No Difference in PFS for Temsirolimus vs Sorafenib as Second-Line Therapy After Sunitinib in Metastatic RCC
In the phase III INTORSECT trial reported in the Journal of Clinical Oncology, Hutson et al compared temsirolimus (Torisel) vs sorafenib (Nexavar) as second-line treatment in patients with metastatic renal cell carcinoma after progression on sunitinib (Sutent). There was no significant difference between treatments in progression-free survival, the primary endpoint, but a benefit in overall survival was observed for sorafenib.
Study Details
In this open-label international trial, 512 patients with disease progression on first-line sunitinib were randomly assigned to receive intravenous temsirolimus at 25 mg once weekly (n = 259) or oral sorafenib at 400 mg twice daily (n = 253). Randomization was stratified by duration of prior sunitinib therapy, Memorial Sloan-Kettering Cancer Center prognostic group, histology, and nephrectomy status.
The temsirolimus and sorafenib groups were well matched for age (median, 60 and 61 years), sex (75% and 76% male), race (69% and 64% white), Eastern Cooperative Oncology Group performance status (0 in 40% and 45%, 1 in 58% and 55%), nephrectomy (86% and 87%), histology (clear cell in 83% and 82%), Memorial Sloan-Kettering Cancer Center prognostic group (69% and 70% intermediate, 12% and 13% poor), and duration of prior sunitinib (> 180 days in 63% and 64%).
No Difference in Progression-Free Survival
Median follow-up was 9.2 months. Median progression-free survival was 4.3 months in the temsirolimus group vs 3.9 months in the sorafenib group (stratified hazard ratio [HR] = 0.87, P =.19). There were no significant differences in progression-free survival between groups in subgroup analysis according to stratification factors. The objective response rate was 8% in both groups.
Overall Survival Differences
Median overall survival was 12.3 months in the temsirolimus group vs 16.6 months in the sorafenib group (stratified HR = 1.31, P = .01). Exploratory subgroup analyses of prespecified factors indicate a significant survival benefit for sorafenib according to prior nephrectomy (HR = 1.45, P = .002), longer duration of prior sunitinib (HR = 1.37, P = .02), clear cell histology (HR = 1.34, P = .01), and Memorial Sloan-Kettering Cancer Center intermediate risk (HR = 1.50, P = .002).
Median overall survival was 17.8 months in the sorafenib group vs 14.4 months in the temsirolimus group among patients receiving > 180 days of prior sunitinib and 11.4 vs 10.1 months in those receiving a shorter duration of sunitinib. The survival benefit in favor of sorafenib was also significant for age < 65 years (P = .0005), male sex (P = .02), and normal hepatic function (P = .007), but not geographic region or racial subgroups.
In a post hoc exploratory analysis, overall survival was significantly greater with sorafenib in patients with normal baseline lactate dehydrogenase (18.7 vs 16.0 months, HR = 1.39, P = .01), but not in those with high lactate dehydrogenase (7.8 vs 8.9 months, HR = 1.05, P = .78).
Safety Profiles
Adverse events of any grade that were > 10% more common in the temsirolimus group included cough (35% vs 23%), anemia (34% vs 14%), and mucosal inflammation (30% vs 14%), and those that were > 10% more common in the sorafenib group included diarrhea (63% vs 31%), palmar-plantar erythrodysesthesia (52% vs 4%), and alopecia (31% vs 2%).
Adverse events of grade 3 or higher occurred in 70% of temsirolimus patients vs 69% of sorafenib patients, and serious adverse events occurred in 41% vs 34% (most commonly, and with similar incidence in both groups, general physical health deterioration, dyspnea, pneumonia, and pleural effusion). Grade 3 or higher adverse events that were > 5% more common with temsirolimus were anemia (9% vs 3%) and hyperglycemia (8% vs 2%); palmar-plantar erythrodysesthesia was more common with sorafenib (15% vs 0). Fatal adverse events occurred in 8% of patients in each group, with 3 deaths considered related to temsirolimus and 2 to sorafenib.
Adverse events resulted in dose reductions in 16% of temsirolimus patients (most common, pneumonitis in 2%) and 33% of sorafenib patients (most common, palmar-plantar erythrodysesthesia in 14%) and dose interruptions in 69% and 63%. The only adverse events leading to study drug discontinuation in more than one patient were palmar-plantar erythrodysesthesia (n = 4) and pneumonia, pain in extremity, and rash (n = 3 each) in the sorafenib group.
The investigators concluded: “[T]emsirolimus did not demonstrate an efficacy advantage compared with sorafenib as second-line therapy after disease progression on sunitinib in patients with [metastatic renal cell carcinoma]. Each drug has a differentiated safety profile, consistent with its class and targeting profile. The longer [overall survival] with sorafenib is consistent with the hypothesis that sequenced VEGFR inhibition results in improvement in [overall survival] in patients with [metastatic renal cell carcinoma].”
Thomas E. Hutson, DO, PharmD, of Baylor Sammons Cancer Center-Texas Oncology, is the corresponding author of the Journal of Clinical Oncology article.
The study was supported by Wyeth Research, which is owned by Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
