Can immune biomarkers predict benefit from targeted agents in metastatic renal cell carcinoma?

We read with great interest the article by Flaifel and colleagues (1), who interrogated the predictive and prognostic value of (I) PD-L1 expression [on tumor and immune cells (IC)], (II) the extent of immune cell infiltrates and (III) the cMET expression in patients receiving targeted agents (TA). The authors analyzed pre-treatment tumor tissue obtained from patients from 2 randomized trials, the METEOR trial (2) (cabozantinib versus everolimus in 2 nd -line) and the CABOSUN trial (3) (cabozantinib versus sunitinib in 1 st -line). The main findings were first, that PD-L1 expression on tumor cells (TC) is associated with poor clinical outcome in all patients and independently of the TA received and second, that cabozantinib is superior to everolimus and sunitinib in terms of PFS and OS, irrespective of PD-L1 expression.

[1]  N. Agarwal,et al.  Investigational MET inhibitors to treat Renal cell carcinoma , 2019, Expert opinion on investigational drugs.

[2]  G. Freeman,et al.  PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN , 2019, Clinical Cancer Research.

[3]  R. Motzer,et al.  Avelumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[4]  T. Powles,et al.  Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[5]  R. Motzer,et al.  Systemic Treatment of Metastatic Clear Cell Renal Cell Carcinoma in 2018: Current Paradigms, Use of Immunotherapy, and Future Directions. , 2019, European urology.

[6]  Bohuslav Melichar,et al.  Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal‐Cell Carcinoma , 2018, The New England journal of medicine.

[7]  L. Butini,et al.  Immunomodulatory Effects of Tyrosine Kinase Inhibitor In Vitro and In Vivo Study. , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[8]  J. Landsberg,et al.  Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c‐MET Limit Cancer Immunotherapy , 2017, Immunity.

[9]  T. Choueiri,et al.  Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  T. Powles,et al.  Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. , 2016, The Lancet. Oncology.

[11]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[12]  Lieping Chen,et al.  Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens , 2015, Oncotarget.

[13]  P. Tamboli,et al.  Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma , 2015, Cancer Immunology Research.

[14]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[15]  S. Ramakrishnan,et al.  Combination Strategy Targeting VEGF and HGF/c-met in Human Renal Cell Carcinoma Models , 2014, Molecular Cancer Therapeutics.

[16]  G. Santoni,et al.  Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR‐TKIs and mTOR inhibitor , 2014, International journal of cancer.

[17]  R. Motzer,et al.  Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  U. Maestroni,et al.  Immune context characterization and heterogeneity in primary tumors and pulmonary metastases from renal cell carcinoma. , 2019, Immunotherapy.