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Lenalidomide Worsens Survival in Advanced Prostate Cancer
VIENNA – Lenalidomide failed to increase overall survival above what was achieved with docetaxel plus prednisone in a phase III trial, leading to doubts that it has any potential value in the treatment of advanced prostate cancer.
Results from the halted MAINSAIL study, showed that median overall survival for men with metastatic castration-resistant prostate cancer (mCRPC) was significantly less for those given lenalidomide (Revlimid) in addition to docetaxel (Taxotere) plus prednisone (hazard ratio, 1.53; P = .0017).
The median was 19.5 months in the patients who received the additional lenalidomide, but has not been reached in the control chemotherapy arm.
"The addition of lenalidomide to docetaxel and prednisone in patients with castration-resistant prostate cancer did not improve overall survival," said study investigator Dr. Daniel Petrylak, leader of prostate medical oncology at Yale Cancer Center in New Haven, Conn.
"Thus docetaxel q3w remains the standard of care for cytotoxic therapy for castration-resistant disease," Dr. Petrylak added at the European Society for Medical Oncology Congress.
Although follow-up is ongoing, the study’s sponsors, Celgene, announced last November that the trial would be stopped following the advice of the study’s data monitoring committee that the results were unlikely to prove positive.
Lenalidomide, a derivative of thalidomide, has antiangiogenic and immunomodulatory effects. It is approved for use in the management of multiple myeloma and myelodysplastic syndromes (MDS) in the United States. Early clinical data suggested that it might have antitumor activity in men with CRPC when used as a single agent and when used in combination with docetaxel and prednisone. The MAINSAIL findings do not support this hypothesis.
The trial involved 1,059 men with mCRPC who had received no recent (up to 3 years) chemotherapy. They were randomized to receive 21-day cycles of docetaxel (75 mg/m2 on day 1), prednisone (5 mg twice daily on days 1-21) with (n = 533) or without (n = 526) lenalidomide. Treatment was until progression, with the survival end points assessed every 3 months for up to 5 years after treatment discontinuation.
The median age of patients in the lenalidomide-containing and lenalidomide-free arms was 69.6 years and 68.6 years, respectively. Baseline characteristics were well balanced. The median number of cycles received was six in the lenalidomide-containing and eight in the lenalidomide-free arms, respectively.
The secondary end point of progression-free survival (PFS) also showed no added benefit of lenalidomide. The median was 45 weeks in the lenalidomide-containing arm vs. 46 weeks in the control arm (HR, 1.32; P = .0187). Overall response rates were similar in patients with a confirmed prostate-specific antigen response.
"The three-drug regimen was associated with greater toxicity than [was] a two-drug regimen in this patient population," Dr. Petrylak said. Indeed, there was significantly more neutropenia (21.7% vs. 16.3%), febrile neutropenia (11.8% vs. 4.6%), diarrhea (7% vs. 2.3%), and pulmonary embolism (6.5% vs.1.5%) reported in the experimental arm vs. the control group.
The lack of effect on overall survival might be related to a number of factors, Dr. Petrylak suggested. "It may be attributed to shorter treatment duration, lower dose–intensity docetaxel, and earlier treatment discontinuation," he noted.
"Pharmacokinetic interactions could not be ruled out and further analysis is underway to elucidate the observed results in the lenalidomide arm," added Dr. Petrylak.
The study was funded by Celgene Corporation, the manufacturers of Revlimid. Dr. Petrylak disclosed receiving research funding and being an advisor for Celgene and Sanofi-Aventis.
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Sara Freeman/IMNG Medical Media
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The negative overall survival result had direct consequences for the patients who took part in the experimental arm of this study as their care was compromised as a result. This was a large study of more than 1,000 patients, and it’s important to mention that by being in this trial, these patients were lost to other trials that were taking place at this time with perhaps more active agents. I think it is reasonable to conclude that whatever the cause for the detrimental effect on overall survival that there is probably no future for lenalidomide in prostate cancer, in any context.
Dr. Robert Jones is senior lecturer and honorary consultant in medical oncology at the University of Glasgow in Scotland. Dr. Jones has acted as a consultant and received honoraria or research funding from Astellas, AstraZeneca, Dendreon, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, and Sanofi-Aventis.
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Sara Freeman/IMNG Medical Media
|
The negative overall survival result had direct consequences for the patients who took part in the experimental arm of this study as their care was compromised as a result. This was a large study of more than 1,000 patients, and it’s important to mention that by being in this trial, these patients were lost to other trials that were taking place at this time with perhaps more active agents. I think it is reasonable to conclude that whatever the cause for the detrimental effect on overall survival that there is probably no future for lenalidomide in prostate cancer, in any context.
Dr. Robert Jones is senior lecturer and honorary consultant in medical oncology at the University of Glasgow in Scotland. Dr. Jones has acted as a consultant and received honoraria or research funding from Astellas, AstraZeneca, Dendreon, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, and Sanofi-Aventis.
|
Sara Freeman/IMNG Medical Media
|
The negative overall survival result had direct consequences for the patients who took part in the experimental arm of this study as their care was compromised as a result. This was a large study of more than 1,000 patients, and it’s important to mention that by being in this trial, these patients were lost to other trials that were taking place at this time with perhaps more active agents. I think it is reasonable to conclude that whatever the cause for the detrimental effect on overall survival that there is probably no future for lenalidomide in prostate cancer, in any context.
Dr. Robert Jones is senior lecturer and honorary consultant in medical oncology at the University of Glasgow in Scotland. Dr. Jones has acted as a consultant and received honoraria or research funding from Astellas, AstraZeneca, Dendreon, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, and Sanofi-Aventis.
VIENNA – Lenalidomide failed to increase overall survival above what was achieved with docetaxel plus prednisone in a phase III trial, leading to doubts that it has any potential value in the treatment of advanced prostate cancer.
Results from the halted MAINSAIL study, showed that median overall survival for men with metastatic castration-resistant prostate cancer (mCRPC) was significantly less for those given lenalidomide (Revlimid) in addition to docetaxel (Taxotere) plus prednisone (hazard ratio, 1.53; P = .0017).
The median was 19.5 months in the patients who received the additional lenalidomide, but has not been reached in the control chemotherapy arm.
"The addition of lenalidomide to docetaxel and prednisone in patients with castration-resistant prostate cancer did not improve overall survival," said study investigator Dr. Daniel Petrylak, leader of prostate medical oncology at Yale Cancer Center in New Haven, Conn.
"Thus docetaxel q3w remains the standard of care for cytotoxic therapy for castration-resistant disease," Dr. Petrylak added at the European Society for Medical Oncology Congress.
Although follow-up is ongoing, the study’s sponsors, Celgene, announced last November that the trial would be stopped following the advice of the study’s data monitoring committee that the results were unlikely to prove positive.
Lenalidomide, a derivative of thalidomide, has antiangiogenic and immunomodulatory effects. It is approved for use in the management of multiple myeloma and myelodysplastic syndromes (MDS) in the United States. Early clinical data suggested that it might have antitumor activity in men with CRPC when used as a single agent and when used in combination with docetaxel and prednisone. The MAINSAIL findings do not support this hypothesis.
The trial involved 1,059 men with mCRPC who had received no recent (up to 3 years) chemotherapy. They were randomized to receive 21-day cycles of docetaxel (75 mg/m2 on day 1), prednisone (5 mg twice daily on days 1-21) with (n = 533) or without (n = 526) lenalidomide. Treatment was until progression, with the survival end points assessed every 3 months for up to 5 years after treatment discontinuation.
The median age of patients in the lenalidomide-containing and lenalidomide-free arms was 69.6 years and 68.6 years, respectively. Baseline characteristics were well balanced. The median number of cycles received was six in the lenalidomide-containing and eight in the lenalidomide-free arms, respectively.
The secondary end point of progression-free survival (PFS) also showed no added benefit of lenalidomide. The median was 45 weeks in the lenalidomide-containing arm vs. 46 weeks in the control arm (HR, 1.32; P = .0187). Overall response rates were similar in patients with a confirmed prostate-specific antigen response.
"The three-drug regimen was associated with greater toxicity than [was] a two-drug regimen in this patient population," Dr. Petrylak said. Indeed, there was significantly more neutropenia (21.7% vs. 16.3%), febrile neutropenia (11.8% vs. 4.6%), diarrhea (7% vs. 2.3%), and pulmonary embolism (6.5% vs.1.5%) reported in the experimental arm vs. the control group.
The lack of effect on overall survival might be related to a number of factors, Dr. Petrylak suggested. "It may be attributed to shorter treatment duration, lower dose–intensity docetaxel, and earlier treatment discontinuation," he noted.
"Pharmacokinetic interactions could not be ruled out and further analysis is underway to elucidate the observed results in the lenalidomide arm," added Dr. Petrylak.
