Immune checkpoint inhibitors: Future of RCC management?
Programmed-death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown promising results in recent clinical trials in metastatic renal cell carcinoma (mRCC), according to data presented at the Hong Kong Society of Uro-Oncology Annual Scientific Meeting.
The phase II, IMmotion150 trial involved randomization of 305 treatment-naïve mRCC patients to receive the PD-L1 inhibitor atezolizumab alone or in combination with the VEGF inhibitor bevacizumab, or the tyrosine kinase inhibitor (TKI) sunitinib. [J Clin Oncol 2017;5(suppl 15): abstract 4505]
Among patients who were PD-L1–positive (54 percent), treatment with atezolizumab and bevacizumab resulted in better progression-free survival (PFS) vs sunitinib (median PFS, 14.7 months vs 7.8 months; hazard ratio [HR], 0.64).
The phase III follow-up to this study, IMmotion151, where 915 patients were enrolled, also showed a significant PFS advantage with atezolizumab plus bevacizumab compared with sunitinib (median PFS, 11.2 months vs 7.7 months; HR, 0.74; p=0.02). [ASCO GU 2018, abstract 578]
“The use of bevacizumab will cause increase of CD8 expression in T lymphocytes. Combining this with atezolizumab will further increase T lymphocyte trafficking,” explained Professor Bernard Escudier of the Institut Gustave Roussy, Villejuif, France.
In the phase III CheckMate-214 trial, 1,096 treatment-naïve mRCC patients were randomized to receive the PD-1 inhibitor nivolumab plus the cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) inhibitor ipilimumab, or sunitinib. Results showed a higher overall response rate (ORR) among patients who received nivolumab plus ipilimumab vs sunitinib (mean, 42 percent vs 27 percent; p<0.0001). [Ann Oncol 2017;28(suppl 5): abstract LBA-5]
“CTLA-4 inhibitors help in priming and activation of T lymphocytes,” said Escudier. “Patients with intermediate or poor risk who were treated with nivolumab plus ipilimumab fared better in terms of PFS and overall survival [OS] vs those who received sunitinib [median PFS, 11.6 months vs 8.4 months; HR, 0.82; p=0.03331] [median OS, not reached vs 26 months; HR, 0.63; p<0.001].”
A recent in vivo study in germ-free or antibiotic-treated mice showed that foecal microbiota transplantation (FMT) from patients who responded to checkpoint inhibitor therapy ameliorated the effects of PD-1 inhibitors, whereas FMT from nonresponding patients failed to do so. [Science 2018;359:91-97]
“Currently ongoing phase III trials are exploring outcomes with combination therapy using avelumab and axitinib, lenvatinib and pembrolizumab, lenvatinib and everolimus, or axitinib and pembrolizumab as compared with sunitinib” Escudier pointed out. [https://clinicaltrials.gov/ct2/show/NCT02684006, https://clinicaltrials.gov/ct2/show/NCT02811861, https://clinicaltrials.gov/ct2/show/NCT02853331]
“The use of PD-1/PD-L1 inhibitor therapy has demonstrated activity in mRCC, with nivolumab approved as a second-line therapy. Combinations with other compounds, such as CTLA-4 and VEGF inhibitors, are also promising and may change the landscape of mRCC management. Current challenges, however, concern the appropriate use of biomarkers and determination of the optimal duration of therapy using these agents,” he concluded.