among these was S-TRAC, which showed that a year of adjuvant sunitinib prolonged disease-free survival by approximately 1 year, although it did not affect overall survival. This trial led the US Food and Drug Administration to approve sunitinib for completely resected RCC at high risk for recurrence.

At this year’s ASCO meeting, investigators presented the results of a randomized trial comparing 1 year of treatment with the TKI pazopanib or placebo in patients with no evidence of disease after metastasectomy for metastatic RCC.[7] Unfortunately, this trial joins others in supporting the notion that such TKIs lack compelling activity in this setting. Patients receiving pazopanib not only failed to experience significantly prolonged progression-free survival, but they also appeared to have worsened overall survival.

Given the significant side-effect and toxicity profiles of these agents, as well as the fairly consistent picture of minimal to zero clinical benefit, this is further evidence against their routine use to prevent relapse after complete surgical resection.

Nonetheless, we eagerly await the results of the many adjuvant checkpoint inhibitor trials that are currently underway (eg, KEYNOTE-564, CHECKMATE-914, PROSPER, IMmotion-010) to see if they show more efficacy in this setting.

Active Surveillance for Select Patients?
In another important study, researchers assessed the safety and outcomes of active surveillance in a large observational Canadian cohort of more than 1800 patients with metastatic RCC. Nearly half (47%) of patients were treated with an initial strategy of surveillance rather than systemic treatment.

While survival outcomes for this group appeared very favorable (70% of patients on active surveillance were alive at 5 years), patients in this cohort probably had more favorable tumor biology as well as lower volume of disease and symptom burden.

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Prior to the approval of nivolumab, a monoclonal antibody targeting programmed death-1 (PD-1), vascular endothelial growth factor-receptor tyrosine kinase inhibitors (VEGFR-TKIs), specifically pazopanib and sunitinib, were the standard of care in the front-line setting for metastatic clear cell renal cell carcinoma (mccRCC). CheckMate 025, a randomized, open label, phase 3 study comparing nivolumab to everolimus in previously treated mccRCC, reported an objective response (ORR) rate of 25% with nivolumab as compared to 5% in the everolimus arm.1 These results led to the US Food and Drug Administration (FDA) approval of nivolumab for patients with previously treated mccRCC, ushering in a new era in the treatment of mccRCC with immune checkpoint inhibition (ICI).

More recently, ICI has been introduced in the front line, with the recent FDA approvals of the VEGF-ICI combination axitinib + pembrolizumab as well as avelumab + axitinib, and ICI-ICI combination nivolumab + ipilimumab.2,3,4 With these new approvals, TKIs previously developed and approved in the first and second-line space, will now shift and be used in the second line and beyond following progression on ICI therapy. There has been a paucity of prospective data reporting the efficacy of TKI after progression on front-line ICI-based therapy; therefore, we report retrospective data assessing outcomes of patients treated with TKIs after first-line ICI, to provide insight in this setting given the shifting standard of care.

This analysis included 70 patients, all with mccRCC. The most common sites of metastatic disease were lung in 61 patients (87%), lymph nodes in 48 patients (69%) and bone in 35 patients (50%). All patients had previously received first line ICI-based therapy in the context of clinical trial, where 12 patients (17%) received single-agent ICI (either nivolumab or atezolizumab), 33 (47%) received combination ICI (ipilimumab + nivolumab) followed by single agent nivolumab maintenance therapy, and 25 (36%) received combination ICI + VEGFR therapy (nivolumab + bevacizumab or atezolizumab + bevacizumab). Second-line TKIs utilized included pazopanib in 19 patients (27%), sunitinib in 6 patients (9%), axitinib in 25 patients (26%) and cabozantinib in 20 patients (28%).

Median progression-free survival (mPFS) on the second-line TKI was 13.2 months (95% CI 10.1-NA) and median overall survival (OS) was not reached. Patient previously treated with first-line ICI monotherapy (n=12) had a mPFS of 7.5 months on second-line TKI, those previously treated with first-line nivolumab + ipilimumab (n=33) had a mPFS of 11.9 months on second-line TKI, and those treated with ICI + bevacizumab (n=25) had a mPFS of 20.8 months on second-line TKI. Objective response rate (ORR) was 41% where 1 patient (1.5%) achieved a complete response (CR) and 27 patients (39.7%) had a partial response. Thirty-six patients (52.9%) had stable disease, with a disease control rate of 94%.

A limitation in interpreting these numbers is the small sample size and the retrospective nature of this work. However, with that caveat in mind, it is intriguing, and replicated in other studies, that the mPFS and ORR of second-line TKI hereafter first-line ICI parallels historic outcomes with front line TKI.6,7 These data can help in counseling our patients as they come off of front-line ICI therapy and can also help inform new trial design in 2L and 3L therapy in mccRCC.

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