The study was funded by Celgene Corporation, the manufacturers of Revlimid. Dr. Petrylak disclosed receiving research funding and being an advisor for Celgene and Sanofi-Aventis.
VIENNA – Lenalidomide failed to increase overall survival above what was achieved with docetaxel plus prednisone in a phase III trial, leading to doubts that it has any potential value in the treatment of advanced prostate cancer.
Results from the halted MAINSAIL study, showed that median overall survival for men with metastatic castration-resistant prostate cancer (mCRPC) was significantly less for those given lenalidomide (Revlimid) in addition to docetaxel (Taxotere) plus prednisone (hazard ratio, 1.53; P = .0017).
The median was 19.5 months in the patients who received the additional lenalidomide, but has not been reached in the control chemotherapy arm.
"The addition of lenalidomide to docetaxel and prednisone in patients with castration-resistant prostate cancer did not improve overall survival," said study investigator Dr. Daniel Petrylak, leader of prostate medical oncology at Yale Cancer Center in New Haven, Conn.
"Thus docetaxel q3w remains the standard of care for cytotoxic therapy for castration-resistant disease," Dr. Petrylak added at the European Society for Medical Oncology Congress.
Although follow-up is ongoing, the study’s sponsors, Celgene, announced last November that the trial would be stopped following the advice of the study’s data monitoring committee that the results were unlikely to prove positive.
Lenalidomide, a derivative of thalidomide, has antiangiogenic and immunomodulatory effects. It is approved for use in the management of multiple myeloma and myelodysplastic syndromes (MDS) in the United States. Early clinical data suggested that it might have antitumor activity in men with CRPC when used as a single agent and when used in combination with docetaxel and prednisone. The MAINSAIL findings do not support this hypothesis.
The trial involved 1,059 men with mCRPC who had received no recent (up to 3 years) chemotherapy. They were randomized to receive 21-day cycles of docetaxel (75 mg/m2 on day 1), prednisone (5 mg twice daily on days 1-21) with (n = 533) or without (n = 526) lenalidomide. Treatment was until progression, with the survival end points assessed every 3 months for up to 5 years after treatment discontinuation.
The median age of patients in the lenalidomide-containing and lenalidomide-free arms was 69.6 years and 68.6 years, respectively. Baseline characteristics were well balanced. The median number of cycles received was six in the lenalidomide-containing and eight in the lenalidomide-free arms, respectively.
The secondary end point of progression-free survival (PFS) also showed no added benefit of lenalidomide. The median was 45 weeks in the lenalidomide-containing arm vs. 46 weeks in the control arm (HR, 1.32; P = .0187). Overall response rates were similar in patients with a confirmed prostate-specific antigen response.
"The three-drug regimen was associated with greater toxicity than [was] a two-drug regimen in this patient population," Dr. Petrylak said. Indeed, there was significantly more neutropenia (21.7% vs. 16.3%), febrile neutropenia (11.8% vs. 4.6%), diarrhea (7% vs. 2.3%), and pulmonary embolism (6.5% vs.1.5%) reported in the experimental arm vs. the control group.
The lack of effect on overall survival might be related to a number of factors, Dr. Petrylak suggested. "It may be attributed to shorter treatment duration, lower dose–intensity docetaxel, and earlier treatment discontinuation," he noted.
"Pharmacokinetic interactions could not be ruled out and further analysis is underway to elucidate the observed results in the lenalidomide arm," added Dr. Petrylak.
The study was funded by Celgene Corporation, the manufacturers of Revlimid. Dr. Petrylak disclosed receiving research funding and being an advisor for Celgene and Sanofi-Aventis.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Median overall survival was 19.5 months in patient given lenalidomide plus docetaxel and prednisone but was not reached in the docetaxel plus prednisone control arm (HR, 1.53; P = .0017) after up to 5 years’ follow up.
Data Source: Results were taken from MAINSAIL, a phase III trial, randomized 1,059 men with metastatic castration-resistant prostate cancer to receive docetaxel plus prednisone with or without lenalidomide every 3 weeks.
Disclosures: The study was funded by Celgene Corporation, the manufacturer of Revlimid. Dr. Petrylak disclosed receiving research funding and being an adviser for Celgene and Sanofi-Aventis.
Abiraterone and Enzalutamide Thwart Prostate Cancer Pain
VIENNA – Two recently approved drugs – abiraterone acetate and enzalutamide – led to better pain control in reports from separate clinical trials conducted among men with metastatic castration-resistant prostate cancer.
Abiraterone (Zytiga) reduced opiate use by 19%, the average pain intensity score by 19%, and the impact of pain on daily lives by 21% for chemotherapy-naive patients, according to new data from the phase III COU-AA-302 study.
Hazard ratios favoring abiraterone were 0.817 for the median time to opiate use, 0.817 for the average pain intensity, 0.792 for pain interference, and 0.845 for worst pain intensity. Abiraterone was given in combination with prednisone during the trial and compared with placebo plus prednisone.
New data from the AFFIRM trial show that enzalutamide (MDV3100, Xtandi) had a beneficial impact on cancer-related pain in men with previously treated metastatic castrate-resistant prostate cancer (mCRPC). Notably, investigators reported a 44% reduction in pain progression vs. placebo (HR, 0.564; P less than .0001).
These findings from both trials were presented at the European Society for Medical Oncology (ESMO) congress. In the United States, the Food and Drug Administration has approved both androgen-signaling inhibitors for second-line treatment of mCRPC after docetaxel (Taxotere) therapy has failed – abiraterone in April 2011 and enzalutamide in August 2012.
Abiraterone: New Data From the COU-AA-302 Trial
"Pain is an important, often feared, and debilitating complication of metastatic, castration-resistant prostate cancer, which can affect up to half of men with metastatic disease," said Dr. Ethan Basch, who presented the COU-AA-302 patient-reported outcome data.
"Understanding the impact of abiraterone and other agents on pain provides valuable information for decision makers," Dr. Basch, of Memorial Sloan-Kettering Cancer Center in New York, added.
Abiraterone’s pain-reducing effects add to benefits reported at American Society of Clinical Oncology (ASCO) annual meeting earlier in the year, where the results of the second planned interim analysis showed it significantly delayed progression and the initiation of chemotherapy in the targeted population.
Trial participants were chemotherapy-naive men with asymptomatic or mildly symptomatic, mCRPC; 546 were randomized to treatment with abiraterone plus prednisone and 542 to placebo plus prednisone. The median treatment duration in each arm was 13.8 months and 8.3 months, respectively.
Patient pain and functional status was assessed using a variety of measures, including the Brief Pain Inventory–Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaires.
The median time to opiate use was not reached in the abiraterone arm vs. 23.7 months in the placebo arm (P = .0001). The median time to progression of average pain intensity was 26.7 months and 18.4 months, respectively (P = .0049). Similar benefits were seen in median time to progression of pain interference (10.3 vs. 7.4 months; P = .005) and worst pain intensity (26.7 vs. 19.4 months; P = .109). The latter only became significant, however, after a post hoc sensitivity analysis was performed (P = .045).
The median time to functional status degradation – assessed using the FACT-P total score – was more than 4 months longer in the abiraterone arm than in the control arm (12.7 vs. 8.3 months; P = .003).
Enzalutamide: AFFIRM Trial Also Gives New Data
Pain-reducing benefits were also seen with enzalutamide vs. placebo in the phase III AFFIRM study. The trial involved 1,199 men with progressive disease who had been previously treated with docetaxel (Taxotere). It randomized 800 to enzalutamide and 399 to placebo. Investigators previously reported that median overall survival was 18.4 months with enzalutamide vs. 13.6 months with placebo (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).
"This was a typical population of patients with advanced prostate cancer," said Dr. Karim Fizazi of the Institut Gustave-Roussy in Paris.
The median age was 69 years, around 28% had a mean pain score of 4 or higher, 91% had bone disease, 21%-25% had disease that had progressed to the liver, and about half had received three or more lines of prior hormonal treatment, and 26%-28% two or more regimens of chemotherapy. Bisphosphonates were used by 43% of patients.
Enzalutamide reduced the time to a first skeletal event by 31% (HR, 0.688, P = .0001), compared with placebo. The median time to the first skeletal event was 16.7 months and 13.3 months, respectively.
Radiation to the bone was the first skeletal event in around one-fifth of patients, with fewer patients experiencing spinal cord compression, clinically apparent pathological bone fracture, a change in antineoplastic therapy, or surgery to the bone
Three pain assessments were used – the BPI-SF, the FACT-P, and a pain diary. Pain palliation was reported in 45% of enzalutamide-treated patients vs. 7% of those on placebo (P = .0079).
"Enzalutamide had a significant impact on all quality of life domains, which was also significant," Dr. Fizazi reported.
Implications for Practice
Dr. Eleni Efstathiou, who was not involved in either trial, put the findings into context.
