Pembrolizumab for the treatment of renal cell carcinoma

ABSTRACT

Introduction

The acquisition of resistance to VEGF-inhibiting therapies has prompted research toward immunotherapy for the treatment of metastatic renal cell carcinoma (mRCC). Among several, checkpoint inhibitors including PD-1 and PD-L1 inhibitors are the most promising approach.

Areas covered

This review addresses the clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab in first- and second-line treatment for mRCC regarding the most recent and significant published and ongoing studies. Attention is also given to its pharmacological characteristics as well as adverse events and its impact on patients’ quality of life.

Expert opinion

Immunotherapy has become the backbone for the treatment of advanced RCC. With the approval of several therapeutic options, research needs now to focus on defining the appropriate therapy for each patient. Axitinib plus pembrolizumab belongs to the combinations of tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors for the first-line treatment of metastatic RCC. New combinations of pembrolizumab plus TKI for the evaluation in first- and second-line treatment of mRCC available. However, studies directly comparing the various treatment regimens using predictive biomarkers and long-term endpoints, including treatment-free survival, are lacking.

KEYWORDS:

• Axitinib
• genitourinary tumors
• immune checkpoint inhibitor
• pd-1
• pd-l1
• pembrolizumab
• renal cell carcinoma

Article highlights

• Renal cancer is characterized by resistance to hormonal therapy and chemotherapy. Evidence of resistance acquisition to VEGF-inhibiting therapies has prompted research towards immunotherapy.

• In the phase III open-label KEYNOTE-426 trial, the combination of axitinib plus pembrolizumab resulted in a significantly longer OS (HR for death 0.53, 95% CI 0.38-0.74; p<0.0001) and PFS (HR for disease progression or death 0.69, 95% CI 0.57-0.84; p<0.001) and a significantly higher ORR (59.3% vs. 35.7%; p<0.001) than the standard treatment sunitinib.

• In the CLEAR trial, lenvatinib and pembrolizumab met the primary endpoint of PFS and the key secondary endpoints of OS and ORR proving to be statistically more effective than sunitinib.

• Pembrolizumab monotherapy demonstrated promising efficacy in the KEYNOTE-427 trial with an ORR of 33.6% (n=36; 95% CI 24.8-43.4) and an ORR of 26.7% (95% CI 20.1-34.1) respectively in clear cell and non-clear cell RCC patients.

• Developments of other immunotherapies and therapeutic strategies will be necessary to overcome obstacles such as tumor immune resistance, immune escape, and immune-related AEs.

Declaration of interest

J Bedke reports Consultancies and Speaker´s Bureau: BMS; Eisai, EUSA, Ipsen, Novartis, MSD, Merck Serono, Pfizer, Roche and study participation with institutional funding: Bayer, BMS; Eisai, Exelixis, Ipsen, Novartis, MSD, Pfizer, Roche. A Stenzl reports Consultancies and Speaker´s Bureau: Ipsen, Roche, Janssen, BMS, Alere, Stebabiotech, Synergo, Ferring, Astellas, Amgen, Sanofi Aventis, CureVac and study participation or research grants with institutional funding: Johnson & Johnson, Roche, Cepheid, Amgen, Bayer, CureVac, GemeDx biotechnologies GmbH, Novartis, Karl Storz, immatics biotechnologies GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.