mTOR Inhibitors Tank in Three Advanced Kidney Cancer Trials

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.