"Abiraterone acetate is a good drug that, beyond a survival benefit, dose delay pain progression, opiate use, and functional decline even in an asymptomatic, oligosymptomatic, chemotherapy-naive disease setting," said Dr. Efstathiou of the University of Texas M.D. Anderson Cancer Center in Houston.
She added the following caveat: "Severe clinical symptoms may not be reduced proportionally to the effect observed in this patient population."
The AFFIRM data represent the first report of quality of life measures and pain amelioration for enzalutamide, Dr. Efstathiou observed. While provision was made in the study design to assess these as planned secondary outcomes, as with the COU-AA-302 data, the study was not powered to demonstrate their statistical significance.
"Androgen-signaling inhibition does not only prolong life, but also ameliorates bone metastases-associated symptoms in men with metastatic castrate-resistant prostate cancer," Dr. Efstathiou concluded. "However, we cannot claim victory given that severe clinical events may remain unaltered and the reported benefit in this advanced setting, of both trials, is still short lived."
Ortho Biotech Oncology Research & Development sponsored the COU-AA-302 study. AFFIRM was supported by Medivation and Astellas Pharma. Dr. Fizazi has participated in advisory boards for Medivation and Astellas Pharma. Dr. Basch reported no conflicts of interest in relation to the COU-AA-302 study. Dr. Efstathiou had no disclosures.
VIENNA – Two recently approved drugs – abiraterone acetate and enzalutamide – led to better pain control in reports from separate clinical trials conducted among men with metastatic castration-resistant prostate cancer.
Abiraterone (Zytiga) reduced opiate use by 19%, the average pain intensity score by 19%, and the impact of pain on daily lives by 21% for chemotherapy-naive patients, according to new data from the phase III COU-AA-302 study.
Hazard ratios favoring abiraterone were 0.817 for the median time to opiate use, 0.817 for the average pain intensity, 0.792 for pain interference, and 0.845 for worst pain intensity. Abiraterone was given in combination with prednisone during the trial and compared with placebo plus prednisone.
New data from the AFFIRM trial show that enzalutamide (MDV3100, Xtandi) had a beneficial impact on cancer-related pain in men with previously treated metastatic castrate-resistant prostate cancer (mCRPC). Notably, investigators reported a 44% reduction in pain progression vs. placebo (HR, 0.564; P less than .0001).
These findings from both trials were presented at the European Society for Medical Oncology (ESMO) congress. In the United States, the Food and Drug Administration has approved both androgen-signaling inhibitors for second-line treatment of mCRPC after docetaxel (Taxotere) therapy has failed – abiraterone in April 2011 and enzalutamide in August 2012.
Abiraterone: New Data From the COU-AA-302 Trial
"Pain is an important, often feared, and debilitating complication of metastatic, castration-resistant prostate cancer, which can affect up to half of men with metastatic disease," said Dr. Ethan Basch, who presented the COU-AA-302 patient-reported outcome data.
"Understanding the impact of abiraterone and other agents on pain provides valuable information for decision makers," Dr. Basch, of Memorial Sloan-Kettering Cancer Center in New York, added.
Abiraterone’s pain-reducing effects add to benefits reported at American Society of Clinical Oncology (ASCO) annual meeting earlier in the year, where the results of the second planned interim analysis showed it significantly delayed progression and the initiation of chemotherapy in the targeted population.
Trial participants were chemotherapy-naive men with asymptomatic or mildly symptomatic, mCRPC; 546 were randomized to treatment with abiraterone plus prednisone and 542 to placebo plus prednisone. The median treatment duration in each arm was 13.8 months and 8.3 months, respectively.
Patient pain and functional status was assessed using a variety of measures, including the Brief Pain Inventory–Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaires.
The median time to opiate use was not reached in the abiraterone arm vs. 23.7 months in the placebo arm (P = .0001). The median time to progression of average pain intensity was 26.7 months and 18.4 months, respectively (P = .0049). Similar benefits were seen in median time to progression of pain interference (10.3 vs. 7.4 months; P = .005) and worst pain intensity (26.7 vs. 19.4 months; P = .109). The latter only became significant, however, after a post hoc sensitivity analysis was performed (P = .045).
The median time to functional status degradation – assessed using the FACT-P total score – was more than 4 months longer in the abiraterone arm than in the control arm (12.7 vs. 8.3 months; P = .003).
Enzalutamide: AFFIRM Trial Also Gives New Data
Pain-reducing benefits were also seen with enzalutamide vs. placebo in the phase III AFFIRM study. The trial involved 1,199 men with progressive disease who had been previously treated with docetaxel (Taxotere). It randomized 800 to enzalutamide and 399 to placebo. Investigators previously reported that median overall survival was 18.4 months with enzalutamide vs. 13.6 months with placebo (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).
"This was a typical population of patients with advanced prostate cancer," said Dr. Karim Fizazi of the Institut Gustave-Roussy in Paris.
The median age was 69 years, around 28% had a mean pain score of 4 or higher, 91% had bone disease, 21%-25% had disease that had progressed to the liver, and about half had received three or more lines of prior hormonal treatment, and 26%-28% two or more regimens of chemotherapy. Bisphosphonates were used by 43% of patients.
Enzalutamide reduced the time to a first skeletal event by 31% (HR, 0.688, P = .0001), compared with placebo. The median time to the first skeletal event was 16.7 months and 13.3 months, respectively.
Radiation to the bone was the first skeletal event in around one-fifth of patients, with fewer patients experiencing spinal cord compression, clinically apparent pathological bone fracture, a change in antineoplastic therapy, or surgery to the bone
Three pain assessments were used – the BPI-SF, the FACT-P, and a pain diary. Pain palliation was reported in 45% of enzalutamide-treated patients vs. 7% of those on placebo (P = .0079).
"Enzalutamide had a significant impact on all quality of life domains, which was also significant," Dr. Fizazi reported.
Implications for Practice
Dr. Eleni Efstathiou, who was not involved in either trial, put the findings into context.
"Abiraterone acetate is a good drug that, beyond a survival benefit, dose delay pain progression, opiate use, and functional decline even in an asymptomatic, oligosymptomatic, chemotherapy-naive disease setting," said Dr. Efstathiou of the University of Texas M.D. Anderson Cancer Center in Houston.
She added the following caveat: "Severe clinical symptoms may not be reduced proportionally to the effect observed in this patient population."
The AFFIRM data represent the first report of quality of life measures and pain amelioration for enzalutamide, Dr. Efstathiou observed. While provision was made in the study design to assess these as planned secondary outcomes, as with the COU-AA-302 data, the study was not powered to demonstrate their statistical significance.
"Androgen-signaling inhibition does not only prolong life, but also ameliorates bone metastases-associated symptoms in men with metastatic castrate-resistant prostate cancer," Dr. Efstathiou concluded. "However, we cannot claim victory given that severe clinical events may remain unaltered and the reported benefit in this advanced setting, of both trials, is still short lived."
Ortho Biotech Oncology Research & Development sponsored the COU-AA-302 study. AFFIRM was supported by Medivation and Astellas Pharma. Dr. Fizazi has participated in advisory boards for Medivation and Astellas Pharma. Dr. Basch reported no conflicts of interest in relation to the COU-AA-302 study. Dr. Efstathiou had no disclosures.
VIENNA – Two recently approved drugs – abiraterone acetate and enzalutamide – led to better pain control in reports from separate clinical trials conducted among men with metastatic castration-resistant prostate cancer.
Abiraterone (Zytiga) reduced opiate use by 19%, the average pain intensity score by 19%, and the impact of pain on daily lives by 21% for chemotherapy-naive patients, according to new data from the phase III COU-AA-302 study.
Hazard ratios favoring abiraterone were 0.817 for the median time to opiate use, 0.817 for the average pain intensity, 0.792 for pain interference, and 0.845 for worst pain intensity. Abiraterone was given in combination with prednisone during the trial and compared with placebo plus prednisone.
New data from the AFFIRM trial show that enzalutamide (MDV3100, Xtandi) had a beneficial impact on cancer-related pain in men with previously treated metastatic castrate-resistant prostate cancer (mCRPC). Notably, investigators reported a 44% reduction in pain progression vs. placebo (HR, 0.564; P less than .0001).
These findings from both trials were presented at the European Society for Medical Oncology (ESMO) congress. In the United States, the Food and Drug Administration has approved both androgen-signaling inhibitors for second-line treatment of mCRPC after docetaxel (Taxotere) therapy has failed – abiraterone in April 2011 and enzalutamide in August 2012.
Abiraterone: New Data From the COU-AA-302 Trial
"Pain is an important, often feared, and debilitating complication of metastatic, castration-resistant prostate cancer, which can affect up to half of men with metastatic disease," said Dr. Ethan Basch, who presented the COU-AA-302 patient-reported outcome data.
