High dose interleukin (HD IL-2) received Food and Drug Administration (FDA) approval for metastatic renal cell carcinoma (mRCC) in 1992, and then for metastatic melanoma (mM) in 1998. HD IL-2 is currently the only agent shown to be associated with durable complete responses in mRCC, for 7% of patients. The observational database, PROCLAIMSM, was established in 2011 to collect and analyze data for patients treated with HD IL-2 in the current era. Since those initial reports of durable long-term benefit from HD IL-2,1,2 novel immunotherapies and targeted therapies have been developed and investigated for the treatment of mM and mRCC. Some targeted therapies have failed to demonstrate an overall survival (OS) advantage in pivotal studies, while others demonstrate an initial high response rate but not durable long term responses.3,4 Moreover, tumors eventually develop resistance to targeted therapy leading to disease progression and their toxicity is often responsible for a decreased quality of life for patients while on treatment.
The emergence of immune checkpoint inhibitors such as the anti-programmed cell death 1 (PD-1), programmed death-ligand 1 (PDL-1) agents, and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents, have reaffirmed the role of immunotherapy as an anti-tumor treatment modality. These agents reduce inhibitory signaling and restore the patient’s natural tumor-specific T-cell-mediated immune responses.5 They have demonstrated objective responses in both mRCC and mM as single agents and in combination, and have extended OS for some responders versus comparator arms such as everolimus.
Similarly, single institution reports of HD IL-2 treated patients have also showed an improvement in OS compared to historical controls.6,7 Data from the PROCLAIMSM registry demonstrated consistency with these reports. The median OS (mOS) was not reached for patients achieving complete responses (CR) or partial response (PR), and was 33.4 months for mM patients with stable disease (SD) and 49.6 months for mRCC patients with SD.8 Another recent publication of data from PROCLAIM documented long term disease free survival, (DFS [>5 years]) after CR or PR from HD IL-2 alone.
Surgical or stereotactic radiosurgery conversion of PR to CR produced durable CRs. Long term DFS was observed in pts with visceral and bone metastases, not only those with lymph node or lung sites. Neither age, sex, nor number of courses of IL-2 predicted long term DFS. Chronic toxicity due to IL-2 is uncommon in long term survivors.14 These data support a continued role for IL-2 within current treatment paradigms and also suggest that further study of combination or sequential treatment with HD IL-2 and immune checkpoint inhibitors is warranted.8 For further information on current PROCLAIM data, please click on the following link for a presentation from ASCO 2017 by Ulka N. Vaishampayan, MD of Wayne State University Karmanos Cancer Center. http://meetinglibrary.asco.org/record/138111/video (ASCO subscription required).
In an interview filmed at the American Society of Clinical Oncology (ASCO) Annual Meeting, June 2–6, 2017, Dr Ajjai Alva of the University of Michigan discussed factors that are known to predict long-term survival after HD IL-2 treatment (add link). One of the key selection criteria is histology. The most common histological subtype of mRCC is clear cell, i.e., under a microscope, the cells appears clear, and is seen in around 75% of cases9 The best responses to HD IL-2 have been seen in this group.10,11 As a result, Dr Alva would not offer HD IL-2 to the 25% of patients with nonclear cell histology. Given the adverse event profile of HD IL-2, careful patient selection is essential. Performance and functional status are also important predictors of response.11 Dr Alva chooses the best performing and best functional patients according to scales such as Eastern Cooperative Oncology Group (ECOG) and Karnofsky performance score. This combination of patient factors and tumor factors predicts longer responses and higher frequency of responses.
