MDACC 2018: Promising Emerging Systemic Therapies for mRCC

Houston, TX (UroToday.com) Treating mRCC successfully lays in harnessing the IL-2 pathway in such a way that increases tumor-infiltrating lymphocytes (TILs).  NKTR-214 is a prodrug being developed by Nektar that when it binds to CD122, triggers the release of TILs.   The slide below summarizes the differences between NKTR-214 and HD IL-2. 

MDACC 2018 UroToday Promising Emerging Systemic Therapies for mRCC
Interestingly, in patients treated with NKTR-213 plus Nivolumab, patients had a >50x increase in activated Tregs in the blood, but no changes or decreases in Tregs in the tumor.  The PIVOT-2 efficacy and safety data established the RP2D for NKTR-214 plus Nivolumab.  It also showed that grade 1/2 adverse effects were predictable, manageable and of short duration.  Additionally, there were few grade 3/4 adverse events and few immune-related adverse events. Importantly, there was a clinical benefit observed NKTR-214 plus Nivolumab as first-line therapy.  According to the NEKTAR website, responses were observed in 12/26 (46%, 11 with partial response).   They are currently enrolling for a trial of triplet therapy of NKTR-214 plus Nivo/Ipi. 

Another promising treatment is Pegilodecakin.  This is a PEGylated recombinant IL-10.  In preclinical tumor models, Pegilodecakin induced tumor rejection by activation and expansion of tumor-specific CD8+ T cells and immune memory 1,2.  One benefit of Pegilodecakin is the PEGylation increases the half-life allowing for once-daily dosing3.  Finally, Dr. Tannir is the global PI for a randomized, double-blind, placebo-controlled phase 2 Study comparing CB-839 in combination with Cabozantinib versus placebo with Cabozantinib in patients with advanced or mRCC for patients who have received prior VEGF directed therapy.  CB-839 selectively and irreversibly inhibits glutaminase which subsequently impairs cell proliferation in rapidly growing cells.

Dr. Tannir presented several new agents targeting the immune system which will hopefully open doors to otherwise treatment-resistant non-responsive disease and pave the path for new combination therapies. 


Presented by: Nizar M. Tannir, MD, Professor, and Deputy Chairman, Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

Written by Dr. Amy H. Lim, MD, PhD, Urologic Oncology Fellow and Ashish M. Kamat, MD, (@UroDocAsh), Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX

References:
1. Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, et al. IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012;72(14):3570-81.
2. Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, et al. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell. 2011;20(6):781-96.
3. Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ, et al. Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. J Clin Oncol. 2016;34(29):3562-9.
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