"Understanding the impact of abiraterone and other agents on pain provides valuable information for decision makers," Dr. Basch, of Memorial Sloan-Kettering Cancer Center in New York, added.
Abiraterone’s pain-reducing effects add to benefits reported at American Society of Clinical Oncology (ASCO) annual meeting earlier in the year, where the results of the second planned interim analysis showed it significantly delayed progression and the initiation of chemotherapy in the targeted population.
Trial participants were chemotherapy-naive men with asymptomatic or mildly symptomatic, mCRPC; 546 were randomized to treatment with abiraterone plus prednisone and 542 to placebo plus prednisone. The median treatment duration in each arm was 13.8 months and 8.3 months, respectively.
Patient pain and functional status was assessed using a variety of measures, including the Brief Pain Inventory–Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaires.
The median time to opiate use was not reached in the abiraterone arm vs. 23.7 months in the placebo arm (P = .0001). The median time to progression of average pain intensity was 26.7 months and 18.4 months, respectively (P = .0049). Similar benefits were seen in median time to progression of pain interference (10.3 vs. 7.4 months; P = .005) and worst pain intensity (26.7 vs. 19.4 months; P = .109). The latter only became significant, however, after a post hoc sensitivity analysis was performed (P = .045).
The median time to functional status degradation – assessed using the FACT-P total score – was more than 4 months longer in the abiraterone arm than in the control arm (12.7 vs. 8.3 months; P = .003).
Enzalutamide: AFFIRM Trial Also Gives New Data
Pain-reducing benefits were also seen with enzalutamide vs. placebo in the phase III AFFIRM study. The trial involved 1,199 men with progressive disease who had been previously treated with docetaxel (Taxotere). It randomized 800 to enzalutamide and 399 to placebo. Investigators previously reported that median overall survival was 18.4 months with enzalutamide vs. 13.6 months with placebo (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).
"This was a typical population of patients with advanced prostate cancer," said Dr. Karim Fizazi of the Institut Gustave-Roussy in Paris.
The median age was 69 years, around 28% had a mean pain score of 4 or higher, 91% had bone disease, 21%-25% had disease that had progressed to the liver, and about half had received three or more lines of prior hormonal treatment, and 26%-28% two or more regimens of chemotherapy. Bisphosphonates were used by 43% of patients.
Enzalutamide reduced the time to a first skeletal event by 31% (HR, 0.688, P = .0001), compared with placebo. The median time to the first skeletal event was 16.7 months and 13.3 months, respectively.
Radiation to the bone was the first skeletal event in around one-fifth of patients, with fewer patients experiencing spinal cord compression, clinically apparent pathological bone fracture, a change in antineoplastic therapy, or surgery to the bone
Three pain assessments were used – the BPI-SF, the FACT-P, and a pain diary. Pain palliation was reported in 45% of enzalutamide-treated patients vs. 7% of those on placebo (P = .0079).
"Enzalutamide had a significant impact on all quality of life domains, which was also significant," Dr. Fizazi reported.
Implications for Practice
Dr. Eleni Efstathiou, who was not involved in either trial, put the findings into context.
"Abiraterone acetate is a good drug that, beyond a survival benefit, dose delay pain progression, opiate use, and functional decline even in an asymptomatic, oligosymptomatic, chemotherapy-naive disease setting," said Dr. Efstathiou of the University of Texas M.D. Anderson Cancer Center in Houston.
She added the following caveat: "Severe clinical symptoms may not be reduced proportionally to the effect observed in this patient population."
The AFFIRM data represent the first report of quality of life measures and pain amelioration for enzalutamide, Dr. Efstathiou observed. While provision was made in the study design to assess these as planned secondary outcomes, as with the COU-AA-302 data, the study was not powered to demonstrate their statistical significance.
"Androgen-signaling inhibition does not only prolong life, but also ameliorates bone metastases-associated symptoms in men with metastatic castrate-resistant prostate cancer," Dr. Efstathiou concluded. "However, we cannot claim victory given that severe clinical events may remain unaltered and the reported benefit in this advanced setting, of both trials, is still short lived."
Ortho Biotech Oncology Research & Development sponsored the COU-AA-302 study. AFFIRM was supported by Medivation and Astellas Pharma. Dr. Fizazi has participated in advisory boards for Medivation and Astellas Pharma. Dr. Basch reported no conflicts of interest in relation to the COU-AA-302 study. Dr. Efstathiou had no disclosures.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Findings: Abiraterone acetate reduced opiate use by 19%, and enzalutamide the risk of pain progression by 44%.
Data Source: Two randomized phase III trials reported on pain outcomes: COU-AA-302 involved 1,088 chemotherapy-naive and men with metastatic, castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone or prednisone plus placebo; AFFIRM involved 1,199 chemotherapy-experienced mCRPC patients comparing enzalutamide vs. placebo.
Disclosures: Ortho Biotech Oncology Research & Development sponsored the COU-AA-302 study. AFFIRM was supported by Medivation and Astellas Pharma. Dr. Fizazi has participated in advisory boards for Medivation and Astellas Pharma. Dr. Basch reported no conflicts of interest in relation to the COU-AA-302 study. Dr. Efstathiou had no disclosures.
Pazopanib Edges Sunitinib as First-Line Kidney Cancer Therapy
VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.
The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.
As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.
This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.
"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.
COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.
Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.
The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.
The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).
Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.
Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).
Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.
Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.
The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.
Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.
"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."
Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.
On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."
Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.
Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.
Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."
During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.
In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.
Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.
"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.
In addition, progression-free survival has been even longer in real-world databases.
Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.
The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.
GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.
VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.
The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.
As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.
This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.
"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.
COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.
Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.
The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.
The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).
Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.
Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).
Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.
Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.
The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.
Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.
"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."
Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.
On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."
Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.
Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.
Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."
During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.
In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.
Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.
"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.
In addition, progression-free survival has been even longer in real-world databases.
Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.
The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.
GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.
VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.
The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.
As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.
This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.
"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.
COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.
Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.
The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.
The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).
Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.
Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).
Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.
Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.
The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.
Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.
"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."
Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.
On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."
Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.
Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.
Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."
During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.
In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.
Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.
"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.
In addition, progression-free survival has been even longer in real-world databases.
Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.
The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.
GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Median progression-free survival was 8.4 months for pazopanib vs. 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998).
Data Source: Investigators analyzed a phase III trial of 1,110 patients with locally advanced or metastatic renal cell carcinoma.
Disclosures: GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.
Health Care Professionals Tank in Cancer Survey
VIENNA – Nearly one in five persons believes that their lifetime risk of cancer is nonmodifiable, a survey found.
"That’s clearly worrying," medical oncologist Dr. Derek Power said at the European Society for Medical Oncology Congress.
Equally disconcerting was the finding that 52% of survey respondents had a college degree and that 17% were health care professionals.
The 48-question, online survey was distributed to 748 people through the Irish Cancer Society.
The majority of the public (80%) and health care professionals (78%) were concerned about developing cancer, but only a small minority (20% and 10%) knew that cancer risk increases with age.
Smoking was ranked as the No. 1 risk factor for cancer by 87% of the cohort. Many overestimated the risk of cancer attributable to genetics, environment, and stress, however, and underestimated the cancer risks associated with age, obesity, and sunlight, said Dr. Power of Mercy University Hospital in Cork, Ireland.
In all, 47% of respondents thought cancer was caused by genetics, specifically family history genetics.
"That’s a huge overestimate," Dr. Power said at a press briefing. "Only about 20% of cancers are hereditary and significant numbers less than that are known to be caused by specific genes, about 5%-8%."
The World Health Organization estimates that about one-third of cancers are preventable by following a sensible diet, maintaining a normal body weight, and exercising, Dr. Power observed.
When the respondents were probed on specific aspects of diet, large knowledge gaps emerged. A significant proportion of respondents reported that "detox" diets (35%) and organic foods (61%) could reduce their cancer risk, but only 46% were aware that salt is a risk factor for cancer.
Vitamin and mineral supplements were also thought to be protective by 51% of the public and 54% of health care professionals, with less than half (40% and 28%) aware that red meat is a risk factor.
Despite years of evidence, only 27% of respondents were unaware that breast-feeding can help reduce breast cancer risk – a finding that has clear implications for any national health promotion strategy, Dr. Power said.
Similarly, only 42% of the public and 46% of health care professionals identified alcohol as cancer risk factor, despite its association with a number of cancers including esophageal, mouth, breast, and colorectal.
Interestingly, 63% of the public and 82% of health care professionals thought certain drinks were more dangerous than others, when in reality it is the quantity of alcohol consumed that is important, said Dr. Power. In addition, 39% of the respondents believed red wine was protective, although there is no data to support this.
Only 32% of the public and 41% of health care professionals were aware that obesity is a cancer risk factor, with 33% and 24%, respectively, unaware that the location of body fat is important.
