Gene expression profiles are associated with differential outcomes to atezolizumab plus bevacizumab or sunitinib as first-line treatment for metastatic renal cell carcinoma

Previously reported data from the phase III IMmotion 151 study demonstrated a superior progression-free survival (PFS) with the combination of atezolizumab and bevacizumab as compared to sunitinib in the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). Biomarker analyses of the phase II IMmotion 150 study, which formed the basis for IMmotion 151, suggested that T-effector and angiogenesis gene expression signatures (GEs) were associated with differential outcomes with atezolizumab + bevacizumab and sunitinib. During ESMO 2018, Rini et al. validated these GEs with clinical outcomes in IMmotion151 and evaluated their association with MSKCC risk groups and sarcomatoid histology.

In IMmotion 150, sunitinib showed an improved PFS in angiogenesis^high patients compared to patients with an angiogenesis^low genomic profile. In addition, atezolizumab plus bevacizumab improved the PFS vs. sunitinib in patients with T-effector^high and angiogenesis^low tumours. Finally, atezolizumab + bevacizumab improved the PFS compared to atezolizumab in T-effector^high myeloid^high tumours. To validate these profiles, a tumour GE analysis was performed on samples from 823 patients enrolled in IMmotion151. Associations of T-effector and angiogenesis GEs with clinical outcome were evaluated at pre-specified expression level cut-offs identified in IMmotion150.

As reported earlier, IMmotion151 met its co-primary endpoint, demonstrating an improved PFS with atezolizumab + bevacizumab vs. sunitinib in PD-L1 positive patients (HR[95%CI]: 0.74[0.57-0.96]; p=0.02) across MSKCC groups. The PFS was also improved in patients having tumours with a sarcomatoid histology (HR[95%CI]: 0.56[0.38-0.83]). In this new analysis, atezolizumab plus bevacizumab improved the PFS as compared to sunitinib in the angiogenesis^low subset with a HR of 0.68 (95%CI: 0.52-0.88; median PFS 5.95 vs. 8.94), while the median PFS did not differ significantly between the two treatments in angiogenesis^high patients (10.12 vs. 12.45 months; HR[95%CI]: 0.95[0.76-1.19]). The latter is mainly attributable to the significantly longer median PFS with sunitinib in angiogenesis^high patients compared to angiogenesis^low patients (median PFS 10.12 vs. 5.95 months; HR[95%CI]: 0.59[0.47-0.75]). Looking at the immune GE profile it became clear that atezolizumab plus bevacizumab demonstrated a significantly improved PFS vs. sunitinib in the T-effector^high cohort (median PFS 12.45 vs. 8.34; HR[95%CI]: 0.76[0.59-0.99]), while the PFS did not differ significantly in T-effector^low patients (median PFS 9.72 vs. 8.41 months; HR[95%CI]: 0.91[0.73-1.14]). The angiogenesis signature was more prevalent in the favourable MSKCC subgroup than in patients with an intermediate/poor MSKCC risk score (74% vs. 57%, p=8.26 x10^-5).

In sarcomatoid tumours, the angiogenesis GE signature was found to be lower than in non-sarcomatoid tumours (34% vs. 65%, p=1.12 x10^-11), while the PD-L1 expression tended to be higher in patients with a sarcomatoid tumour histology (63% vs. 39%; p=5.25 x10^-7)

In summary, the angiogenesis and T-effector signatures identified in IMmotion 150 were validated in IMmotion 151. Atezolizumab + bevacizumab improved the PFS in comparison to sunitinib in T-effector^high and angiogenesis^low tumours, while the sunitinib arm patients with an angiogenesis^high gene signature had a longer PFS than patients with an angiogenesis^low signature. In addition, this analysis revealed that MSKCC favourable-risk patients are characterised by a predominant angiogenesis^high signature. Sarcomatoid RCC on the other hand was characterised by an angiogenesis^low signature, a T-effector^high gene signature and a higher expression of PD-L1. The findings of this study improve the understanding of the RCC biology and could potentially be used to enable personalized care for patients with mRCC.

Reference

Rini B, Huseni M, Atkins M, et al. Molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): results from a Phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC). Presented at ESMO 2018; Abstract LBA31.