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ASCO 2018

ASCO 2018: Pegilodecakin with Nivolumab or Pembrolizumab in Patients with Metastatic Renal Cell Carcinoma

Chicago, IL (UroToday.com) Pegilodecakin (AM0010, ARMO Biosciences) is a long-acting form of recombinant human Interleukin 10 (IL-10). IL-10 suppresses inflammatory cytokines and at high concentrations leads to activation of tumor CD8+ T cells1.  In preclinical studies, IL-10 deficient mice had increased tumor incidence and decreased immune surveillance. Mice treated with IL-10 induced rejection of large tumors and the development of immunological memory against tumor cells2. A phase I study of single agent pegilodecakin showed that it was well tolerated without any autoimmune adverse events in a small cohort of 33 heavily pre-treated patients, with 2 patients achieving partial response and 5 patients achieving disease control3. 

In this phase Ib study of pegilodecakin with nivolumab or pembrolizumab, 38 patients with metastatic renal cell carcinoma (RCC) received either nivolumab (n=29, 3 mg/kg q2 weeks) or pembrolizumab (n=9, 2mg/kg, q3 weeks) in combination with pegilodecakin. Almost all patients were intermediate or poor risk by IMDC criteria (94%) and had been treated by at least one VEGFR-TKI. The population was heavily pretreated with up to 5 prior therapies in the combination arms. 

The combination therapy was well tolerated in both groups. Notable side effects included cytokine release syndrome and immune mediated hemophagocytic lymphohistiocytosis in two patients – both patients recovered and had partial responses to the therapy. There was a strong biomarker study built into this study evaluating T cell clonality – pegilodecakin demonstrated a strong ability to expand previously undetectable T cell clones which corresponded with tumor response.  

By immune RECIST criteria, there were 14 partial responses (41%) including 3 complete responses (9%). By RECIST criteria, the overall response rate (ORR) was 53% and disease control rate was 81%. Median progression free survival (PFS) was 16.7 months with pegilodecakin + pembrolizumab, and was not reached for pegilodecakin + nivolumab at a median follow up of 13.8 months. 1 year overall survival was 89%.  Similar numbers are being presented during this annual meeting for this combination therapy in non-small cell lung cancer (Responses and durability in NSCLC treated with pegilodecakin and anti-PD-1.  - Abstract 9018). In that study of 26 patients, overall response rate was also quite impressive at 41% with another 46% of patients having stable disease. 

While this is only a small phase I study, these results are very exciting. Current FDA approved second line therapies for mRCC have ORR in 10-30% range (Axitinib4 – 19%, Nivolumab5 – 25%, Cabozantinib6 – 21%, Lenvatinib+Everolimus7 – 30%). Should this ORR hold up in phase II/III studies, this drug duo could be a major contender for the second line space. During the poster discussion session, Dr. Laurence Albiges also noted that the overall response rate was quite impressive compared to nivolumab and pembrolizumab and recommended that the community move this combination further in larger clinical trials. Dr. Albiges notes two questions that have yet to be answered will be whether or not this combination will replace ipi/nivo in front line, and how this combination fits in patients pre-treated with ipi/nivo. 

Presented By: Nizar M Tannir, MD, FACP, MD Anderson 

Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA 

References 
http://www.armobio.com/pipeline-main.php#am0010  
1.Oft M. IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity. Cancer Immunology Research 2014;2:194-9. 
2.Mumm John B, Emmerich J, Zhang X, et al. IL-10 Elicits IFNγ-Dependent Tumor Immune Surveillance. Cancer Cell 2011;20:781-96. 
3.Infante JR, Cassier PA, Gerecitano JF, et al. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients With Advanced Solid Tumors and Lymphomas. Clinical Cancer Research 2016. 
4.Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. The Lancet 2011;378:1931-9. 
5.Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2015;373:1803-13. 
6.Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. The New England journal of medicine 2015;373:1814-23. 
7.Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. The Lancet Oncology 2015;16:1473-82.