When given a list of potential behaviors relevant to cancer risk, a stunning 48% of respondents thought that a blow to the breast could increase a woman’s risk of cancer, whereas 29% said wearing a tight bra could do so.
Other "cancer myths" about risks for which there is little supportive data were cell phone use (68%), aerosol use (71%), eating genetically modified foods (81%), and the effects of stress (94%).
"What we found is that a sizeable proportion of the population is misinformed about cancer risk," Dr. Power said.
One explanation for the poor knowledge of cancer risk factors, particularly in a cohort of so many college graduates and health care professionals, is that the cancer prevention message has been too narrow.
"A lot of national programs are very good at disseminating information on cardiovascular risk and diet through healthy eating and exercise, but for cancer prevention, what gets out there is really ‘Don’t smoke,’ " he said. "That’s the biggest thing the public was aware of, as you saw from our figures, but – in terms of lifestyle choices like obesity, healthy eating, physical exercise – that just doesn’t get out there amongst cancer prevention strategies."
Dr. Power said he hopes that the results of the survey will be used to highlight cancer risk misperceptions and that there will be more emphasis in national cancer prevention campaigns on lifestyle choices, particularly in light of the obesity epidemic and increasingly sedentary lifestyle of children.
He highlighted a recent report by the World Cancer Research Fund/American Institute for Cancer Research that grades the current evidence on the relationship between food, nutrition, and physical exercise for 17 cancer sites and offers 10 recommendations to reduce the risk of developing cancer (J. Fam. Health Care 2010;20:100-2).
As to whether the survey results were unique to Ireland, Dr. Power said the data are relatively consistent among Western countries, but that the perception of cancer risk does vary among regions. For example, HPV-associated cancers and environmental factors weigh heavily in Japan, whereas obesity is more of a concern in Western countries.
The cohort included 648 women and 100 men. Their average age was 37 years (range, 18-74 years). The investigators did not ascertain how many of the health care professionals were physicians.
Dr. Power reported no conflicts of interest.
VIENNA – Nearly one in five persons believes that their lifetime risk of cancer is nonmodifiable, a survey found.
"That’s clearly worrying," medical oncologist Dr. Derek Power said at the European Society for Medical Oncology Congress.
Equally disconcerting was the finding that 52% of survey respondents had a college degree and that 17% were health care professionals.
The 48-question, online survey was distributed to 748 people through the Irish Cancer Society.
The majority of the public (80%) and health care professionals (78%) were concerned about developing cancer, but only a small minority (20% and 10%) knew that cancer risk increases with age.
Smoking was ranked as the No. 1 risk factor for cancer by 87% of the cohort. Many overestimated the risk of cancer attributable to genetics, environment, and stress, however, and underestimated the cancer risks associated with age, obesity, and sunlight, said Dr. Power of Mercy University Hospital in Cork, Ireland.
In all, 47% of respondents thought cancer was caused by genetics, specifically family history genetics.
"That’s a huge overestimate," Dr. Power said at a press briefing. "Only about 20% of cancers are hereditary and significant numbers less than that are known to be caused by specific genes, about 5%-8%."
The World Health Organization estimates that about one-third of cancers are preventable by following a sensible diet, maintaining a normal body weight, and exercising, Dr. Power observed.
When the respondents were probed on specific aspects of diet, large knowledge gaps emerged. A significant proportion of respondents reported that "detox" diets (35%) and organic foods (61%) could reduce their cancer risk, but only 46% were aware that salt is a risk factor for cancer.
Vitamin and mineral supplements were also thought to be protective by 51% of the public and 54% of health care professionals, with less than half (40% and 28%) aware that red meat is a risk factor.
Despite years of evidence, only 27% of respondents were unaware that breast-feeding can help reduce breast cancer risk – a finding that has clear implications for any national health promotion strategy, Dr. Power said.
Similarly, only 42% of the public and 46% of health care professionals identified alcohol as cancer risk factor, despite its association with a number of cancers including esophageal, mouth, breast, and colorectal.
Interestingly, 63% of the public and 82% of health care professionals thought certain drinks were more dangerous than others, when in reality it is the quantity of alcohol consumed that is important, said Dr. Power. In addition, 39% of the respondents believed red wine was protective, although there is no data to support this.
Only 32% of the public and 41% of health care professionals were aware that obesity is a cancer risk factor, with 33% and 24%, respectively, unaware that the location of body fat is important.
When given a list of potential behaviors relevant to cancer risk, a stunning 48% of respondents thought that a blow to the breast could increase a woman’s risk of cancer, whereas 29% said wearing a tight bra could do so.
Other "cancer myths" about risks for which there is little supportive data were cell phone use (68%), aerosol use (71%), eating genetically modified foods (81%), and the effects of stress (94%).
"What we found is that a sizeable proportion of the population is misinformed about cancer risk," Dr. Power said.
One explanation for the poor knowledge of cancer risk factors, particularly in a cohort of so many college graduates and health care professionals, is that the cancer prevention message has been too narrow.
"A lot of national programs are very good at disseminating information on cardiovascular risk and diet through healthy eating and exercise, but for cancer prevention, what gets out there is really ‘Don’t smoke,’ " he said. "That’s the biggest thing the public was aware of, as you saw from our figures, but – in terms of lifestyle choices like obesity, healthy eating, physical exercise – that just doesn’t get out there amongst cancer prevention strategies."
Dr. Power said he hopes that the results of the survey will be used to highlight cancer risk misperceptions and that there will be more emphasis in national cancer prevention campaigns on lifestyle choices, particularly in light of the obesity epidemic and increasingly sedentary lifestyle of children.
He highlighted a recent report by the World Cancer Research Fund/American Institute for Cancer Research that grades the current evidence on the relationship between food, nutrition, and physical exercise for 17 cancer sites and offers 10 recommendations to reduce the risk of developing cancer (J. Fam. Health Care 2010;20:100-2).
As to whether the survey results were unique to Ireland, Dr. Power said the data are relatively consistent among Western countries, but that the perception of cancer risk does vary among regions. For example, HPV-associated cancers and environmental factors weigh heavily in Japan, whereas obesity is more of a concern in Western countries.
The cohort included 648 women and 100 men. Their average age was 37 years (range, 18-74 years). The investigators did not ascertain how many of the health care professionals were physicians.
Dr. Power reported no conflicts of interest.
VIENNA – Nearly one in five persons believes that their lifetime risk of cancer is nonmodifiable, a survey found.
"That’s clearly worrying," medical oncologist Dr. Derek Power said at the European Society for Medical Oncology Congress.
Equally disconcerting was the finding that 52% of survey respondents had a college degree and that 17% were health care professionals.
The 48-question, online survey was distributed to 748 people through the Irish Cancer Society.
The majority of the public (80%) and health care professionals (78%) were concerned about developing cancer, but only a small minority (20% and 10%) knew that cancer risk increases with age.
Smoking was ranked as the No. 1 risk factor for cancer by 87% of the cohort. Many overestimated the risk of cancer attributable to genetics, environment, and stress, however, and underestimated the cancer risks associated with age, obesity, and sunlight, said Dr. Power of Mercy University Hospital in Cork, Ireland.
In all, 47% of respondents thought cancer was caused by genetics, specifically family history genetics.
"That’s a huge overestimate," Dr. Power said at a press briefing. "Only about 20% of cancers are hereditary and significant numbers less than that are known to be caused by specific genes, about 5%-8%."
The World Health Organization estimates that about one-third of cancers are preventable by following a sensible diet, maintaining a normal body weight, and exercising, Dr. Power observed.
When the respondents were probed on specific aspects of diet, large knowledge gaps emerged. A significant proportion of respondents reported that "detox" diets (35%) and organic foods (61%) could reduce their cancer risk, but only 46% were aware that salt is a risk factor for cancer.
Vitamin and mineral supplements were also thought to be protective by 51% of the public and 54% of health care professionals, with less than half (40% and 28%) aware that red meat is a risk factor.
Despite years of evidence, only 27% of respondents were unaware that breast-feeding can help reduce breast cancer risk – a finding that has clear implications for any national health promotion strategy, Dr. Power said.
Similarly, only 42% of the public and 46% of health care professionals identified alcohol as cancer risk factor, despite its association with a number of cancers including esophageal, mouth, breast, and colorectal.
Interestingly, 63% of the public and 82% of health care professionals thought certain drinks were more dangerous than others, when in reality it is the quantity of alcohol consumed that is important, said Dr. Power. In addition, 39% of the respondents believed red wine was protective, although there is no data to support this.
Only 32% of the public and 41% of health care professionals were aware that obesity is a cancer risk factor, with 33% and 24%, respectively, unaware that the location of body fat is important.
When given a list of potential behaviors relevant to cancer risk, a stunning 48% of respondents thought that a blow to the breast could increase a woman’s risk of cancer, whereas 29% said wearing a tight bra could do so.
