Based on that clinical track record and HD IL-2’s well-established toxicity profile, only patients with “very good” performance status who have intact organ function are really candidates for this treatment, Dr Msaouel noted. “This treatment can be very rough,” Dr Msaouel added. “It can be very difficult to tolerate, so patients who are very sick should not receive this therapy.”

IL-2 can cause serious toxicities, including cognitive changes, hypotension, pulmonary fluid accumulation, difficulty breathing, kidney damage, heart attacks, and intestinal bleeding. Because it is so toxic, HD IL-2 should be given only at cancer centers with experienced care teams that are familiar with its use, Dr Hurwitz emphasized.

When HD IL-2 was first approved, there were patient deaths associated with the therapy’s toxicity, but those statistics have improved “significantly” in the years since, Dr Hurwitz said.

“This is due to at least 2 factors,” Dr Hurwitz explained. “One is that experienced centers know how to deal with toxicity more effectively, and secondly, patient selection has become stricter for HD IL-2 as other therapies have become available. Our site will only treat patients with adequate cardiac function and reasonably good performance status with HD IL-2.”

For eligible patients, HD IL-2 can be a good frontline therapy despite its toxicity, Dr Hurwitz noted. “I do not think HD IL-2 should necessarily be reserved for disease that is resistant to other treatments,” Dr Hurwitz argued. “Although this treatment is toxic, it is usually given over a short period of time and then it is done and patients do not need further treatment for quite some time if they have a durable response.”

In contrast, newer immune checkpoint-inhibiting immunotherapies are administered for years.

And, when selecting candidates to receive HD IL-2 therapy, Dr Msaouel told Cancer Therapy Advisor that tumor burden should be an important consideration. The primary tumor should ideally be removed prior to initiation of this therapy, in part because it can influence immunomodulatory factors.

“Different oncologists have different preferences,” Dr Msaouel acknowledged. “Many of us would much rather give this therapy in patients whose kidney has already been removed […] because we would like to have a lower disease burden when we try this therapy, and based on clinical data showing that patients who have undergone nephrectomy before HD IL-2 have better outcomes. Certainly, we would avoid this therapy in patients with other histologies [than clear-cell RCC] in which HD IL-2 has lower, if any, efficacy.”

Most of the patients in the PROCLAIMSM registry had their affected kidney removed entirely prior to receipt of HD IL-2.1

The location of metastatic tumors is also an important consideration, Dr Msaouel added. HD IL-2 should be avoided in patients who have metastases in liver or bone tissue, where tumors appear to be less responsive to this treatment, he explained. 

“Immunotherapy with checkpoint inhibitors [ipilimumab/nivolumab] is now the standard first-line therapy for intermediate- and poor-risk disease and will likely be soon be the standard of care in good-risk disease (with axitinib/pembrolizumab and maybe axitinib/avelumab),” Dr Hurwitz said. “The latter combinations will also be standard-of-care treatments in intermediate- and poor-risk disease.”

But the optimal role of IL-2 immunotherapy across the treatment landscape remains “very unclear,” Dr Hurwitz warned.

“For one thing, this therapy will be difficult to get out to the general population because of toxicity and the experience required by the treating team,” he explained. “For another [thing], given the high response rates for [other immunotherapy] combinations, trials to compare them to HD IL-2 alone or in combination with immune checkpoint inhibitors will be difficult to do. It is noteworthy that an early-phase frontline trial of HD IL-2 with pembrolizumab was reported at [the American Society of Clinical Oncology’s Genitourinary Cancers Symposium] this year with very high response rates, so that might be a way forward if those results hold up.”5

References

  1. Fishman M, Dutcher JP, Clark JI, et al. Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry. J Immunother Cancer. 2019;7(1):84.
  2. Bentebibel SE, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel ILRβγ-biased cytokine, in patients with advanced or metastatic solid tumors [published online April 15, 2019]. Cancer Discov. doi: 10.1158/2159-8290
  3. Silva D-A, Yu S, Ulge UY, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature. 2019;565(7738):186-191.
  4. Considine B, Hurwitz ME. Current status and future directions of immunotherapy in renal cell carcinoma. Curr Oncol Rep. 2019;21(4):34.
  5. Chatzkel JA, Swank J, Ludlow S, et al. Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: a single center, single arm trial. J Clin Oncol. 2019;37(7_suppl):657.