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High-Dose Interleukin-2 Effective in Metastatic Renal Cell Cancer Pretreated With VEGF-Targeted Therapies

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Key Points

  • Over 45% of metastatic renal cell cancer patients with favorable histology responded to high-dose interleukin-2, with a 23% complete remission rate.
  • There was no significant difference in response or survival rate between treatment-naive and pretreated patients.
  • The median overall survival in those achieving a complete response has not yet been reached.

High-dose interleukin-2 can be effective in selected metastatic renal cell cancer patients pretreated with VEGF-targeted agents, according to research presented recently at the ESMO Symposium on Immuno-Oncology in Geneva (Abstract 4O).

“Despite the wide and increasing range of therapies available, the management of metastatic renal cell carcinoma remains challenging,” said lead author Manon Evans, research fellow at the Christie Hospital in Manchester, UK. “Agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways are currently the standard of care. Whilst these therapies are well-tolerated and demonstrate impressive response rates, the responses seen are very rarely complete and durable.”

She added, “High-dose interleukin-2—a protein that activates the immune system—can induce durable complete responses in small numbers of patients with metastatic renal cell cancer. However, due to significant toxicities, its use remains limited. To date, it has been used as an option in the treatment-naive population only, with concerns over its efficacy and safety post-VEGF targeted agents.”

Given the expanding treatment options now available, selecting the therapy most likely to yield the best long-term response for patients is of increasing importance. Dr. Evans noted that a previous study demonstrated that preselecting patients by a combination of clinical and histologic criteria can generate impressive results in treatment-naive populations. Patients were classified as “favorable” or “other” based on their histologic makeup.

Study Details

The current study is a retrospective analysis of 180 patients treated with high-dose interleukin-2 at the Christie NHS Foundation Trust over the past 10 years. The majority of patients were treated in the first-line setting, with a smaller cohort receiving treatment following VEGF-targeted agents. The researchers also investigated whether expression of the biomarker carbonic anhydrase IX (CAIX) correlated with outcome and could potentially be added to the selection criteria for high-dose interleukin-2 therapy.

A total of 180 patients with metastatic renal cell cancer were treated with high-dose interleukin-2, 145 in the treatment-naive cohort and 35 in the pretreated cohort. Of these, 158 had “favorable” histology, of whom over 45% responded with a 23% complete remission rate. Of those achieving a complete response to therapy, over 75% are alive and disease free. The median overall survival in those achieving a complete response has not yet been reached. There was no significant difference in response or survival rate between the two treatment cohorts.

CAIX positivity correlated favorably with response and survival as did disease burden and tolerance of treatment. All patients experienced toxicity as anticipated. The incidence of treatment-related myocarditis was higher in the pretreated cohort (8.5%) compared to the treatment-naive group (3.4%).

Dr. Evans said, “Our data confirms that there remains a role for high-dose interleukin-2 in the management of metastatic renal cell cancer and demonstrates, in a selected population, complete responses of over 20%, most of which are durable. In contrast to initial reports, it can be safe and effective in carefully selected patients pretreated with VEGF-targeted agents with response rates and complete responses similar to first-line therapy. Its application should strongly be considered in both the treatment-naive and pretreated population.”

She continued: “Outcomes were clearly superior in patients with ‘favorable’ histology (incorporating those with solid/alveolar clear cell renal cell cancer), but there were rare durable complete remissions in patients with ‘other’ histologies, and the role of high-dose interleukin-2 in this group is less well defined with further assessment required.”

Study Implications

Commenting on the implications of the findings, Michele Maio, MD, PhD, Chair of the Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Italy, said, “The authors found that high-dose interleukin-2 seems to work in second line to the same extent as it works in first line. This is important for the treatment algorithm of patients with metastatic renal cell cancer. One must now consider high-dose interleukin-2 as first- or even second-line treatment in patients with metastatic renal cell cancer who have a favorable histology. This means that high-dose interleukin-2 is still an important drug to be cleverly utilized in the treatment algorithm of patients with metastatic renal cell cancer now that we also have VEGF inhibitors available.”

“The treatment algorithm of these patients will change again in the near future,” added Dr. Maio, “because it will include immune checkpoint blocking antibodies, mainly anti–PD-1 and anti–PD-L1 antibodies, that are being actively developed in clinical trials in renal cell carcinoma. This is an additional form of immunotherapy that hopefully will also contribute to the improved long-term survival of these patients.”

He concluded: “Until a few years ago we had very limited treatment possibilities for metastatic renal cell cancer patients. Now we have confirmation that high-dose interleukin-2 is still an important option for patients with a favorable histology. High-dose interleukin-2 can be very toxic so this is a strategy that is mainly reserved for patients with a very good performance status and it has to be administered by professionals who are experienced with the drug and its side effects.”

The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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