Other "cancer myths" about risks for which there is little supportive data were cell phone use (68%), aerosol use (71%), eating genetically modified foods (81%), and the effects of stress (94%).
"What we found is that a sizeable proportion of the population is misinformed about cancer risk," Dr. Power said.
One explanation for the poor knowledge of cancer risk factors, particularly in a cohort of so many college graduates and health care professionals, is that the cancer prevention message has been too narrow.
"A lot of national programs are very good at disseminating information on cardiovascular risk and diet through healthy eating and exercise, but for cancer prevention, what gets out there is really ‘Don’t smoke,’ " he said. "That’s the biggest thing the public was aware of, as you saw from our figures, but – in terms of lifestyle choices like obesity, healthy eating, physical exercise – that just doesn’t get out there amongst cancer prevention strategies."
Dr. Power said he hopes that the results of the survey will be used to highlight cancer risk misperceptions and that there will be more emphasis in national cancer prevention campaigns on lifestyle choices, particularly in light of the obesity epidemic and increasingly sedentary lifestyle of children.
He highlighted a recent report by the World Cancer Research Fund/American Institute for Cancer Research that grades the current evidence on the relationship between food, nutrition, and physical exercise for 17 cancer sites and offers 10 recommendations to reduce the risk of developing cancer (J. Fam. Health Care 2010;20:100-2).
As to whether the survey results were unique to Ireland, Dr. Power said the data are relatively consistent among Western countries, but that the perception of cancer risk does vary among regions. For example, HPV-associated cancers and environmental factors weigh heavily in Japan, whereas obesity is more of a concern in Western countries.
The cohort included 648 women and 100 men. Their average age was 37 years (range, 18-74 years). The investigators did not ascertain how many of the health care professionals were physicians.
Dr. Power reported no conflicts of interest.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Only 10% of health professionals and 20% of the public knew that cancer risk increases with age, but while 41% and 32% knew that obesity is a cancer risk factor, only 24% and 33% were aware that the location of body fat is important.
Data Source: Results were taken from an online survey of 748 persons, of which 17% were health care professionals.
Disclosures: Dr. Power reported no conflicts of interest.
EMILIA Confirms T-DM1 Overall Survival Advantage
VIENNA – T-DM1 resulted in a significant 5-month overall survival benefit over capecitabine plus lapatinib in the treatment of metastatic breast cancer that had progressed following treatment with trastuzumab plus a taxane in a phase III trial.
Updated results from the open-label, EMILIA trial showed that the median overall survival was 25.1 months with capecitabine (Xeloda) plus lapatinib (XL), but 30.9 months with T-DM1. The hazard ratio for the survival benefit was 0.68 (P =.0006), indicating a 32% reduction in the risk of dying if treated with T-DM1 versus XL.
The findings were presented at the European Society for Medical Oncology Congress, with simultaneous online publication in the New England Journal of Medicine (doi:10.1056/NEJMoa1209124).
"The second overall survival interim analysis saw that the patients who received T-DM1 lived longer," said Dr. Javier Cortes, the invited discussant who commented on the significance of the findings.
"I do not remember any clinical trial in the history of metastatic breast cancer with these numbers," observed Dr. Cortes of the Vall d’Hebron Institute of Oncology in Barcelona.
Overall survival was a co-primary end point of the EMILIA study, but was not initially statistically better with T-DM1 than with XL. Indeed, results of the first interim analysis, which were presented at ASCO in June, showed that there was a trend, but not a definite overall survival benefit. In the T-DM1 vs. the XL arms, overall survival was 84.1% and 77% at 1 year and 65.4% and 47.5% at 2 years.
Those data were based on a data cut-off of Jan. 14, at a median follow up of 12.4 and 12.9 months in the T-DM1 and XL arms, when the progression-free analysis was also performed. This showed a clear progression-free survival benefit in favor of T-DM1 (9.6 months vs. 6.4 months, P less than .0001).
The second interim overall survival analysis performed up to the end of July 31 accounts for 18.6 months and 19.1 months of median follow-up. Estimated 1-year survival rates were 85.2% in the T-DM1 arm and 78.4% in the XL arm, with 2-year survival rates of 67.6% and 51.8%.
"A decision was made to conduct a second interim overall survival analysis after 50% of the targeted number of OS events had taken place," study investigator Dr. Sunil Verma of Sunnybrook Odette Cancer Center in Toronto explained.
"The final overall survival analysis is expected in 2014," he added, but this will only be descriptive, since following the beneficial findings of the second interim overall survival analysis, patients in the XL arm are now allowed to cross over to the T-DM1 arm.
Results for all additional secondary end points favored treatment with T-DM1 over XL. The objective response rate was 43.6% and 30.8% (P less than .001), and the median duration of response was 12.6 months versus 6.5 months. There were also greater improvements in patient-reported outcomes, such as symptom worsening assessed by the Functional Assessment of Cancer Therapy–Breast (FACT-B).
As with any new agent, toxicity is a potential concern, but data so far show that there are no untoward safety concerns. Specifically, cardiotoxicity was not increased in the T-DM1 arm. Cardiac events of grade 3 or higher occurred in 1 (0.2%) of 490 patients vs. 2 (0.4%) of 488 XL-treated patients. Other side effects increased in the T-DM1 arm were thrombocytopenia (12.9%) and altered liver enzymes and anemia. Adverse events in the XL arm were similar to those seen in clinical practice, including diarrhea and hand-foot syndrome.
Patient choice will also be a deciding factor when it comes to how T-DM1 could be used in routine practice. As an intravenous therapy – given every 3 weeks until progression – patients may prefer to stick to an oral regimen such as XL – although some patients may not like to take the multiple, and in the case of capecitabine, large pills to swallow.
Further trials with T-DM1 are ongoing and will help determine its role in the management of women with metastatic disease. The MARIANNE trial, for example, is investigating the use of T-DM1 in combination with taxanes after failure of taxane-based chemotherapy plus trastuzumab or pertuzumab in patients with HER-2–positive metastatic breast cancer. In the trial, T-DM1 plus taxanes are being compared with T-DM1 alone and with T-DM1 plus pertuzumab.
The EMILIA study was funded by F. Hoffmann–La Roche/Genentech. Dr. Verma disclosed receiving compensation for consultancy/advisory services and honoraria from both Roche and GlaxoSmithKline, and research funding from Roche/Genentech. Dr. Javier Cortes has received honoraria from Roche.
It’s very rare to see a survival impact in metastatic disease, Dr. Stephen Johnston said. The magnitude of difference seen in progression-free and now in overall survival are both significant findings. There are enough event deaths to know that these data are not going to change with regard to overall survival, and that’s what will lead T-DM1 to becoming an approved therapy in the future.
 |
|
Treatment with capecitabine and lapatinib (XL) was discontinued because of adverse events in a higher percentage of patients than in the T-DM1 group (10.7% vs. 5.9%);however, because this was an open-label trial, it’s not possible to tell if there might have been a lower threshold for discontinuation in those taking the tablets rather the intravenous treatment. The rates of grade 3/4 diarrhea seen in the XL vs. T-DM1 arm (20.7% vs. 1.6%) are no higher than those reported previously.
T-DM1 will almost certainly become a new treatment option post trastuzumab, and possibly even a front-line option based on previous data. The challenge then will be how we sequence our other therapies in the second-line setting.
Dr. Johnston is professor of breast cancer medicine, consultant medical oncologist, and director of clinical research and development at he Royal Marsden and the Institute of Cancer Research in London. He is also director of the United Kingdom’s National Institute for Health Research (NIHR) Biomedical Research Centre for Cancer, also based at the Royal Marsden. Dr. Johnston has received consultancy fees, advisory board fees, and research support from GlaxoSmithKline.
It’s very rare to see a survival impact in metastatic disease, Dr. Stephen Johnston said. The magnitude of difference seen in progression-free and now in overall survival are both significant findings. There are enough event deaths to know that these data are not going to change with regard to overall survival, and that’s what will lead T-DM1 to becoming an approved therapy in the future.
|
|
Treatment with capecitabine and lapatinib (XL) was discontinued because of adverse events in a higher percentage of patients than in the T-DM1 group (10.7% vs. 5.9%);however, because this was an open-label trial, it’s not possible to tell if there might have been a lower threshold for discontinuation in those taking the tablets rather the intravenous treatment. The rates of grade 3/4 diarrhea seen in the XL vs. T-DM1 arm (20.7% vs. 1.6%) are no higher than those reported previously.
T-DM1 will almost certainly become a new treatment option post trastuzumab, and possibly even a front-line option based on previous data. The challenge then will be how we sequence our other therapies in the second-line setting.
Dr. Johnston is professor of breast cancer medicine, consultant medical oncologist, and director of clinical research and development at he Royal Marsden and the Institute of Cancer Research in London. He is also director of the United Kingdom’s National Institute for Health Research (NIHR) Biomedical Research Centre for Cancer, also based at the Royal Marsden. Dr. Johnston has received consultancy fees, advisory board fees, and research support from GlaxoSmithKline.
