Both immune modulators and inhibitors of the VEGF pathway provide clinical benefit for patients with metastatic clear cell renal carcinoma (mRCC). Inhibitors of the VEGF pathway include the antibody bevacizumab (approved for the treatment of mRCC in combination with interferon-alfa), and the small molecules sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib (the latter is approved in combination with the mTOR inhibitor everolimus).1 The small molecules are not identical and generally inhibit additional receptor tyrosine kinases, although most of their anti-tumor activity in mRCC is attributed to VEGF receptor inhibition and the consequent anti-angiogenesis effect.

VEGF pathway inhibitors rarely produce complete responses, and resistance almost always develops over time. Options for immune therapy of mRCC were expanded by the approval of nivolumab (anti-PD-1), which improved survival compared with everolimus in patients whose disease progressed after treatment with a VEGF pathway inhibitor.2

More recently, a phase 3 randomized trial in mRCC with no prior systemic therapy demonstrated a survival advantage for the combination of ipilimumab (anti-CTLA-4) and nivolumab over sunitinib.3 In this trial, the primary analysis for survival was conducted in patients with intermediate- and poor- risk disease as assessed by the International Metastatic Renal Cell Carcinoma Database (IMDC) criteria. In the subset of patients with good-risk disease, sunitinib produced a higher rate of objective response and longer progression-free survival compared with ipilimumab/nivolumab, but survival data were not presented separately for this cohort. An important feature of the PD-1 or PD-L1 inhibitors is their ability to produce prolonged responses, which persist in a subset of patients even after treatment is stopped.

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The substantial clinical activity of both VEGF and PD-1 pathway inhibitors in mRCC, and their distinct mechanisms of action, provided a rationale for testing combinations of these agents in the clinic. An early phase 1/2 study combined sunitinib (33 patients) or pazopanib (20 patients) with nivolumab, producing promising objective response rates, at 52% and 45%, respectively.4

The combinations were, however, associated with higher than expected rates of renal and liver toxicity compared with historical data for the single agents, although the toxicities were considered manageable. The high objective response rates observed in this trial supported further studies combining other VEGF and PD-1 pathway inhibitors.

In a small cohort of a phase 1 trial, the combination of bevacizumab (anti-VEGF) with atezolizumab (an anti-PD-L1) was active in mRCC.5 Pre- and post-treatment tumor biopsies demonstrated that a single cycle of bevacizumab alone given prior to the combination increased intra-tumoral T cell numbers, suggesting a potential mechanism by which VEGF inhibition would increase the activity of an anti-PD-L1.

In a subsequent randomized phase 2 study evaluating atezolizumab/bevacizumab, atezolizumab alone, or sunitinib, the combination increased progression-free survival compared with sunitinib in the subset of patients whose tumors were PD-L1-positive.6,7 PD-L1 was assessed in the tumor immune cells using the SP142 assay; exploratory analyses indicated that atezolizumab was most effective in the subset of patients with a baseline intra-tumoral T-lymphocyte effector gene signature. Bevacizumab restored sensitivity to atezolizumab in T-cell-infiltrated tumors that also demonstrated a high myeloid inflammatory gene signature.

At the 2018 Genitourinary Cancers Symposium, Motzer et al presented the results of the IMmotion151 trial, in which patients with untreated mRCC were randomly assigned to receive bevacizumab plus atezolizumab or sunitinib.8 In the PD-L1-positive population, progression-free survival was improved by the combination from 7.7 to 11.2 months, and objective responses rates were also numerically higher compared to sunitinib, at 43% vs 35%. Similar trends were noted in the overall intent-to-treat population.

The improvement in median PFS for atezolizumab/bevacizumab over sunitinib was similar to that observed in the randomized trial of ipilimumab/nivolumab vs sunitinib, although overall survival data have not yet been released for the atezolizumab/bevacizumab combination.