The treatment of metastatic renal cell carcinoma (mRCC) is now undergoing a paradigm shift, from the monotherapy of vascular endothelial growth factor (VEGF)-targeted agents to combination strategies with immune checkpoint inhibitors. Recently released findings from the IMmotion151 trial demonstrated that the atezolizumab/bevacizumab combo reduced the risk of progression or death by 26% compared with sunitinib for patients with untreated programmed death-ligand 1 (PDL1)–positive mRCC.1 The results were presented by Dr. Robert J. Motzer from the Memorial Sloan Kettering Cancer Center, US, at the 2018 Genitourinary Cancers Symposium.1
The treatment of mRCC is likely to differ greatly in the next decade because of recent changes in the landscape. Notable was the emergence of a frontline immunotherapy combination — nivolumab plus ipilimumab, which outperformed the standard of care sunitinib in the CheckMate-214 trial, as presented in European Society for Medical Oncology (ESMO) 2017.2 The combo showed a survival advantage over sunitinib, with a 37% reduction in the risk of death in intermediate- and poor-risk patients.2 Keeping this momentum of immunotherapy going was the appearance of another novel combo: atezolizumab (a PDL1-inhibitor) plus bevacizumab (VEGF-inhibitor), which are being investigated in the ongoing IMmotion151 trial.
In this phase III trial, 915 treatment-naïve patients, regardless of the prognostic risk group, were randomized 1:1 to receive either the combo (atezolizumab 1,200mg plus bevacizumab 15mg/kg intravenously every 3 weeks) or sunitinib alone (50mg/day orally for 4 weeks, followed by 2 weeks off treatment).1 Patients were stratified by PD-L1 status (<1% vs. ≥1% PD-L1 expression on tumor-infiltrating immune cells), with a total of 362 patients being PD-L1 positive. The co-primary endpoints were investigator-assessed progression-free survival (PFS) in PD-L1 positive patients, and overall survival (OS) in intent-to-treat (ITT) population.1
After a median follow-up of 15 months, significant improvement of median PFS was observed in the combination arm (11.2 months with atezolizumab/bevacizumab vs. 7.7 months with sunitinib; HR=0.74; 95% CI: 0.57-0.96; p=0.0217).1
“For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5 month longer PFS… is an important development,” said Dr. Motzer.
Initial observations of OS in the ITT population were encouraging, but the data is still immature.1 In addition to improvements in efficacy, Dr. Motzer thinks that the tolerability profile of atezolizumab/bevacizumab is another major attribute that set the combo apart from conventional care. Overall, treatment-related grade 3/4 adverse events occurred in 40% of patients in the combination arm vs. 54% of those treated with sunitinib.1
The safety profile of the individual medicines was consistent to what has been previously reported in the phase II IMmotion150 study, and no new safety signals were identified with the combination.1 “The side effects of atezolizumab plus bevacizumab were decidedly less harsh than sunitinib. And because PFS was also better, I am confident that this relatively easy-to-administer combination will be a strong treatment choice in all medical practices,” said Dr. Motzer.3
Dr. Sumanta Pal, co-director of the Kidney Cancer Program at City of Hope, US, agreed that the data support the consideration of bevacizumab and atezolizumab as a first-line option. “This study represents an important breakthrough in kidney cancer therapy. For several years now, we have hosted debates on which treatment strategy is best for our patients —targeted therapy or immune therapy. This treatment, which is really a first of its kind, points to a combination of both as being highly effective at delaying cancer growth and there’s an early trend toward improving survival as well,” he said.3
Simply put, the addition of immunotherapy agents has brought the treatment landscape of mRCC to a new level. The future holds promise to expand these immuno-oncology treatments in providing better care for patients.
1. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Genitourinary Cancers Symposium; San Francisco, US. February 10, 2018. Abstract #578.
2. Escudier B. Tannir N, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO 2017 Congress; Madrid, Spain. September 10, 2017. Abstract #LBA5.
3. PFS Improvement with atezolizumab combination in metastatic renal cell carcinoma. Targeted Oncology 2018. (Accessed February 25, 2018, at http://www.targetedonc.com/news/pfs-improvement-with-atezolizumab-combination-in-metastatic-renal-cell-carcinoma).