ESMO 2018: Molecular Correlates Differentiate Response to Atezolizumab plus Bevacizumab vs Sunitinib: Results From a Phase III Study IMmotion151 in Untreated mRCC

Munich, Germany ( In this abstract, the authors of ImMotion151, which assesses the immune checkpoint combination of atezolizumab and prior immunotherapy bevacizumab against the traditional standard of sunitinib for patients with untreated metastatic renal cell carcinoma (mRCC), focus on the molecular correlates utilized and their preliminary results. InMotion151 is a phase III study and has previously reported at ASCO – it was first randomized Phase III trial of a PD-L1/PD-1 pathway inhibitor combined with an anti-VEGF agent in 1L mRCC. In the primary results, the median PFS HR for atezo + bev (AB) vs sunitinib (SUN) was 0.74 (95% CI 0.57, 0.96) in PD-L1+ pts and 0.83 (95% CI 0.70, 0.97) in ITT pts.

However, this particular abstract focused more on the correlative studies incorporated into the study protocol. Specifically, prior biomarker analyses in IMmotion150, the phase II study, suggested that T effector/IFNγ (Teff) and Angiogenesis (Angio) gene expression signatures (GEs) were associated with differential outcomes based on treatment arm. Since similar correlative tests were conducted in the phase III study, the authors conducted analyses validate these GEs with clinical outcomes in IMmotion151 and evaluated their association with MSKCC risk groups and sarcomatoid histology.

With regards to methods, tumor GE analysis was performed by RNASeq in 823 pts from IMmotion151. Associations of T-eff and Angio signatures GEs with clinical outcome were evaluated at pre-specified expression level cutoffs identified in IMmotion150. PD-L1 status on immune cells was assessed with the SP142 IHC assay.

Across treatment arms (AB vs. SUN) and within the SUN arm –

  • SUN should be given in patients with Ang-high tumors but not Ang-low (PFS HR 0.59)
  • AB > SUN in Ang-low patients (PFS HR 0.68)
  • AB > SUN in T-eff high (PD-L1+) patients (PFS HR 0.86) – but not in T-eff low patients
Across different biologic subgroups:

  • Favorable risk patients: show more frequently Ang-high signature than intermediate/poor risk (74% vs 26%)
  • Intermediate/poor risk: show more frequently T-eff high signature and PD-L1+ than favorable risk (64% vs. 36%)
  • Sarcomatoid RCCs: show more frequently Ang-high signature and more frequently T-eff high/PD-L1+ than non-sarcomatoid tumors
Based on this, there are specific patients that may benefit from either sunitinib or ICIs. However, at this time, the data is prognostic and the data needs to be validated prospectively.

Sunitinib – patients with favorable risk disease (as 74% Ang-high and only 36% are T-eff high) and non-sarcomatoid histology.

In contrast, patients who should receive ICI are:

  • Intermediate/poor risk patients because they are
    • More likely to be Ang-low than favorable risk
    • Higher chance to be T-eff high or PD-L1+
  • Patients with sarcomatoid features
    • High chance to be Ang-low (66%)
    • Higher chance of being T-eff high / PD-L1 positive

Presented by: Brian I. Rini, MD Hematology and Medical Oncology,  Cleveland Clinic Main Campus, Cleveland, Ohio, USA

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, twitter: @tchandra_uromd, @TjuUrology at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany