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The Evolving Role of Cytokine Therapy for Renal Cell Carcinoma: Past, Present, and Future

Brendan D. Curti, MD
Released: October 1, 2020

High-Dose IL-2: Rationale for Use in RCC

Rationale for Using HD IL-2: Rate of CR

In light of these pivotal trials and practice‑changing studies, many clinicians are unsure of the current role of IL-2. HD IL-2 was originally approved in 1992 for the treatment of patients with advanced RCC. There remains solid rationale for considering HD IL-2 in certain patients with advanced RCC. One main advantage for use of HD IL-2 is the prospect of achieving a durable CR. The rate of CR with HD IL-2 in studies has ranged from approximately 2.5% to nearly 12.0%.[7-11]

Although there have been no head‑to‑head comparisons of HD IL-2 vs more-modern regimens, cross-trial comparisons can still be illuminating. In the original 2018 publication of CheckMate-214 by Motzer and colleagues[3] in the New England Journal of Medicine describing ipilimumab and nivolumab, the CR rate was 9%. In updated results from 2020, the CR rate to ipilimumab and nivolumab was 10.1%.[12] By contrast, in the phase III KEYNOTE-426 study in untreated advanced RCC, the combination of pembrolizumab and axitinib produced a CR rate of 8.8%.[13] Lastly, in CABOSUN, the CR rate was just 1.3%.[5]

Rationale for Using HD IL-2: Durable Response

In addition to considering HD IL‑2 therapy due to its ability to induce a CR in a subset of patients, the potential for prolonged duration of response is also a consideration.

Kaplan-Meier curves from various clinical trials with HD IL-2 depict the long tail on the curve for OS in select patients who received HD IL-2, highlighting the potential for a prolonged response to therapy in a subset of patients who achieve a response. Now, let’s look at each of these studies in more detail.

IL-2–Based Therapy for Metastatic RCC: The Cytokine Working Group Experience

The duration of response to IL-2 is the main reason for clinicians to consider HD IL-2 in RCC treatment today.

This survival curve includes data from 3 randomized phase II trials involving 255 patients with metastatic RCC treated with IL-2.[10] The ORR to HD IL-2 in this analysis was 17% (7% CRs), with a median duration of response of 53 months. In a subset of patient who achieved response (approximately 35% of patients), their duration of response continued for longer than 180 months, highlighting the impressive durability of response in select patients.

Phase III Trial of HD IL-2 vs Subcutaneous IL-2 Plus Interferon in Metastatic RCC

The “tail on the curve” is also evident in OS results from a phase III comparison of HD IL-2 vs subcutaneous IL-2 and interferon in 67 patients with metastatic RCC.[8] This study described the outcomes in 192 patients treated in the late 1990s through mid‑2000. The objective response for the patients receiving HD IL‑2 was 23.2% (with 8.4% of patients achieving CR) with a median duration of response of 24 months. Again, a small subset of patients remained in response for longer than 60 months.

It was noted that the durability of responses with HD IL‑2 was superior to moderate‑dose IL‑2 plus interferon.

HD IL-2 Treatment of Metastatic RCC in a Retrospective Analysis of Community Hospital Biotherapy Program

In a retrospective analysis of the outcomes of patients with metastatic RCC performed at my institution, we administered HD IL-2 to 186 patients with RCC between 1997 and 2012.[9] The ORR was 24% (7% CRs). The median OS for patients with a CR was not reached, and the 3-year OS for all patients was 44%.

We observed a higher proportion of response in patients who required vasopressor support, exhibited metabolic acidosis, or thrombocytopenia. This supports individualized maximum tolerable dosing strategies for HD IL-2 to maximize the efficacy of this therapy. 

HD IL-2 in Metastatic RCC Following PD-1 or PD-L1 Inhibition

With the success of ICI-based therapies for patients with RCC, the use of HD IL-2 therapy has declined; however, many patients will experience disease progression following ICI therapy and require additional treatment.

Buchbinder and colleagues[11] conducted a retrospective analysis in which 57 patients with either metastatic melanoma or RCC (n = 17 with RCC) were treated with HD IL-2 after progressing on PD-1 or PD-L1–targeted ICIs.