It’s very rare to see a survival impact in metastatic disease, Dr. Stephen Johnston said. The magnitude of difference seen in progression-free and now in overall survival are both significant findings. There are enough event deaths to know that these data are not going to change with regard to overall survival, and that’s what will lead T-DM1 to becoming an approved therapy in the future.
|
|
Treatment with capecitabine and lapatinib (XL) was discontinued because of adverse events in a higher percentage of patients than in the T-DM1 group (10.7% vs. 5.9%);however, because this was an open-label trial, it’s not possible to tell if there might have been a lower threshold for discontinuation in those taking the tablets rather the intravenous treatment. The rates of grade 3/4 diarrhea seen in the XL vs. T-DM1 arm (20.7% vs. 1.6%) are no higher than those reported previously.
T-DM1 will almost certainly become a new treatment option post trastuzumab, and possibly even a front-line option based on previous data. The challenge then will be how we sequence our other therapies in the second-line setting.
Dr. Johnston is professor of breast cancer medicine, consultant medical oncologist, and director of clinical research and development at he Royal Marsden and the Institute of Cancer Research in London. He is also director of the United Kingdom’s National Institute for Health Research (NIHR) Biomedical Research Centre for Cancer, also based at the Royal Marsden. Dr. Johnston has received consultancy fees, advisory board fees, and research support from GlaxoSmithKline.
VIENNA – T-DM1 resulted in a significant 5-month overall survival benefit over capecitabine plus lapatinib in the treatment of metastatic breast cancer that had progressed following treatment with trastuzumab plus a taxane in a phase III trial.
Updated results from the open-label, EMILIA trial showed that the median overall survival was 25.1 months with capecitabine (Xeloda) plus lapatinib (XL), but 30.9 months with T-DM1. The hazard ratio for the survival benefit was 0.68 (P =.0006), indicating a 32% reduction in the risk of dying if treated with T-DM1 versus XL.
The findings were presented at the European Society for Medical Oncology Congress, with simultaneous online publication in the New England Journal of Medicine (doi:10.1056/NEJMoa1209124).
"The second overall survival interim analysis saw that the patients who received T-DM1 lived longer," said Dr. Javier Cortes, the invited discussant who commented on the significance of the findings.
"I do not remember any clinical trial in the history of metastatic breast cancer with these numbers," observed Dr. Cortes of the Vall d’Hebron Institute of Oncology in Barcelona.
Overall survival was a co-primary end point of the EMILIA study, but was not initially statistically better with T-DM1 than with XL. Indeed, results of the first interim analysis, which were presented at ASCO in June, showed that there was a trend, but not a definite overall survival benefit. In the T-DM1 vs. the XL arms, overall survival was 84.1% and 77% at 1 year and 65.4% and 47.5% at 2 years.
Those data were based on a data cut-off of Jan. 14, at a median follow up of 12.4 and 12.9 months in the T-DM1 and XL arms, when the progression-free analysis was also performed. This showed a clear progression-free survival benefit in favor of T-DM1 (9.6 months vs. 6.4 months, P less than .0001).
The second interim overall survival analysis performed up to the end of July 31 accounts for 18.6 months and 19.1 months of median follow-up. Estimated 1-year survival rates were 85.2% in the T-DM1 arm and 78.4% in the XL arm, with 2-year survival rates of 67.6% and 51.8%.
"A decision was made to conduct a second interim overall survival analysis after 50% of the targeted number of OS events had taken place," study investigator Dr. Sunil Verma of Sunnybrook Odette Cancer Center in Toronto explained.
"The final overall survival analysis is expected in 2014," he added, but this will only be descriptive, since following the beneficial findings of the second interim overall survival analysis, patients in the XL arm are now allowed to cross over to the T-DM1 arm.
Results for all additional secondary end points favored treatment with T-DM1 over XL. The objective response rate was 43.6% and 30.8% (P less than .001), and the median duration of response was 12.6 months versus 6.5 months. There were also greater improvements in patient-reported outcomes, such as symptom worsening assessed by the Functional Assessment of Cancer Therapy–Breast (FACT-B).
As with any new agent, toxicity is a potential concern, but data so far show that there are no untoward safety concerns. Specifically, cardiotoxicity was not increased in the T-DM1 arm. Cardiac events of grade 3 or higher occurred in 1 (0.2%) of 490 patients vs. 2 (0.4%) of 488 XL-treated patients. Other side effects increased in the T-DM1 arm were thrombocytopenia (12.9%) and altered liver enzymes and anemia. Adverse events in the XL arm were similar to those seen in clinical practice, including diarrhea and hand-foot syndrome.
Patient choice will also be a deciding factor when it comes to how T-DM1 could be used in routine practice. As an intravenous therapy – given every 3 weeks until progression – patients may prefer to stick to an oral regimen such as XL – although some patients may not like to take the multiple, and in the case of capecitabine, large pills to swallow.
Further trials with T-DM1 are ongoing and will help determine its role in the management of women with metastatic disease. The MARIANNE trial, for example, is investigating the use of T-DM1 in combination with taxanes after failure of taxane-based chemotherapy plus trastuzumab or pertuzumab in patients with HER-2–positive metastatic breast cancer. In the trial, T-DM1 plus taxanes are being compared with T-DM1 alone and with T-DM1 plus pertuzumab.
The EMILIA study was funded by F. Hoffmann–La Roche/Genentech. Dr. Verma disclosed receiving compensation for consultancy/advisory services and honoraria from both Roche and GlaxoSmithKline, and research funding from Roche/Genentech. Dr. Javier Cortes has received honoraria from Roche.
VIENNA – T-DM1 resulted in a significant 5-month overall survival benefit over capecitabine plus lapatinib in the treatment of metastatic breast cancer that had progressed following treatment with trastuzumab plus a taxane in a phase III trial.
Updated results from the open-label, EMILIA trial showed that the median overall survival was 25.1 months with capecitabine (Xeloda) plus lapatinib (XL), but 30.9 months with T-DM1. The hazard ratio for the survival benefit was 0.68 (P =.0006), indicating a 32% reduction in the risk of dying if treated with T-DM1 versus XL.
The findings were presented at the European Society for Medical Oncology Congress, with simultaneous online publication in the New England Journal of Medicine (doi:10.1056/NEJMoa1209124).
"The second overall survival interim analysis saw that the patients who received T-DM1 lived longer," said Dr. Javier Cortes, the invited discussant who commented on the significance of the findings.
"I do not remember any clinical trial in the history of metastatic breast cancer with these numbers," observed Dr. Cortes of the Vall d’Hebron Institute of Oncology in Barcelona.
Overall survival was a co-primary end point of the EMILIA study, but was not initially statistically better with T-DM1 than with XL. Indeed, results of the first interim analysis, which were presented at ASCO in June, showed that there was a trend, but not a definite overall survival benefit. In the T-DM1 vs. the XL arms, overall survival was 84.1% and 77% at 1 year and 65.4% and 47.5% at 2 years.
Those data were based on a data cut-off of Jan. 14, at a median follow up of 12.4 and 12.9 months in the T-DM1 and XL arms, when the progression-free analysis was also performed. This showed a clear progression-free survival benefit in favor of T-DM1 (9.6 months vs. 6.4 months, P less than .0001).
The second interim overall survival analysis performed up to the end of July 31 accounts for 18.6 months and 19.1 months of median follow-up. Estimated 1-year survival rates were 85.2% in the T-DM1 arm and 78.4% in the XL arm, with 2-year survival rates of 67.6% and 51.8%.
"A decision was made to conduct a second interim overall survival analysis after 50% of the targeted number of OS events had taken place," study investigator Dr. Sunil Verma of Sunnybrook Odette Cancer Center in Toronto explained.
"The final overall survival analysis is expected in 2014," he added, but this will only be descriptive, since following the beneficial findings of the second interim overall survival analysis, patients in the XL arm are now allowed to cross over to the T-DM1 arm.
Results for all additional secondary end points favored treatment with T-DM1 over XL. The objective response rate was 43.6% and 30.8% (P less than .001), and the median duration of response was 12.6 months versus 6.5 months. There were also greater improvements in patient-reported outcomes, such as symptom worsening assessed by the Functional Assessment of Cancer Therapy–Breast (FACT-B).
As with any new agent, toxicity is a potential concern, but data so far show that there are no untoward safety concerns. Specifically, cardiotoxicity was not increased in the T-DM1 arm. Cardiac events of grade 3 or higher occurred in 1 (0.2%) of 490 patients vs. 2 (0.4%) of 488 XL-treated patients. Other side effects increased in the T-DM1 arm were thrombocytopenia (12.9%) and altered liver enzymes and anemia. Adverse events in the XL arm were similar to those seen in clinical practice, including diarrhea and hand-foot syndrome.
