Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-α for metastatic renal cell cancer

Abstract

This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD.

Dose-finding Trial of a Combined Regsimen With Bevacizumab, Immunotherapy, and Chemotherapy in Patients With Metastatic Renal Cell Cancer: An Italian Oncology Group for Clinical Research (GOIRC) Study

“…19 Recently, good activity of CT has been described by our group in patients with mRCC progressing to a regimen of low doses of IL-2+IFN-a. 10,15 To the best of our knowledge, this is the first study that has explored the toxicity, feasibility, and efficacy of the BIC combination in mRCC. The aim of combining 3 different drugs is to look for a regimen with a broader range of activity in various mRCC patients with different risk factors: low, intermediate, and high.…”

“…9 A subsequent multicenter randomized trial, including 183 mRCC patients, aimed at testing the value of maintenance with this IT regimen, confirmed its tolerability and efficacy with an RR of 13% and a stable disease (SD) of 20% with no impact of the maintenance. 10 Combinations with IL-2 and IFN-a have been administered in the outpatient setting with RRs similar to those of high-dose inpatient IL-2 regimens. 11,12 Moreover, a randomized study showed that the combination of IL-2 and IFN-a results in superior RR and event-free survival compared with either agent alone.…”

“…The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m 2 bid on days 8, 9, 15, 16, and 1 MIU/m 2 /d on days 10-12 and 17-19), and interferon-a-2a (3 MIU on days 10,12,17,19). Of the 27 enrolled patients, 59% had been pretreated.…”

Chemotherapy in metastatic renal cell carcinoma today? A systematic review

“…However, with expanded access trials, which have more numerous and fewer selected samples because of greater the inclusion and exclusion criteria, it is possible to gain insights into chemotherapy administration (mean 17% of patients, range 14-39% of patients); we have listed in Table 7 the use of chemotherapy for all expanded access trials with targeted therapies. Furthermore, interest in the use of traditional cytotoxic chemotherapy in mRCC has re-emerged because of a recent interesting finding from a phase III trial of immunotherapy with low-dose IL-2 and IFN-a until PD versus the same immunotherapy continued indefinitely beyond the progression (maintenance) [134]; indeed, the authors have reported that the use of chemotherapy (mainly gemcitabine plus 5-FU, which was allowed in both arms) after initial progression on immunotherapy was significantly associated with a longer time from first progression to death [135].…”

Delivery of interferons and siRNA targeting STAT3 using lentiviral vectors suppresses the growth of murine melanoma

“…However, the effects of IFNs in a clinical setting have not been as positive as expected. 25,26 Longer survival times resulting from treatment with IFNa are often accompanied by autoimmunity. More importantly, treatment with IFNg is not beneficial in patients with certain tumors.…”