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High-dose IL-2, hydroxychloroquine appears effective in metastatic renal cell carcinoma, but not a ‘home run’
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CHICAGO — Patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 and hydroxychloroquine appeared to demonstrate similar responses to patients who previously received high-dose interleukin-2 alone, according to data presented at the ASCO Annual Meeting.
Additionally, the combination appeared to demonstrate a similar toxicity profile to high-dose interleukin-2 (IL-2) alone, according to the results.
“Although we have a lot of new therapies, [kidney cancer] is still a lethal disease for most people,” Leonard J. Appleman, MD, PhD, of the division of hematology/oncology at the University of Pittsburgh Medical Center Hillman Cancer Center, told HemOnc Today.
“Since the 1990s, we’ve had an approved treatment called high-dose interleukin-2 which [has demonstrated] durable complete remissions in 5%- to-10% of patients that can last for decades,” he said.
The problem with high-dose IL-2 is that it is a toxic treatment and typically forces patients into the hospital for a week at a time, Appleman added.
“We don’t use it for most patients,” he said. “We only use it for the youngest, most fit patients that we have. We are looking for a way to make that treatment work for more patients, and possibly to be less toxic. And one hypothesis [that we] had was that cells were escaping being killed by the T-lymphocytes that the IL-2 simulates by an escape mechanism called autophagy where they avoid the stress of the T-cell attack by basically consuming their own proteins as fuel to stay alive during the stress period.”
Appleman said that based on observations from a co-author’s lab, the researchers wondered if they could get better results with a high-dose IL-2 if they were able to inhibit autophagy.
“It turns out that there are inhibitors of autophagy that are available,” he said.
“There’s a drug called hydroxychloroquine, which has been around for decades as a treatment for malaria and for rheumatologic diseases which is an inhibitor of autophagy. Because it has been around for so long, it’s very inexpensive, it’s very safe to use [and] there’s a lot of experience using it.”
As a result, Appleman said, it was feasible to combine high-dose IL-2 with hydroxychloroquine for patients with metastatic renal cell carcinoma.
In this single-arm, phase 2 study, Appleman and colleagues evaluated the safety, tolerability and efficacy of hydroxychloroquine and high-dose IL-2 among patients with metastatic renal cell carcinoma.
The analysis included data from 31 patients (median age, 57.5 years; 71% male). Six patients received 600 mg daily with no dose-limiting toxicities, while an additional 13 patients received 1,200 mg daily at enrollment.
The escalated dose was declared intolerable and the remaining 12 patients received 600 mg daily at enrollment.
Complete response served as the primary endpoint; secondary endpoints included safety and toxicity.
Three patients out of 29 evaluable for response reached a complete response and an additional 3 patients reached a partial response.
“Most of the patients on the study are still alive and some have moved on to other therapies,” Appleman said. “But, as long as 5 years out, most of them are still alive undergoing treatment or are even off treatment.”
The most important question that the researchers answered revolved around if the combination therapy was considered a “home run,” according to Appleman.
“I think we’ve probably excluded that possibility,” he said. “I think it was a good question to ask and I think the answer is it’s probably not an obvious huge step forward and if there’s a benefit, it’s probably something that would need a comparative trial with hundreds of patients to detect a difference. Maybe it wasn’t the answer we were hoping for, but we did get an answer.” – by Ryan McDonald
Reference:
Appleman LJ, et al. Abstract 4573. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: The trial received some support from Prometheus Laboratories Inc. Appleman reports no relevant financial disclosures.