ASCO: Triple-Drug Therapy Not a Winner for Metastatic Kidney Cancer

By Crystal Phend
CHICAGO, 05 june 2008A triple-drug treatment regimen may hold little meaningful advantage over standard interferon alfa alone for treatment of metastatic renal cell carcinoma or recurrence after nephrectomy, results of two studies indicate.
Despite the fact that the combination of interleukin-2 (IL-2), interferon alfa, and fluorouracil (Adrucil) increased response rates (24% versus 16%, P=0.004) compared with interferon alfa alone, the combination failed to prevent disease progression or improve survival, results of a large randomized trial presented at the American Society of Clinical Oncology meeting showed.
This "puts the nail in the coffin of this triple combination regimen," commented Mario Sznol, M.D., of the Yale Cancer Center in New Haven, Connecticut, who was a discussant for the study.
Following promising results in several phase II studies, Martin Gore, Ph.D., of the Royal Marsden Hospital in London, and colleagues tested the regimen in one of the largest phase III studies ever done in this patient population.
Their European Organization for Research and Treatment of Cancer (EORTC) RE04 trial included 1,006 patients with metastatic kidney cancer randomized to receive single agent interferon 10 MU three times a week until progression or toxicity or a combination of interferon alfa, IL-2, and fluorouracil for two cycles.
The median age of patients was 57 and 57% were WHO performance status 0. Nearly all (90%) had undergone nephrectomy.
After a median follow-up of 27.8 months, the triple-drug regimen was associated with no improvement in progression-free survival compared with interferon alone (median 5.3 months versus 5.5, hazard ratio 1.04, P=0.56).
Nor was there an advantage to the three-drug treatment for the primary outcome of overall survival (median 18.5 months versus 18.7, HR 1.05, P=0.57).
However, for the secondary outcomes of response, the advantage was significant for combination therapy with an 8% absolute improvement (24% versus 16%, P=0.004).
Among the findings for individual best response rates, the researchers reported:
Complete response in 2% of patients in both groups.
Partial response in 22% of combination-group patients versus 14% of control-group patients.
Stable disease in 46% versus 52% of patients, respectively.
Progression in 30% of patients treated with the combination regimen versus 32% of those treated with interferon alfa alone.
Michael Aitchison, M.D., of Nuffield Hospital in Glasgow, Scotland, and colleagues also looked at the same three-drug combination.
They randomized 154 patients post-nephrectomy for renal cell carcinoma without macroscopic residual disease with stage T3b-c,T4 or any pT and pN 1 or pN 2 or positive microscopic margins or microscopic vascular invasion, and no metastases to the combination therapy or to observation alone.
Patients receiving treatment showed no real benefit for disease-free survival (HR 0.86, P=0.353) or overall survival (HR 0.91, P=0.631) in the preliminary analysis.
The researchers also found that the regimen showed significant toxicity, with 92% of the patients randomized to combination therapy reporting grade 3-4 adverse events.
"The chances that this study will meet its endpoints are low," Dr. Sznol said.
And it's not clear that an increase in response rate alone justifies an adjuvant trial in metastatic disease, he added. Better predictors of outcome are needed, Dr. Sznol said.
Furthermore, he said, "I'm a little worried about adjuvant studies even now with the agents that we have because again, if biology is important it may be just as effective and much more efficient to treat the patients when they develop metastatic disease."
Dr. Gore's group reported conflicts of interest in the form of honoraria and other renumeration from Roche and Schering-Plough as well as research support from Chiron, Roche, and Schering-Plough.
Dr. Aitchison's group reported no conflicts of interest. Dr. Sznol reported serving in a consulting or advisory role for Bristol-Myers Squibb, Medarex, Pfizer, Lpath, Eisai, and Anaeropharma.
Primary source: American Society of Clinical Oncology meetingSource reference:Gore ME, et al "Interferon-α (IFN), interleukin-2 (IL2) and 5-fluorouracil (5FU) vs IFN alone in patients with metastatic renal cell carcinoma (mRCC): Results of the randomized MRC/EORTC RE04 trial" ASCO Meeting 2008; Abstract 5039. Additional source: American Society of Clinical Oncology meetingSource reference: Aitchison M "Preliminary results from a randomized phase III trial of adjuvant interleukin-2, interferon alpha and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC)" ASCO Meeting 2008; Abstract 5040.