Everolimus anti-tumour activity independent of first-line response

REPORT FROM THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) ANNUAL MEETING, CHICAGO, IL, JUNE 3-7, 2011 - A retrospective study in Germany has tried to predict the second-line anti-tumour activity of everolimus in mRCC patients according to the PFS achieved during first-line therapy (Gruenwald et al. J Clin Oncol 2011; 29(suppl): e15028; http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77905).

A total of 56 patients were included in the analysis. First-line treatment was with either sunitinib or sorafenib. Disease control, defined as either objective response or stable disease, was achieved in 82%, and progressive disease was the best response in 14%. Median PFS during first-line treatment was 10.7 months; median overall survival was 37.6 months. Thirteen patients (23%) had PFS < 6 months.

With everolimus, disease control was achieved in 60% of patients and progressive disease was seen in 35%. Median PFS was 5.5 months. In patients with PFS >6 months during first-line therapy, median OS (including everolimus) was 40 months, compared to 16.9 months in patients with PFS < 6 months. Thus, a PFS of 6 months or less during first-line treatment appeared to be associated with a poorer prognosis.

However, PFS during everolimus treatment was similar regardless of first-line treatment response. PFS with everolimus was 5.8 months in patients with PFS >6 months during first-line treatment, and 3.6 months if PFS ≤6 months. The study concluded that the anti-tumour activity of everolimus in the second-line setting is unaffected by disease response to the first-line agent.

Comment
Dr. Sebastien Hotte: The small retrospective study by Gruenwald et al. appears to show that prior benefit with first-line treatment may not necessarily translate into a higher time to disease progression from second-line therapy, which may potentially be explained by the different mechanisms of action of first- and second-line agents (VEGF vs. mTOR). However, it is also possible that the small sample size could mask a statistically significant difference given the numerical difference in median PFS of 2.4 months between patient groups. Furthermore, no mention of the overall survival estimates of each group following the start of second-line therapy is given, which would be useful to see.

Both studies by Gruenwald and Seidel et al. (see PFS with first-line therapy prognostic for OS in mRCC) give added weight to the importance of clinical response to first-line therapy and lends added credibility regarding the appropriateness of PFS as an important endpoint in metastatic renal cell cancer clinical trials. Patients who obtain clinical benefit with first-line treatment appear to achieve much better survival than those who progress quickly. Although this may be somewhat intuitive and predictable, it does stress the importance of optimizing dose and schedule to maximize therapeutic effect. Potential biomarkers of activity, such as hypertension, may play a role in achieving this goal.