The use of IL-2 in combination with immune checkpoint inhibitors is an active area of research and an important way forward, according to Dr Alva. While he acknowledged the justifiable hype around immune checkpoint inhibitors, he emphasized the fact that these therapies lead to effective tumor shrinkage in only 25% of patients with mRCC.12 The 75% of patients who do not respond represent an important unmet need. A recent prospective study of HD IL-2 in mRCC also had an overall response rate of 25% and produced durable remissions with a 3-year progression-free survival of 11% and prolonged survival of 42.8 months.11 There is still the need to increase the numbers of patients responding to treatment and thriving off treatment. Sequencing or combining treatments may be the path to further improving patient outcomes. Mechanistically, IL-2 acts at an earlier stage of lymphocyte proliferation while immune checkpoint inhibitors are active at a later stage. It is therefore hypothesized that combining the two therapies will have a synergistic effect, allowing higher responses and, more importantly, more potent immune responses. A 2016 analysis of data from the PROCLAIMSM registry involved mRCC patients who initially received HD IL-2 and subsequent immunotherapy. These results suggest that HD IL-2 therapy followed by immune checkpoint inhibitors may be associated with noteworthy survival benefit.13
A study of the combination of HD IL-2 and nivolumab in patients with mRCC is currently recruiting (NCT02989714). A 600,000 IU/kg/dose of IL-2 will be administered intravenously during two 5-day cycles, 9 days apart. Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1–3 weeks after the start date of the first cycle of IL-2 and continued for up to 48 weeks total in the absence of disease progression.14
In summary, HD IL-2 continues to play a role in the treatment of mRCC and mM. Preliminary data demonstrate impressive survival statistics for patients initially receiving HD IL-2 followed by immune checkpoint blockade. The ultimate aim of combined therapy is to develop a regimen that is tolerable, safe and widely applicable to patients.
Support: Katrina Mountfort is a freelance medical writer working on behalf of Touch Medical Media. The publication of this article was supported by Prometheus.
1. FDA, PROLEUKIN® (aldesleukin) for injection, for intravenous infusion. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf (accessed June 15, 2017).
2. Fyfe G, Fisher RI, Rosenberg SA, et al., Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy, J Clin Oncol, 1995;13:688–96.
3. Sternberg CN, Davis ID, Mardiak J, et al., Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial, J Clin Oncol, 2010;28:1061-8.
4. Motzer RJ, Escudier B, Oudard S, et al., Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial, Lancet, 2008;372:449–56.
5. Buchbinder EI, Desai A, CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition, Am J Clin Oncol, 2016;39:98–106.
6. Hanzly M, Aboumohamed A, Yarlagadda N, et al., High-dose interleukin-2 therapy for metastatic renal cell carcinoma: a contemporary experience, Urology, 2014;83:1129–34.
7. Payne R, Glenn L, Hoen H, et al., Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program, J Immunother Cancer, 2014;2:13.
8. Alva A, Daniels GA, Wong MK, et al., Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma, Cancer Immunol Immunother, 2016;65:1533–44.
9. Lopez-Beltran A, Scarpelli M, Montironi R, et al., 2004 WHO classification of the renal tumors of the adults, Eur Urol, 2006;49:798–805.
10. Upton MP, Parker RA, Youmans A, et al., Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, J Immunother, 2005;28:488–95.
11. McDermott DF, Cheng SC, Signoretti S, et al., The high-dose aldesleukin “select” trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma, Clin Cancer Res, 2015;21:561–8.
12. Motzer RJ, Escudier B, McDermott DF, et al., Nivolumab versus everolimus in advanced renal-cell carcinoma, N Engl J Med, 2015; 373:1803–13.
13. Clark J, McDermott DF, Dutcher JP, et al., Extension of overall survival in patients with metastatic renal cell carcinoma who received HD IL-2 followed by targeted therapy and/or immune checkpoint blockade from the PROCLAIM registry, J Clin Oncol, 2016;34:suppl; abstr 4548.
14. ClinicalTrials.gov. Phase Ib/II trial of interleukin-2 and PD-1 checkpoint inhibitor, nivolumab in metastatic clear cell renal cell cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02989714?term=interleukin-2&draw=2&rank=18 (accessed 2 October, 2017).