Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha 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.

Fig. 1

CONSORT diagram. IT immunotherapy, PD progression of disease. Asterisks indicate number of patients who received at least one cycle of maintenance immunotherapy after progression. Nine patients in arm A received maintenance after progression, thus violating the protocol, because no maintenance was scheduled in this arm. Dagger symbol indicates number of patients who did not receive at least one cycle of maintenance immunotherapy after progression. Thirty-four (47%) of the patients in arm B did not receive maintenance for various reasons: rapid disease progression, lost to follow-up, non-compliance with the protocol

Fig. 2

a Overall survival amongst 183 patients randomly assigned to suspension of immunotherapy (n = 95 thin line) or maintenance of immunotherapy (n = 88 thick line). p = 0.91 by log-rank test. b Time from first progression to death amongst the 148 patients who experienced progression to immunotherapy and randomly assigned to suspension of immunotherapy after progression (n = 78 thin line) or maintenance of immunotherapy (n = 70 thick line). p = 0.98 by log-rank test. c Overall survival amongst 53 female patients randomly assigned to suspension of immunotherapy after progression (n = 30 thin line) or maintenance of immunotherapy (n = 23 thick line). p = 0.09 by log-rank test