Among the patients with RCC, 8 received nivolumab, 1 received pembrolizumab, 3 received atezolizumab, and the remainder received PD-1 inhibition without identification of the agent used. In this analysis, patients may have received ≥ 1 PD-1 or PD-L1–targeted agent.

This is a small study of 17 patients, but the objective response in patients with RCC was 24.0% after checkpoint inhibitor failure (11.8% of patients achieved a CR). Of importance, none of the responding patients progressed during 2 years of follow-up.

Although this is a small retrospective study, it is clear that HD IL‑2 has activity in patients who have progressed after treatment with ICIs.

My Experience With HD IL-2

In our clinic, we treat each individual to their maximum tolerated dose. Currently, most of our patients treated with HD IL‑2 have previously received ICIs, and we have a hypothesis that this results in differences in their immune response compared with patients treated before the ICI era. As a result, we have noticed a trend in giving fewer IL‑2 doses per cycle compared with 5, 10, or 20 years ago. However, although the previous treatment history of our patients has changed, the proportion of responses observed has been maintained and, in our practice, has increased in recent years. I do not wish to draw any conclusions from a single-institution’s observations, but our experience echoes some of the data discussed earlier where responses to HD IL‑2 were seen after progression on ICIs. I hope this will be explored in more-extensive and larger studies.

In clinical practice, my bias is to sequence therapies with the highest probability of CR, which today means starting with a regimen containing an ICI. HD IL-2 should be considered in the second or third line, in my opinion, due to the likelihood of achieving a CR and/or a durable response compared with other current options. Again with the caveat that this is our single-institution observation, our experience is that the durability of response to a TKI after IL‑2 is more than double the durability in the medical literature for TKIs used in the first line. I am confident that the probability of response after IL‑2 failure is not significantly compromised. For a community practitioner, I would encourage referral to an IL‑2 center for patients with RCC and good functional status but who have progressed on some of the more recent ICI combination regimens.

Case Discussion (Cont’d)

Now, returning to our patient case example, this patient was a 67-year-old man who presented with back pain. He had multiple sites of bone metastases, lung nodules, and involved lymph nodes, as well as a pathologic fracture of his right femur. He had a poor IMDC risk status. An open reduction and internal fixation procedure was performed to address the femur fracture, and pathology showed clear-cell RCC.

The patient opted to volunteer for a research study comparing stereotactic body radiation plus HD IL-2 vs HD IL-2 monotherapy (NCT02306954) and was assigned to the combined group.

Also, he opted to have a nephrectomy before therapy with HD IL-2 commenced. This decision is supported by an older study by Flanigan and colleagues[14] that compared nephrectomy followed by interferon immunotherapy vs interferon immunotherapy without nephrectomy. In this study, there was a significant benefit to a nephrectomy followed by interferon immunotherapy. The utility of nephrectomy remains controversial in the era of our more modern treatments, as mentioned with the CARMENA data, but in fact, nephrectomy remains a good option in patients with a good functional status.

This patient’s ultimate goal was a “cure.” Anecdotally, in my approximately 30 years of practicing genitourinary oncology, I can only think of one instance of a radiographic CR in a renal primary tumor. It is unusual to achieve a CR with any therapy in the kidney itself, and this was part of the logic in choosing nephrectomy for this patient.

Per the clinical trial (NCT02306954), the patient received stereotactic radiation (20 Gy x 2 administered on the Wednesday and Friday before the start of HD IL-2 on the following Monday) to a right central lung nodule. This timing was important in a preclinical study of radiation and IL-2 immunotherapy published by my colleague, Marka Crittenden. In her study, murine tumor models had significantly better outcomes when radiation was administered within 48 hours of the start of IL-2 therapy.

In this recently completed clinical trial, after the radiation therap,y patients received IL-2 at 600,000 IU/KG IV every 8 weeks for 14 planned doses. Imaging was conducted after 2 cycles (ie, 1 course). Patients who responded or achieved clinical benefit could receive additional courses of IL-2 (6 cycles maximum).

Case Continued: IL-2 Clinical Course

This table depicts the clinical course of this patient. A total of 6 cycles of HD IL-2 therapy were given, with the number of IL‑2 doses gradually decreasing over time; this is a common observation in most IL‑2 centers, including our clinic. The main dose‑limiting toxicity in each cycle was hypotension, and the patient was given phenylephrine to support his blood pressure.

