Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

Abstract

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

Current status of prognostic factors in patients with metastatic renal cell carcinoma

“…Their data suggest that PBRM1 loss in ccRCC might be associated with responsiveness to immune checkpoint therapy through alteration of the gene expression profile. In contrast, data from IMotion150 showed that PBRM1 mutations were also associated with the improvement of the outcome of sunitinib, which was consistent with the results from another previous study of first‐line agents for mRCC …”

“…In addition to tumor cells, the impact of PD‐L1 expression on tumor‐infiltrating immune cells was reported. It was positively related with high T‐effector gene signature expression, which was associated with improved PFS with atezolizumab + bevacizumab in IMmotion 150, a randomized phase II study of atezolizumab alone or combined with bevacizumab versus sunitinib in patients with mRCC as a first‐line option …”

Vascular endothelial growth factor and programmed death‐1 pathway inhibitors in renal cell carcinoma

“…Despite having low PD‐L1 expression, some patients have a durable response to immunotherapy . In the IMmotion150 study, there was a trend toward improved PFS with atezolizumab plus bevacizumab versus sunitinib in patients with PD‐L1–positive tumors (HR, 0.64; 95% CI, 0.38‐1.08; P = .095) . IMmotion150 explored other potential biomarkers in mRCC.…”

“…The median PFS was 11.7 months with atezolizumab plus bevacizumab, 8.4 months with sunitinib, and 6.1 months with atezolizumab. The ORR was 32%, with a 7% CR rate for atezolizumab plus bevacizumab; 29%, with a 5% CR rate for sunitinib; and 25%, with an 11% CR rate for atezolizumab . These studies show a significant response from ICI alone, and whether (or to what degree) there is an augmentation of immune response from VEGF blockade is not yet understood.…”

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

“…Biomarker studies are helpful for us to understand the biological activity of the regimen, and to select the populations who may have benefits from our treatment. For example, angiogenesis signature can predict the clinical response to atezolizumab‐bevacizumab combination therapy in renal cell carcinoma . In melanoma, MHC protein expression can predict differential activity to anti‐CTLA4 or anti‐PD1 .…”