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Aldesleukin (Recombinant Interleukin-2)

A Review of its Pharmacological Properties, Clinical Efficacy and Tolerability in Patients with Metastatic Melanoma

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Abstract

Synopsis

Aldesleukin [recombinant interleukin-2 (IL-2)] is a biological response modifier which, like endogenous IL-2, has a range of immunomodulatory properties. Although aldesleukin is currently approved only for treatment of renal cell carcinoma, it has been widely used in patients with metastatic melanoma and has been assessed in numerous noncomparative trials in this indication. Durable complete responses have been reported in a small proportion of patients with good performance status who received immunotherapy or chemoimmunotherapy involving aldesleukin in several clinical trials. Overall median survival times of about 10 or 11 months are typical. Combination chemoimmunotherapy involving aldesleukin has produced relatively high response rates (up to 56%), but these are not predictive of increased survival time. Aldesleukin has not been directly compared with standard chemotherapy in randomised studies.

The use of continuous intravenous infusion and subcutaneous administration of aldesleukin, together with improved patient selection, has successfully reduced the severity of adverse events produced by the drug (the original intravenous bolus regimen is particularly toxic and often necessitates admission to an intensive care unit). However, the risk/benefit profile of aldesleukin in the treatment of melanoma requires further study, particularly after subcutaneous administration.

Thus, aldesleukin has shown modest efficacy in the treatment of metastatic melanoma. Although aldesleukin-containing regimens have produced promising results in many noncomparative trials, their clinical value in comparison with standard chemotherapy remains to be determined in phase HI studies. Until results from such trials are available, clinicians will need to carefully balance the potential benefits of the drug against the risks and likely quality-of-life implications associated with its toxicity in each patient. Current investigations centre on the use of aldesleukin as part of complex biochemotherapy regimens, and results from these trials are awaited with interest.

Pharmacodynamic Properties

Interleukin-2 (IL-2) is a cytokine which plays an important role in both cytotoxic and humoral immune responses. Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. The results of this immunomodulatory activity are most evident as activation and/or proliferation of T lymphocytes, cytotoxic natural killer (NK) cells and lymphokine-activated killer (LAK) cells, and induction of cytokine production and eosinophilia.

The relationship between the immunomodulatory effects of aldesleukin and clinical outcome has yet to be fully characterised. Nevertheless, clinical response associated with T cell activation, increased LAK cell cytotoxicity or increased activation of NK cells has been documented in patients with melanoma. The precise mechanism of action of aldesleukin with respect to antitumour response in patients with metastatic melanoma remains unclear; some melanoma cell lines express the IL-2 receptor and thus may be subject to direct interactions with aldesleukin. Immunotherapy with aldesleukin and interferon-α (IFNα) may either induce or augment strong oligoclonal T cell selection, leading to tumour regression.

Pharmacokinetic Properties

Aldesleukin is rapidly distributed to intravascular and extracellular spaces, with a half-life of 6 to 20 minutes, after intravenous bolus administration in patients with cancer. A slower elimination phase is evident, with a half-life of about 60 to 85 minutes. Serum concentrations are linearly proportional to dose after intravenous aldesleukin administration. The pharmacokinetics of aldesleukin during continuous infusion are similar to those after bolus administration. Subcutaneous administration of aldesleukin produces serum concentrations which are about 2% of those seen with intravenous delivery; peak concentrations were obtained 2 to 6 hours after subcutaneous administration.

Distribution of aldesleukin to body tissues may vary depending on the route of administration and drug formulation. Aldesleukin is metabolised and eliminated via the kidneys, with little or none of the active molecule found in urine. The pharmacokinetic properties of aldesleukin may change during its administration, as a result of some of its pharmacodynamic properties.

Clinical Efficacy

Monotherapy with high-dose bolus aldesleukin produced objective antitumour responses in 10 to 31% of patients with metastatic melanoma in clinical trials. The largest single study of aldesleukin monotherapy produced complete responses in 7% of 134 patients with melanoma, and these responses were maintained for >9 to >91 months. More than half of those with a complete response were still alive after 2 years. The estimated actuarial 3-year and 5-year survival rates for patients in this trial were 22 and 11%.

Combination immunotherapy with aldesleukin and IFNα produced objective responses in 18 to 41% of patients with melanoma (2 to 11% for complete response). The highest response rates were obtained in patients who received an initial high-dose infusion of aldesleukin which was then quickly tapered to maintenance levels; 41% of these patients had objective response (11% were complete responses) and median response duration was >11 months.

Aldesleukin has been combined with a number of single-agent chemotherapy regimens: objective and complete response rates were 4 to 25% and 0 to 5% in combination with cyclophosphamide, 16 to 26% and 2 to 11 % in combination with dacarbazine, and 17 or 37% and 6 or 11% in combination with cisplatin. Addition of IFNα to aldesleukin plus either dacarbazine or cisplatin produced objective and complete response rates of 26 to 54% and 4 to 13%. More complex chemoimmunotherapy regimens (most commonly involving aldesleukin, 2 or more chemotherapeutic drugs and, in some cases, IFNα) produced objective and complete response rates of 35 to 56% and 0 to 16%.

In general, complete responses for aldesleukin-containing regimens were more durable than those seen with dacarbazine, the standard treatment option in this indication, in previous studies (typically ≈9 months to 2 or 3 years vs ≈4 to 6 months), although there are no appropriate prospective comparisons.

Despite a >3-fold difference in objective response rates and a 12-fold difference for complete response rates across a range of clinical trials of aldesleukin, overall median survival times were relatively constant (10 or 11 months in most studies, range ≈9 to 13 months). However, this compares favourably with a typical survival duration of 6 to 9 months for patients with metastatic melanoma (many of whom would have received chemotherapy). A median survival time of 33 (range 13 to >36) months was reported for patients who experienced a complete response (16% of all patients) during treatment with aldesleukin, dacarbazine and cisplatin in one study.

Tolerability

Aldesleukin may be associated with a wide range of clinical adverse events, including cardiopulmonary, renal, hepatic, gastrointestinal, CNS, haematological, endocrine and constitutional effects. The precise profile and severity of events varies with total dose, dose frequency and duration and route of administration. In general, intravenous bolus administration is the most toxic route, while subcutaneous delivery produces the least severe adverse events.

The most common adverse events in clinical trials of aldesleukin (monotherapy or in combination with other treatments, administered by bolus, continuous infusion or subcutaneously) in patients with metastatic melanoma were hypotension, flu-like symptoms, nausea, vomiting, diarrhoea, nephrotoxicity and haematological abnormalities (most commonly thrombocytopenia and neutropenia); grade 4 toxicity was evident in up to a quarter of all patients or treatment courses. Transient and generally nonsevere dermatological reactions (other than injection site events) occur in many patients receiving aldesleukin.

Most recent trials used continuous infusion or subcutaneous delivery; data from patients with a range of malignancies (predominantly renal cell carcinoma) indicate that subcutaneous administration can significantly reduce the severity of aldesleukin toxicity with no apparent loss of antitumour efficacy/Continuous infusion generally produced moderate and manageable toxicity in patients with melanoma. Subcutaneous administration of aldesleukin was associated with mild to moderate adverse events and was generally considered to be ‘well tolerated’ (there was no severe hypotension or oedema caused by capillary leak syndrome). Flu-like symptoms and injection-site events (e.g. transient local inflammation and/or induration) were common with subcutaneous administration.

Dosage and Administration

Aldesleukin is currently approved only for treatment of renal cell carcinoma, but has been widely used in the treatment of melanoma. The original high-dose bolus regimen (based on 6 × 105 IU/kg as a 15-minute intravenous infusion every 8 hours) was initially approved in the US, whereas continuous intravenous infusion (treatment cycle based on 18 × 106 IU/m2 for 5 days) was approved in Europe. In practice, however, lower dose continuous infusion and subcutaneous regimens are most commonly used. Aldesleukin recipients should have a good general performance status (with the exception of their metastatic disease) and should have no significant cardiac, pulmonary, hepatic, renal or CNS impairment (although patients with controlled brain metastases are routinely treated). They should be monitored carefully for toxicity, particularly haematological, cardiac and respiratory adverse events; many aldesleukin-induced adverse events can be managed with routine treatments and interventions. Concurrent treatment with cardiotoxic, myelotoxic, hepatotoxic, nephrotoxic or psychotropic agents may potentiate the toxic effects of aldesleukin. Aldesleukin should be withdrawn (not reduced in dosage) in the event of serious adverse events. Aldesleukin has been used successfully as part of home therapy (self-injection by the patient) in patients with melanoma. Formal dosage or treatment guidelines for subcutaneous administration are not available.

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    Stuart Noble & Karen L. Goa

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Various sections of the manuscript reviewed by: L. Bergmann, Medizinische Klinik III, Universitätsklinik, Frankfurt, Germany; R.O. Dillman, Hoag Cancer Center, Hoag Hospital, Newport Beach, California, USA; R. Dummer, Department of Dermatology, University of Zurich Medical School, Zurich, Switzerland; M. Green, Department of Clinical Haematology and Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; U. Keilholz, Medizinische Klinik und Poliklinik V, Hämatologie, Onkologie und Rheumatologie, Universität Heidelberg, Heidelberg, Germany; D. Khayat, Department of Medical Oncology, Salpêtrière Hospital, Paris, France; S.S. Legha, Department of Melanoma/Sarcoma, Medical Oncology, MD Anderson Cancer Center, Texas Medical Center, Houston, Texas, USA; G. Semenzato, Dipartimento di Medicina Clinica e Sperimentale, Università Degli Studi di Padova, Padua, Italy; L.T. Vlasveld, Department of Internal Medicine, Diaconessenhuls, Eindhoven, The Netherlands; R.P. Whitehead, School of Medicine/Department of Internal Medicine, Texas University Health Sciences Center, Lubbock, Texas, USA.

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Noble, S., Goa, K.L. Aldesleukin (Recombinant Interleukin-2). BioDrugs 7, 394–422 (1997). https://doi.org/10.2165/00063030-199707050-00007

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