Each IL-2 center has its own protocols. Our clinic treats patients more aggressively than many other programs, but we feel this is warranted based on long‑term outcomes and our observation that there are not discernible long‑term effects of aggressive therapy with HD IL-2 in carefully selected patients.

Of note, creatinine was elevated in each of the cycles with HD IL-2 and reached a significant level in this patient with just 1 kidney. Data from our group is reassuring in that patients regain their baseline renal function between cycles, and this was the case for this patient as well. The trends in bicarbonate and platelets illustrate that this patient developed significant metabolic acidosis as well as significant thrombocytopenia in the course of his treatment.

Managing HD IL-2 Toxicities

Although HD IL-2 can result in impressive long-term responses for a subset of patients, this treatment can be difficult to tolerate and is associated with varied adverse events, including hypotension, lack of organ perfusion, fluid instabilities, and neurocognitive complications. For this reason, the appropriate labs and tests are warranted  baseline as well as throughout the treatment duration.

Managing Cytokine-Release Syndrome Associated With HD IL-2

High-dose IL-2 is associated with cytokine-release syndrome (CRS), previously known as capillary leak syndrome), which is characterized by hypotension and risk of organ failure. Much of the recent discussion of CRS in the current literature is in the context of CAR T-cell therapy.[15] There is a great deal of overlap with the physiology of CRS associated with IL‑2 and with the adoptive transfer of engineered CAR T-cells. Specifically, CRS in both is driven by IL-6, TNF, and the release of interferons, primarily interferon gamma. Management of CRS with either of these therapies can be similar.

A major consequence of CRS with IL-2 treatment is hypotension. However, based on clinical observation, the efficacy of HD IL-2 treatment is thought to be greater in patients who experience CRS. For this reason, we administer the maximum number of tolerable doses of HD IL-2 to qualifying patients with the goal of achieving a long-term response while aggressively providing supportive care measures to ensure safe treatment and address signs of toxicity.

In our clinic, patients with hypotension initially receive fluid boluses. If a patient remains hypotensive, we transition to phenylephrine, which we consider to be the best vasopressor agent for patients receiving HD IL‑2. There are fewer cardiac tachydysrhythmias with phenylephrine, which can be an issue with norepinephrine or dopamine pressure support.

Our medical oncology unit has a specially trained team of nurses who receive education on CRS and its management who help us with the patients receiving HD IL-2. This allows us to treat patients in a clinical setting where the nurses are familiar with the needs of patients with cancer. Other clinics administer HD IL-2 in an intensive care unit; certainly that provides the appropriate level of care, but we have noted better continuity of care on our unit that has the capacity for ECG, continuous blood pressure monitoring, and vasopressor administration. In addition, we established rules for the titration of phenylephrine and for when it is safe and appropriate to administer the next dose. In addition to management of hypotension, there are many other facets to consider when managing adverse events associated with HD IL-2. For example, many institutions have standing orders that relate to electrolyte repletion in patients receiving HD IL-2 including bicarbonate, calcium phosphate, and magnesium. Resources such as the 2014 consensus guidelines provide best practices for managing adverse events associated with HD IL-2.[16]

HD IL-2 in RCC: Conclusions

HD IL-2 is one of a small number of regimens with the potential for both cure and durable remission in advanced RCC, including patients with intermediate-risk or poor‑risk disease. In my experience, the probability of a “cure” with any other current regimen is low. Most patients receiving ICIs or TKI‑based therapy will have a response followed by progression. These new agents and approaches have certainly improved the lives of patients with RCC, and they are living longer, but the goal of cure or a truly durable remission remains elusive.

Therefore, HD IL‑2 should still be considered for eligible patients. In addition, HD IL-2 has been shown to have activity after disease progression on ICI therapy. However, more clarification and scientific understanding is needed to understand the optimal sequence of the many new therapies with HD IL-2. Identification of biomarkers to select an optimal regimen for individual patients would also be very helpful.

As discussed, the role of nephrectomy remains unresolved after more than 20 years of deliberation and publication, but in my opinion, it should be considered in selected patients.

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