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Robert W. Franz Endowed Chair for Clinical Research
Earle A. Chiles Research Institute
Providence Cancer Institute
Brendan D. Curti, MD, has disclosed the he has received funds for research support from AstraZeneca, Clinigen, and Galectin and consulting fees from Clinigen and Merck.
High-dose (HD) interleukin (IL)-2 is an immunotherapy that is effective in multiple tumor types, including metastatic renal cell carcinoma (RCC), where the ORR can be as high as 25% with responses potentially lasting for decades. However, HD IL-2 should be administered in a specialty center with a highly trained team to manage the administration and potential for complex immune-mediated toxicities and, therefore, has not been widely used among clinicians in the community. In this commentary, I use a case study to illustrate how our clinic currently uses HD IL-2 in the treatment of advanced RCC.
Case Study: Initial Treatment of Advanced RCC With HD IL-2
Approximately 4 years ago, a 63‑year‑old gentleman presented to our clinic with a history of back pain for several months. His primary care physician obtained a spine MRI, assuming he had disc disease, but instead it showed multiple bone metastatic deposits and a 10-cm mass in the right kidney. He was initially evaluated by a urologist and was considering a nephrectomy. However, while walking in his yard, he had sudden severe pain in his left leg, which turned out to be due to a pathologic fracture in the left femur. He received an orthopedic procedure for stabilization of the leg and then came to see me. Pathology confirmed metastatic renal cancer and additional imaging showed multiple lung metastases.
Although he had good functional status, he was deemed a poor prognosis patient due to his bone disease and lung metastases. He was anemic at the time of presentation and had a corrected calcium concentration greater than the upper limit of normal. Regardless of prognostic model, patients like this typically have a median survival time of less than 8 months.
In light of his prognosis and his desire to take an aggressive approach and to try to “hit a home run,” we discussed HD IL-2 in addition to oral tyrosine kinase inhibitor (TKI) therapy and combination immunotherapy. At the time, the combination of the PD-1 antibody pembrolizumab and the VEGF TKI axitinib was not yet approved by the FDA, but that would certainly be considered today. Similarly, although we would consider the dual checkpoint inhibitor combination of ipilimumab and nivolumab today, those data didn’t come out until after this patient’s initial presentation.
The rationale for considering HD IL-2 was based on the possibility of achieving a CR vs a PR or no response. This patient wanted access to treatment with a possibility of durable disease control rather than a treatment that might offer a higher probability of response but a shorter duration of response, as might be the case with an oral TKI. We enrolled the patient on a randomized clinical trial of radiation plus HD IL-2 vs IL-2 alone, where he was assigned to the combination arm. In addition, there were ample clinical indications for radiation in this patient, including several painful areas, so we would have considered radiation anyway.
On the clinical trial, he received radiation to the L3 lesion and a lung metastatic site, followed by HD IL-2 for a total of 6 cycles. He achieved a radiographic CR and has returned to normal activities with no residual pain. There were residual radiographic abnormalities at some of the bone lesion sites, but there was also new bone formation and they did not appear to be active sites of his cancer. Now, approximately 4 years from his initial visit and 3 years since completing HD IL-2, all of his pulmonary lesions have resolved. Moreover, he has required no other treatments or intervention.
HD IL-2: Toxicity
HD IL‑2 has long been associated with immune‑mediated adverse events. In the early days, this was called “capillary leak” but the more modern term is “cytokine-release syndrome,” which has been discussed extensively in the context of CAR T-cells and bispecific antibody immunotherapies. The biology is believed to be due to secondary vascular mediators induced by HD IL‑2, such as nitric oxide, IL‑6, and interferon gamma, among others. Nearly all patients treated with HD IL-2 experience some degree of transient hypotension, renal injury, and liver injury. In addition, patients may suffer electrolyte imbalances, such as hypomagnesemia, hypocalcemia, and metabolic acidosis. Low platelet counts are seen as well, which is believed to be due to the platelets being consumed in repair of the capillary leak. Our patient endured all of these toxicities.
