The combination of temsirolimus (Torisel) plus bevacizumab (Avastin) was not superior to interferon plus bevacizumab as first-line therapy for patients with clear cell metastatic renal cell carcinoma (mRCC), according to results from the phase IIIb INTORACT study presented at the 2012 ESMO Congress. The interferon/bevacizumab arm achieved longer duration of response and longer progression- free survival (PFS). The two combinations had distinct side effect profiles.

“Interferon/bevacizumab remains a treatment option in mRCC, but other combination therapies [such as temsirolimus/ bevacizumab] remain investigational,” said lead author Brian Rini, MD, Cleveland Clinic Taussig Cancer Institute, Ohio.

Combination therapy with bevacizumab plus interferon is FDA-approved in the frontline setting in patients with mRCC. The mTOR-inhibitor temsirolimus is FDA-approved as single-agent therapy in patients with advanced RCC. The INTORACT study was undertaken based on initial positive data with the temsirolimus/ bevacizumab combination.

The trial enrolled 791 patients with previously untreated advanced mRCC stratified according to risk and nephrectomy status. Patients were randomized 1:1 to bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) plus either temsirolimus (25 mg IV weekly) or interferon (9 MU subcutaneously three times weekly). Treatment was administered until progressive disease or unacceptable toxicity.

During the treatment phase, patients were assessed monthly by a clinician and every 8 weeks with radiographic assessment. All patients had a bone scan at baseline; repeat bone scan was performed if there were signs or symptoms of bone metastases. Following treatment, survival status was assessed every 8 weeks.

The mean patient age was 58 years. About 70% were male, 83% were Caucasian, 13% were Asian, and 4% were “other.” Eighty-five percent had prior nephrectomy. About 93% were good or intermediate risk according to MSKCC criteria

Median PFS was 9.3 months with interferon/ bevacizumab versus 9.1 months with temsirolimus/ bevacizumab (hazard ratio [HR] = 1.07; 95% CI, 0.89- 1.28; P = .759). A subset analysis further showed that in patients in the interferon/bevacizumab arm with prior nephrectomy, PFS was 10.9 months versus 6.8 months for those with no prior nephrectomy.

Median overall survival was similar in both arms at 25.8 months with temsirolimus/bevacizumab versus 25.5 months with interferon/bevacizumab (HR = 1.04; (95% CI, 0.85-1.26; P = .638).

Using RECIST, response rates greater than 25% were seen in both treatment arms. Median duration of response was longer with the interferon combination than with the temsirolimus combination at 17 months versus 11 months respectively.

Safety data were consistent with known profiles of these agents. Grade 3 or higher mucosal inflammation, stomatitis, hyperglycemia, hypophosphatemia, and hypercholesterolemia were more common with temsirolimus/bevacizumab (P <.001). A lowerthan- expected 1% rate of grade 3 pneumonitis was observed in the temsirolimus arm. Grade 3 or higher neutropenia was more common in the interferon arm versus the temsirolimus arm at 8% versus 2%, respectively (P <.001).

---