Single-agent ICI yields a response in one of four patients with metastatic RCC.7,8 Defining resistance mechanisms is a key step toward developing more effective therapeutic strategies. Tumor vasculature dysfunction resulting from aberrant angiogenesis can establish a barrier toward effector T-cells trafficking into tumor niche. Inhibition of vascular endothelial growth factor A (VEGF-A) enhances CD8+ T-cell recruitment.9,10 Combining ICIs with anti-angiogenesis is postulated to normalize tumor vasculature and improve treatment efficacy. Synergy was demonstrated in several tumor types including RCC, NSCLC, HCC, and endometrial carcinoma.11 On the other hand, the dual role of IL-10 is very intriguing. Known as the first inhibitory cytokine to be discovered, it has later been shown that, at higher concentrations, IL-10 may exhibit pro-inflammatory functions leading to stimulation and expansion of antigen-stimulated effector T cells.12,13
The IVY study presents a promising model aiming at tumor microenvironment (TME) modulation toward a less inhibitory phenotype with an ultimate goal of enhancing ICI-induced anti-tumor immunity. In this phase 1 trial, Tannir et. al. reported safety, tolerability and preliminary efficacy of a novel pegylated recombinant IL-10, pegilodecakin, as monotherapy, and in combination with either an anti-PD-1 agent (pembrolizumab or nivolumab) or an angiogenesis inhibitor (pazopanib). The study reported outcomes of patients with metastatic RCC who failed at least one prior line of therapy.
Pegilodecakin monotherapy was well-tolerated, consistent with previous reports, as were both combination arms in the trial. A maximum tolerated dose was not established and the rate of treatment discontinuation due to adverse events was very low.14,15 Most grade 3/4 toxicities occurred outside the window and thus did not qualify as a DLT. More importantly, immune-related toxicities were not increased in the pegilodecakin plus anti-PD-1 arm compared to single-agent use of an ICI.7,8,14,15 No cases of pruritis or mucositis noted, and a 3% incidence of pneumonitis and peripheral edema was reported.
Anti-tumor activity was likewise very encouraging. The IVY trial reported an ORR of 43% with a median PFS of 13.9 months and a 61% probability of survival at 2 years in the pegilodecakin plus ICI arm. Moreover, the pazopanib plus pegilodecakin arm had an ORR of 33%. In these cohorts of heavily pretreated patients where the majority of patients received two or more lines of prior therapy, efficacy outcomes are indeed very intriguing. In contrast, historical controls of ICI monotherapy in the first and subsequent lines of therapy reported an ORR of around 20-25% with the use of single-agent anti-PD-1,7,8,16 and 42% with the use of combination of anti-PD-1 and anti-CTLA-4 combination.6 It is also noteworthy to mention that some patients in the IVY trial received prior immunomodulatory therapy, including ICIs, IL-2, and/or IFN. Specific data on response outcomes of patients who failed prior immunotherapy was not presented, however, the study certainly raises interest in investigating whether the addition of pegilodecakin can reverse acquired resistance to ICI. The study was not powered to detect differences between the two combinational arms, or to draw a conclusion of efficacy according to histology i.e., clear vs nonclear cell. Nonetheless, pegilodecakin should continue to be evaluated in phase III trials as part of a combination with ICIs, i.e., PD-(L)1 inhibitors with or without a CTLA-4 inhibitor. A more interesting therapeutic approach would be to study a triple combination of ICI, anti-angiogenic and pegilodecakin in phase II/III trial. Furthermore, some patients with RCC present with locally advanced nonmetastatic or oligometastatic disease. Evaluation of a neoadjuvant triple combination approach for such patients may offer several advantages. First, it would uncover give unique histologic and molecular insights into the responses of raw tumors to such therapy. Second, if a high response rate is achieved, it may improve the efficacy of curative-intent therapies in such patients and could potentially present an appealing new standard of care.
Written by: Mohamad A. Salkeni,1 Nizar M. Tannir 2
- Department of Internal Medicine, West Virginia University, Morgantown, WV
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, USA
- SEER Stat Fact Sheets: Kidney and Renal Pelvis https://seer.cancer.gov/statfacts/html/kidrp.html.
- Rini, B.I., et al., Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2019. 380(12): p. 1116-1127.
- Powles, T., et al., Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol, 2020. 21(12): p. 1563-1573.
- Choueiri, T.K., et al., Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2021. 384(9): p. 829-841.
- Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290.
- Motzer, R.J., et al., Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol, 2019. 20(10): p. 1370-1385.
- Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373(19): p. 1803-13.
- McDermott, D.F., et al., Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma. J Clin Oncol, 2021. 39(9): p. 1029-1039.
- Motz, G.T., et al., Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med, 2014. 20(6): p. 607-15.
- Georganaki, M., L. van Hooren, and A. Dimberg, Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Front Immunol, 2018. 9: p. 3081.
- Hack, S.P., A.X. Zhu, and Y. Wang, Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities. Front Immunol, 2020. 11: p. 598877.
- Emmerich, J., 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): p. 3570-81.
- Chan, I.H., et al., The Potentiation of IFN-gamma and Induction of Cytotoxic Proteins by Pegylated IL-10 in Human CD8 T Cells. J Interferon Cytokine Res, 2015. 35(12): p. 948-55.
- Naing, A., 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): p. 3562-3569.
- Naing, A., et al., Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial. Lancet Oncol, 2019. 20(11): p. 1544-1555.
- Motzer, R.J., et al., Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol, 2015. 33(13): p. 1430-7.
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