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IMmotion151: Investigator sheds light on potentially practice-changing data
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In February 2018, Robert J. Motzer, MD, presented results from the phase 3 IMmotion151 trial at the Genitourinary Cancers Symposium. The highly anticipated findings showed significant promise for the combination of atezolizumab plus bevacizumab in patients with untreated metastatic renal cell carcinoma when compared with the standard treatment of sunitinib. In an interview with Healio, Motzer, who was one of the lead investigators of IMmotion151 and is an attending physician at Memorial Sloan Kettering Cancer Center in New York, spoke in detail about the trial, discussing the catalyst, key findings and what the results may mean for the future of the specialty.
Before becoming involved in the IMmotion151 trial, you were part of the investigative team behind the phase 2 IMmotion150 trial, which served as an important precursor to the phase 3 trial. Can you provide a brief overview of the methodology and outcomes of IMmotion150?
In IMmotion150, we randomly assigned previously untreated renal cell carcinoma patients into one of three treatment arms: sunitinib (Sutent, Pfizer), atezolizumab (Tecentriq, Genentech) plus bevacizumab (Avastin, Genetech), or atezolizumab alone. At the time of progression, patients on sunitinib or atezolizumab could crossover to the combination if they were in the United States; patients in Europe were unable to crossover.
For all comers, the findings failed to indicate significant benefit for atezolizumab plus bevacizumab or atezolizumab alone compared with sunitinib. However, among the PD-L1–positive population, both objective response rate and progression-free survival improved, particularly for the atezolizumab plus bevacizumab combination arm compared with the sunitinib arm.
How did you become involved in the IMmotion151 trial?
In addition to being a clinical investigator for IMmotion150, I was a member of the steering committee that designed the phase 3 trial and counseled its running. As an investigator in the phase 2 trial, I enrolled the most patients and was very much impressed by the atezolizumab plus bevacizumab combination. As a result, I supported the idea of the phase 3 trial, and then I helped write and design the protocol with Genentech/Roche.
What was the impetus behind conducting IMmotion151?
There is a rationale that bevacizumab may enrich the immune response and activity of atezolizumab. Bevacizumab has single-agent activity in renal cancer and is approved in combination with interferon. The IMmotion150 trial revealed the efficacy of atezolizumab plus bevacizumab and confirmed its safety. In addition, the combination is easy to administer; the drugs are given every 3 weeks intravenously and are well tolerated.
At the 2018 Genitourinary Cancers Symposium, you presented results of progression-free survival in patients expressing PD-L1, one of the two primary endpoints of IMmotion151. What did you and your colleagues observe?
The results demonstrated a PFS benefit in patients who were treated with atezolizumab plus bevacizumab compared with sunitinib in the population expressing PD-L1 (HR = 0.74; 95% CI, 0.57-0.96). Furthermore, the response rate was higher with the combination therapy (43% vs. 35%).
After the presentation, one area that prompted discussion was the independent review committee’s assessment of PFS and response rates. The committee found that response rates were higher and PFS longer in the PD-L1–positive patients treated with atezolizumab plus bevacizumab, but it was not as strong a signal as the investigator-assessed outcome data. Otherwise, the safety profile was favorable for atezolizumab plus bevacizumab. In fact, an analysis of the IMmotion151 trial showed improved quality of life for atezolizumab plus bevacizumab compared with sunitinib.
At the time of presentation, overall survival, the other primary endpoint, was considered encouraging but still immature, according to a manufacturer-issued press release. Can you share any additional details on this endpoint?
Because it takes longer to achieve the number of events necessary with overall survival than PFS, information on the former is indeed immature. Specifically, we had only about 30% of the survival events necessary for a formal analysis. However, from what we have seen, the curves are tracking favorably. I am hopeful that when the final analysis is complete, the regimen will demonstrate a survival benefit for atezolizumab plus bevacizumab compared with sunitinib.
What adverse events have been reported thus far?
Atezolizumab plus bevacizumab demonstrated fewer grade 3/4 events compared with sunitinib, as well as a lower incidence of many of the adverse events that impact quality of life, such as fatigue, rash and skin sores. Hypertension was about the same because both bevacizumab and sunitinib cause hypertension. Additionally, proteinuria was more common with atezolizumab plus bevacizumab compared with sunitinib, although it is usually not associated with symptoms, but rather it is a test we monitor.
Taken together, what do you believe these results mean for clinical practice?
Based on the data we have so far, the atezolizumab plus bevacizumab combination should receive FDA approval as an option for treating patients with kidney cancer, particularly those who are PD-L1–positive. The combination is quite effective and easy to administer as infusion every 3 weeks, and it has a favorable safety profile.
The management of patients with metastatic renal cell carcinoma has made significant strides in the past 12 months. How do you anticipate the field evolving in the coming years?
There has been a lot of progress in the treatment of advanced kidney cancer. In the last 10 years, 10 drugs have been developed and approved. This period began as the era of the VEGF tyrosine kinase inhibitors with sunitinib, sorafenib (Nexavar, Bayer) and most recently with lenvatinib (Lenvima, Eisai), and has grown to incorporate immunotherapies as well. For perspective, I have been in the field for almost 30 years, and when I started, we had nothing to offer patients with kidney cancer.
Going forward, the field will continue to evolve. For instance, in addition to the phase 3 trial results from IMmotion151 and CheckMate-214,3 three or four more trials are also looking at promising regimens. Within the next 2 to 3 years, I anticipate these trials reading out and the first-line treatment for kidney cancer changing dramatically. We will have to decide which treatment option is best for a given patient: an immuno-oncology agent and VEGF combination, like atezolizumab plus bevacizumab; one of the VEGF TKIs; or combinations of immuno-oncology agents like nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb). We have a lot of work to do to see if we can identify what is the best treatment approach for a given patient.
References:
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). Presented at: Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, California. Abstract 578.
McDermott D, Huseni M, Rini B, et al. Molecular correlates of differential response to atezolizumab +/- bevacizumab vs sunitnib in a phase II study in untreated metastatic renal cell carcinoma (RCC) patients. Presented at: American Association for Cancer Research Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT081.
Escudier B, Tannir N, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Presented at: European Society of Medical Oncology Congress; Sept. 8-12, 2017; Madrid, Spain. Abstract LBA5.
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