ASCO 2017: IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma patients of atezolizumab and bevacizumab vs and following atezo or sunitinib

Chicago, IL (UroToday.com)Targeted therapies, since their introduction in 2006, have remained the mainstay of therapy for metastatic renal cell carcinoma (mRCC). However, while providing progression-free survival (PFS) benefit, they have never demonstrated cure. PFS was typically in the range of 8-12 months for most agents in this disease space. Additionally, with a significant adverse event profile, these therapies came at significant cost to the patient, particularly those with lower volume disease.

As such, the introduction of immune checkpoint inhibitors (ICIs) represents a potential new frontier for the treatment of mRCC. With established oncologic benefit in other solid malignancies, trials are underway to assess the role of ICIs in all stages of RCC.

Atezolizumab is a well-established anti-PD-L1 antibody. Bevacizumab is a monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). Sunitinib is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor, and current first-line therapy for mRCC.

Study design:
In this multicenter, randomized, open-label study, patients with untreated advanced or metastatic RCC are treated with one of three possible treatment regimens: atezolizumab (atezo) 1200 mg IV q3w + bevacizumab (bev) 15 mg/kg IV q3w, atezo alone or sunitinib 50 mg PO QD 4 wk on/2 wk off. Interestingly, in patients who fail first-line monotherapy alone, they are allowed to cross-over to arm 1 (combination therapy) as a second-line therapy.

Included patients were stratified by PDL-1 status, prior nephrectomy, and MSKCC risk stratification. As with many ICI studies, PD-L1 status on tumor-infiltrating cells (TILs) was assessed prior to treatment.

Co-primary endpoints: 1) IRF-assessed PFS based on RECIST v1.1 criteria in intention-to-treat (ITT) patients, 2) patients with PD-L1 expression on ≥ 1% of TILs (PD-L1+).

Results:
305 patients were recruited for this study, 101 in arm 1 (combination), 103 in arm 2 (atezo), and 101 in arm 3 (sunitinib). 54% were PD-L1+.

In arm 1, which considers atezo+bev first line therapy, in patients who were PD-L1 +, a PFS hazard ratio (HR) of 0.64 was noted, when compared against sunitinib alone. The ORR was 48% in combination therapy patients, but 27% for suninitib monotherapy and 28% for atezolizumab monotherapy. But for all comers, in the ITT analysis (regardless of PD-L1 status), the HR was 1.00 – no significant difference. ORR was approximately 25-35% for all arms.

In arm 2, atezo monotherapy did not provide any PFS benefit over sunitib alone, regardless of PDL-1 status.

When considering cross-over as well, after first-line monotherapy, 78% of sunitinib (54 patients) and 60% of atezo pts (41 patients) who progressed subsequently received atezo + bev (primarily due to regional restrictions) and achieved ORRs of 28% and 24%, respectively. Patients who crossed over were more likely to be primary non-responders or early progressors (PFS with monotherapy wa 4.8 months for atezo patients, 5.7 months for sunitinib patients) rather than responders. Patients who had an initial response to monotherapy had a slightly higher ORR to 2nd line combination therapy. Crossover PFS was 8.3 months in the sunitib monoterhapy arm and 12.6 months in the atezo arm.

In terms of safety summary, the 1st line arm A combination therapy patients had a 63% of Grade 3-4 adverse events, but only a 40% treatment-related Grade 3-4 adverse event rate. There were 3 adverse events leading to death. There were 9 TRAEs leading to withdrawal. Results were similar in the crossover cohort. Monotherapy resulted in less adverse events, as expected, but proportions were comparable.

Lastly, Dr. Atkins briefly reviewed some of their exploratory work using transcriptomics to identify a potential biomarker of response. Based on expression data regarding immune antigen presentation genes and myeloid inflammation genes, they were able to identify two distinct cohorts – patients with high T-effector cell function and either high or low myeloid inflammation. They found that addition of bev to atezo in 1st line therapy was associated with benefit in patients with high T-effector cell function & high myeloid inflammation, but not in patients with high T-effector cell function & low myeloid inflammation.

Based on these results, the authors identify atezo+bev as a potential promising first line therapy for mRCC; even in the second line setting, it appears to salvage some proportion of patients. Atezo monotherapy did not appear to provide any oncologic benefit over current standard of care.

Presented By: Toni K. Choueiri

Co-Authors: David F. McDermott, Thomas Powles, Robert J. Motzer, Brian I. Rini, Lawrence Fong, Richard Wayne Joseph, Sumanta K. Pal, Mario Sznol, John D. Hainsworth, Walter Michael Stadler, Thomas E. Hutson, Alain Ravaud, Sergio Bracarda, Cristina Suarez, Toni K. Choueiri, Jiaheng Qiu, Mahrukh A. Huseni, Christina Schiff, Bernard J. Escudier

Institution(s): Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC; Beth Israel Deaconess Medical Center, Boston, MA; Barts Cancer Institute, London, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, NY; Cleveland Clinic Taussig Cancer Insitute, Cleveland, OH; University of California, San Francisco, San Francisco, CA; Mayo Clinic, Jacksonville, FL; City of Hope Comprehensive Cancer Center, Duarte, CA; Yale School of Medicine and Yale Cancer Center, New Haven, CT; Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; The University of Chicago, Chicago, IL; Baylor Sammons Cancer Center-Texas Oncology, Dallas, TX; Groupe Hospitalier Saint Andre - Hopital Saint Andre, Bordeaux Cedex, France; Ospedale San Donato Azienda USL-8, Perugia, Italy; Vall d’Hebron University Hospital Institute of Oncology (VHIO), Barcelona, Spain; Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA; Genentech, Inc., San Francisco, CA; Gustave Roussy Cancer Campus, Villejuif, France

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
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