SAN FRANCISCO-In a phase III clinical trial of people with previously untreated metastatic renal cell cancer (mRCC), combining immunotherapy atezolizumab with targeted therapy bevacizumab delayed cancer growth by about 3 months longer than sunitinib, another targeted therapy. The benefit of atezolizumab plus bevacizumab was greater for patients with PD-L1-positive tumors. These findings were presented at the 2018 Genitourinary Cancers Symposium (Abstract 578).
"The side effects of atezolizumab plus bevacizumab were decidedly less harsh than sunitinib. And because progression-free survival was also better, I am confident that this relatively easy-to-administer combination will be a strong treatment choice in all medical practices," said lead study author Robert J. Motzer, MD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, New York, N.Y.
About the Study
IMmotion151 is the first randomized, phase III combined immunotherapy with bevacizumab trial in people with untreated mRCC. Starting in 2015, sites worldwide enrolled 915 adults who were randomly assigned to receive either atezolizumab plus bevacizumab intravenously every 3 weeks or take a sunitinib pill daily for 4 weeks followed by 2 weeks off treatment.
Atezolizumab is an immune checkpoint inhibitor that blocks the PD-L1 protein on the surface of tumor cells, allowing the immune system to recognize and attack those cells. Bevacizumab and sunitinib are targeted medicines that block the growth of blood vessels to the tumor, thereby limiting its growth.
"With the introduction of checkpoint inhibitors, clinicians started looking at combinations of these medicines with anti-angiogenic medicines like bevacizumab," said Motzer. "Bevacizumab may affect the local immune response in the tumor and help prime the response of tumor and immune cells to immune-system activators like atezolizumab."
Key Findings
For the analysis, the researchers grouped patients according to PD-L1 expression on immune cells in the tumor. Tumors that had the PD-L1 protein detected on the surface of at least 1 percent of those immune cells were considered PD-L1-positive, and all other tumors were considered PD-L1-negative.
The study had co-primary endpoints:
* Investigator-assessed progression-free survival in the PD-L1-positive group
* Overall survival in the group of all enrollees, also called the intention-to-treat (ITT) population
At a median follow-up of 15 months, patients in the PD-L1-positive group treated with atezolizumab and bevacizumab had a 26 percent lower chance of the cancer worsening than those who received sunitinib. The median time until the cancer worsened was also 3.5 months longer (median 11.2 months in the atezolizumab plus bevacizumab group vs. 7.7 months in the sunitinib group).
In the ITT group, a benefit of atezolizumab plus bevacizumab was also observed, though more modest. Those treated with atezolizumab and bevacizumab had a 17 percent lower chance of cancer worsening, with a median time of 2.4 months longer until the cancer worsened. The difference in overall survival between the two treatment regimens was not statistically significant at this early interim analysis. Overall survival data are still immature, and the authors are planning an updated analysis as more data accrues.
Treatment-related side effects were less frequent in the atezolizumab and bevacizumab group, occurring in 40 percent of people, compared to 54 percent of people in the sunitinib group. Twelve percent of patients in the atezolizumab and bevacizumab group, and 8 percent in the sunitinib group, stopped at least one treatment component due to treatment-related side effects during the trial.
"For an aggressive cancer like this, where less than 20 percent of people survive 5 years after diagnosis, we think a 3.5 month longer progression-free survival, given the tolerability for this new combination treatment regimen, is an important development," Motzer noted.
Next Steps
The study will continue to assess overall survival as specified by protocol as well as secondary endpoints. In addition, the researchers collected tumor tissue and will look at molecular profiles to try to tease out markers, in addition to PD-L1, in the people who responded best to the combination therapy. Motzer said the researchers may look at novel therapies that could be added to atezolizumab so they could devise treatments to boost survival odds even higher.
"Adding immunotherapy to existing targeted therapies has shown promising results in recent clinical trials," noted ASCO Expert Sumanta K. Pal, MD, Assistant Clinical Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, Duarte, Calif. "We're pleased to see validation of this approach through this large trial in advanced kidney cancer, a disease that remains incurable for most patients."