Most clinics that employ HD IL‑2 have similar institution‑specific protocols for managing the toxicities. At our institution, we have an inpatient oncology unit to accommodate patients who need an ICU level of care. This includes ECG monitoring, pressor support for hypotension, and direct nursing care. Anecdotally, many oncology nurses manage 6-8 patients on their shift. For our patients who are receiving HD IL-2, we can accommodate staffing of 1 nurse for every 2 patients, more like in an ICU. In addition, our nurses have all received specific training for how to manage patients receiving HD IL-2 and have clinical experience in managing its adverse events.
With HD IL-2, unlike most other immunotherapeutics and certainly different than chemotherapy or targeted therapy, each patient is treated to an individualized maximum tolerated dose. The standard traditional HD IL-2 regimen is an IV bolus every 8 hours for up to 14 doses, with a second cycle administered 10‑14 days later. It is very unusual for patients to be able to tolerate all 14 doses. Anecdotally, in our clinic, patients are tolerating fewer doses in recent years compared with previous years, which is probably because many of these patients are much more heavily pretreated compared with 5 or 10 years ago. Of importance, the adverse events from HD IL-2 are really the clinical manifestations of boosting immune system activity and pushing those physiologic limits to achieve a response. We coach our patients to embrace the adverse events because this is how HD IL-2 works!
When considering HD IL-2 therapy, it is important to select patients who can tolerate this form of HD immunotherapy. This usually involves cardiac and pulmonary screening, including pulmonary function tests such as lung volume, and DLCO to assess the diffusing capacity of carbon monoxide. We use a standard Bruce protocol treadmill test to assess cardiac reserve, but a pharmacologic stress test or stress echocardiography are also appropriate to ensure that patients who may receive HD IL-2 do not have underlying ischemia or significant cardiovascular disease.
That said, even properly selected patients do get quite sick during treatment, but then typically make a rapid full recovery after the last HD IL-2 dose. So, although there is need for active management of HD IL-2–related symptoms seen throughout the weeks of treatment, most patients are able to resume their normal activities after treatment. By contrast, other more modern immunotherapies or targeted therapies have less intense adverse events but can be far more persistent.
When to Use IL-2 vs Newer Agents
Now that newer agents, such as immunotherapies and VEGF-targeted TKIs, are available, how should clinicians select patients with RCC for HD IL-2 treatment? This is typically a trade-off regarding adverse events, quality of life, and the patient’s short-term and long-term goals. It is always a difficult conversation with patients when they have advanced disease: The computer models suggest they won’t do well, and yet the patients are hopeful for a guaranteed 100% cure. The reality of our many current treatment options in RCC is that, at best, they can slow the course of RCC and convert what was a relentlessly progressive malignancy with terrible short‑term prospects to a chronic condition that can be managed over the course of years.
The more-recently approved agents do represent an advance, but there is ample room for improvement. For instance, nivolumab plus ipilimumab, which is a first-line standard of care for patients with intermediate-risk/poor-risk RCC at our cancer institute, results in a CR rate of approximately 10%. The combination of pembrolizumab and axitinib, which is also a first-line standard of care for these patients, has a reported CR rate of approximately 11%. The CR rate for HD IL-2, depending on the study, is 7% to 8%. These are all very low percentages, and I don’t see a significant difference among them.
Another consideration during the initial discussion with patients is to let them know that they will likely need multiple lines of therapy to manage their RCC. Given this information, many patients like to try the easier agents first. However, over time, patients acquire more symptoms from their underlying malignancy along with potential accumulation of toxicities from previous treatments. We conducted decision modeling experiments (ie, game theory) and concluded that patients have a better chance at a good outcome from treatment when the more aggressive treatment approaches that have the potential to induce a long-term CR (such as HD IL-2 and nivolumab plus ipilimumab) are used first.
Regarding the patient discussed above, he initially seemed like a poor candidate for HD IL-2 by the strict definition because of his bone disease and the decrease in functional status due to symptoms of his malignancy. But like many patients with advanced RCC whom I’ve seen in the last 30 years, if they are physiologically robust, even with significant symptoms, I think that they should be considered for HD cytokine therapy. As discussed, this patient did very well with HD IL-2, and I have many more examples from my practice. The lesson is that typical selection criteria used to suggest a good vs poor prognosis or functional status are not as helpful as we’d like.
How has your use of HD IL-2 shifted in your clinical practice? Share your thoughts in the comment box below!