The findings of this French phase II trial in 171 patients suggest that a combination of bevacizumab and temsirolimus cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma (RCC). The researchers aimed to test whether there was an additive or synergistic effect of combining these two agents which have different mechanisms of action. Bevacizumab acts against the VEGF receptor and temsirolimus is an mTOR inhibitor.

The study was designed as an open label, multicentre, randomised study conducted across 24 centres in France. Participants consisted of patients aged 18 years or over with untreated metastatic RCC. Patients were randomised to one of three treatment groups (2:1:1) with randomisation being carried out centrally and independently through computer-generated permuted blocks of four and eight patients stratified by participating centre and the Eastern Cooperative Oncology Group (ECOG) performance status.  They were randomised to the following groups:

(A) received the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; n= 88)

or one of the following standard treatments

(B) received sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; n=42)

(C) received a combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; n= 41)

The primary endpoint measure considered in this study was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis of the results was carried out on an intention to treat basis. The results found (direct from source):

• PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C.

• Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C.

• 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C.

• Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C.

• Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively.

The researchers conclude, “The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic RCC.”

The study is ongoing for long-term overall survival.

The author of a related Comment article discusses this study and notes that the finding is important because “it shows that combination therapy is toxic and might not necessarily lead to better responses or survival.” He writes, “Unless combination therapy can show a clinically important benefit, such as a substantial complete response rate or prolonged overall survival, sequential therapy will remain the standard of care.”

Please note: only the abstract of this study was available to the news team at time of writing.