MIAMI — The use of third-line targeted therapy is prevalent in patients with metastatic renal cell carcinoma (mRCC), and has demonstrated activity in this population. Therefore, it should be offered to clinically eligible patients, according the authors of a new study.
However, the effectiveness of third-line targeted therapy has not been well characterized in these patients, and it is not reimbursed in many jurisdictions around the world.
In Canada, for example, third-line therapy is not routinely funded by the government, explained first author Igor Stukalin, a medical student at the University of Calgary, Alberta, Canada. However, he explained, "we have the therapies and there are specific ways to get them approved."
"If a patient develops toxicity to second-line therapy, then they can move on, but if a patient simply progresses on the current therapy, the doctor has to vouch for it," he told Medscape Medical News.
"Now that we have validated the usefulness of third-line therapy, hopefully this will help access," he said.
The findings were presented during a poster session here at the 14th International Kidney Cancer Symposium.
Stukalin and his colleagues assessed the efficacy of third-line therapy in patients mRCC. They also validated the usefulness of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model — already validated in the first and second line — in the third-line setting.
The team looked at retrospective data from patients treated with first-line targeted therapy in the IMDC, which consists of patient series from 25 international cancer centers. Of those 4824 patients, 2534 (52.5%) received second-line therapy and 1060 (22%) received third-line targeted therapy.
"We looked at 1012 patients in our cohort who received third-line therapy, and we queried those patients for specific sequences within the database," Stukalin reported. "We found that third-line therapies are similar to second-line therapies in terms of frequencies. The most frequently used drug was everolimus, which was also the most frequent given in second-line treatment."
Everolimus (Afinitor, Novartis) was used in 26% of patients, sorafenib (Nexavar, Bayer and Onyx) in 12%, sunitinib (Sutent, Pfizer) in 12%, pazopanib (Votrient, Novartis) in 11%, temsirolimus (Torisel, Pfizer) in 10%, and axitinib (Inlyta, Pfizer) in 8%.
Progression-free and overall survival — the primary end points — were used to evaluate third-line therapy. "We stratified for the different drugs and there were some differences between them, but mostly that was due to the retrospective study design," he said. "Overall, the drugs were very similar."
"There was a slight difference between axitinib and temsirolimus, which could be due to the fact that temsirolimus is used primarily in poor-risk patients, and we included patients with all levels of risk," he said. "But we can see that the drug can have an effect, and there is a progression-free and overall survival benefit."
Progression-free survival was better with axitinib than with temsirolimus (5.9 vs 3.2 months), as was overall survival (19.2 vs 9.9 months). For the other drugs, progression-free and overall survival fell between those ranges.
Validation of Prognostic Model
Patients were then stratified using the IMDC prognostic criteria, such as anemia, thrombocytosis, neutrophilia, Karnofsky performance status score below 80, and time from diagnosis to first-line targeted therapy of less than 1 year. On multivariable analysis, these were found to be independent predictors of poor overall survival.
When patients were stratified as low risk (no risk factor), intermediate risk (one or two risk factors), or high risk (at least three risk factors), there were significant differences in progression-free and overall survival between the three groups.
Overall survival for third-line therapy was 29.9 months in low-risk patients (95% confidence interval [CI], 19.1 - 64.3; P < .0001), 15.5 months in intermediate-risk patients (95% CI, 13.0 - 17.7; P < .0001), and 5.5 months in high-risk patients (95% CI, 4.6 - 6.9; P < .0001).
Overall survival for third-line therapy was 7.5 months in low-risk patients (95% CI, 5.7 - 12.0; P < .0001), 4.3 months in intermediate-risk patients (95% CI, 3.5 - 5.4; P < .0001), and 2.6 months in high-risk patients (95% CI, 1.9 - 3.0; P < .0001).
On multivariable analysis, after adjustment for IMDC criteria, the difference in hazard ratio for death between the different third-line therapies was not significant.
Further studies are needed to determine appropriate sequencing, the authors note. In addition, stratifying patients by risk, according to IMDC criteria, appears to work well in the third-line setting.
14th International Kidney Cancer Symposium (IKCS). Presented November 7, 2015.