Patient choice will also be a deciding factor when it comes to how T-DM1 could be used in routine practice. As an intravenous therapy – given every 3 weeks until progression – patients may prefer to stick to an oral regimen such as XL – although some patients may not like to take the multiple, and in the case of capecitabine, large pills to swallow.
Further trials with T-DM1 are ongoing and will help determine its role in the management of women with metastatic disease. The MARIANNE trial, for example, is investigating the use of T-DM1 in combination with taxanes after failure of taxane-based chemotherapy plus trastuzumab or pertuzumab in patients with HER-2–positive metastatic breast cancer. In the trial, T-DM1 plus taxanes are being compared with T-DM1 alone and with T-DM1 plus pertuzumab.
The EMILIA study was funded by F. Hoffmann–La Roche/Genentech. Dr. Verma disclosed receiving compensation for consultancy/advisory services and honoraria from both Roche and GlaxoSmithKline, and research funding from Roche/Genentech. Dr. Javier Cortes has received honoraria from Roche.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Median overall survival was 30.9 months for T-DM1 and 25.1 months for capecitabine plus lapatinib (hazard ratio = 0.68, P = .0006).
Data Source: Data are from a randomized, open-label, phase III EMILIA trial of 991 women with HER2+ metastatic breast cancer treated with T-DM1 or capecitabine plus lapatinib who had progressed despite treatment with trastuzumab plus a taxane.
Disclosures: The EMILIA study was funded by F. Hoffmann–La Roche/Genentech. Dr. Verma disclosed receiving compensation for consultancy/advisory services and honoraria from both Roche and GlaxoSmithKline, and research funding from Roche/Genentech. Dr. Javier Cortes has received honoraria from Roche. Dr. Johnston has received research support from AstraZeneca and GSK, and consultancy fees from GSK, Novartis, and Roche.
Gefitinib Offers Palliative Care in Advanced Esophageal Cancer
VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.
Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.
In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor (EGFR) inhibitor.
Median overall survival increased significantly from 1.97 months in patients with a performance status of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).
"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.
The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.
"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing.
He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."
More Study Details
COG was prompted by a round of promising single-agent phase II trials involving the EGFR inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress EGFR.
At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.
Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression. Patients with stable brain metastases who had received prior cranial irradiation were not excluded.
Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments. Performance status (PS) was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.
Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.
Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.
This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).
At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.
Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.
Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.
There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.
Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.
"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth.
Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.
VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.
Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.
In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor (EGFR) inhibitor.
Median overall survival increased significantly from 1.97 months in patients with a performance status of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).
"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.
The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.
"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing.
He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."
More Study Details
COG was prompted by a round of promising single-agent phase II trials involving the EGFR inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress EGFR.
At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.
Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression. Patients with stable brain metastases who had received prior cranial irradiation were not excluded.
Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments. Performance status (PS) was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.
Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.
Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.
This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).
At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.
Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.
Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.
There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.
Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.
"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth.
Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.
VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.
Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.
In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor (EGFR) inhibitor.
Median overall survival increased significantly from 1.97 months in patients with a performance status of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).
"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.
The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.
"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing.
He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."
More Study Details
COG was prompted by a round of promising single-agent phase II trials involving the EGFR inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress EGFR.
At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.
Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression. Patients with stable brain metastases who had received prior cranial irradiation were not excluded.
Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments. Performance status (PS) was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.
Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.
Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.
This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).
At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.
Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.
Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.
There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.
Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.
"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth.
Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Median overall survival was 3.73 months with gefitinib vs. 3.60 months with placebo (P = .285).
Data Source: Data are from a phase III randomized trial of gefitinib in patients with esophageal cancer progressing after chemotherapy.
Disclosures: Cancer Research U.K. sponsored the trial and AstraZeneca supplied gefitinib and the matched placebo. Dr. Ferry reported grant support, honoraria, and advising AstraZeneca in the development of gefitinib.
Dual Kinase Therapy Slows BRAF-Mutated Metastatic Melanoma
VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.
"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.
In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.
The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.
As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.
There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.
Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.
In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.
Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.
After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.
The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.
Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.
"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."
Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.
Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.
Vemurafenib/GDC-0973 Combination Tested
In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.
The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.
Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).
Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.
Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.
The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.
VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.
"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.
In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.
The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.
As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.
There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.
Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.
In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.
Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.
After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.
The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.
Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.
"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."
Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.
Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.
Vemurafenib/GDC-0973 Combination Tested
In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.
The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.
Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).
Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.
Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.
The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.
VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.
"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.
In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.
The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.
As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.
There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.
Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.
In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.
Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.
After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.
The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.
Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.
"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."
Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.
Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.
Vemurafenib/GDC-0973 Combination Tested
In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.
The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.
Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).
Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.
Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.
The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Findings: Progression-free survival was 9.4 months using a combination of dabrafenib 150 mg and trametinib 2 mg as compared with 5.8 months with dabrafenib alone (P less than .0001) in the phase II trial.
Data Source: Results were taken from two randomized clinical studies: a phase II trial comparing dabrafenib/trametinib vs. dabrafenib alone; BRIM7, a phase IB study comparing different two doses of vemurafenib in combination with different dosing schedules of GDC-0973 in patients with BRAF V600-mutated metastatic melanoma.
Disclosures: GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.
Crizotinib Changes Practice for Advanced ALK-Positive NSCLC
VIENNA – Long-awaited data from the phase III PROFILE 1007 confirm that crizotinib provides superior progression-free survival and responses, compared with second-line chemotherapy in advanced anaplastic lymphoma kinase–positive non–small cell lung cancer.
Median progression-free survival more than doubled from 3.0 months with single-agent chemotherapy to 7.7 months with crizotinib, according to an independent radiologic review (P value less than .0001; hazard ratio, 0.49).
Crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months; P less than .0001) or pemetrexed (Alimta) (7.7 vs. 4.2; P = .0004), an agent previously shown to be effective against ALK-positive NSCLC.
The overall response rate was 65.3% for crizotinib and 19.5% for chemotherapy in the intent to treat population of 347 patients (overall response rate ratio 3.4; P less than .0001).
Crizotinib was also associated with significantly greater improvement in lung cancer symptoms and quality of life, Dr. Alice Shaw reported during a presidential symposium at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
"Taken together, these results establish crizotinib as the standard of care for patients with advanced, previously treated ALK-positive non–small cell lung cancer," she said.
ALK rearrangements are present in about 5% of lung cancers, typically in younger, never smokers.
Overall survival in the study was 22.8 months for chemotherapy and 20.3 months for crizotinib (P = .5394; HR, 1.02).
The interim survival analysis was immature with just 40% of expected deaths reported and likely confounded by the high number (87%) of chemotherapy patients who crossed over to crizotinib after progression, she noted. After adjusting for crossover, the hazard ratio suggests a survival advantage with crizotinib (HR, 0.83).
Discussant Jean-Charles Soria of Institut Gustave Roussy, Villejuif, France, agreed and said the survival times in either arm were impressive, observing that just two years ago survival in second-line ALK-positive NSCLC was just nine months.
"This is really changing the natural history of the disease," he said.
Crizotinib, an oral, first in class ALK inhibitor, was given accelerated approval in 2011 in the United States to treat advanced ALK-positive NSCLC but is not approved in Europe, where regulatory agencies have required data from the randomized trial.
"While the U.S. treats, Europe randomizes," Dr. Soria lamented to a loud round of laughter.
He observed that worldwide use of crizotinib will require that several financial and practical issues surrounding implementation of molecular testing in daily practice be addressed including the optimal technique, type of sample, and tissue availability.
Testing for epidermal growth factor receptor, another molecular alteration that directs targeted therapy in lung cancer, "should not compete with ALK," he said, adding that multiplexing test strategies "are key."
Investigators at 105 sites across 21 countries in Europe, the Americas, and Asia-Pacific, randomized 173 patients to crizotinib 250 mg twice-daily in a 21-day cycle and 174 patients to chemotherapy containing pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle.
Treatment duration varied significantly, with patients receiving a median of 11 cycles of crizotinib vs. 4 cycles of chemotherapy. This may have influenced the higher number of all-cause deaths among crizotinib patients (25 deaths vs. 7 deaths), said Dr. Shaw, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston.
Crizotinib patients were more likely than were chemotherapy patients to experience the now well-known side effect of visual disturbances (any grade 60% vs. 9%), as well as diarrhea, nausea, elevated transaminases (16% grade 3/4 ), edema, upper respiratory infection, dysgeusia, and dizziness.
In contrast, fatigue, alopecia, dyspnea, and rash were more common in those receiving chemotherapy.
Despite the fact that patients on crizotinib experienced more nausea and vomiting, antiemetic use was significantly higher in the chemotherapy arm (67% vs. 20%), observed Dr. Shaw, who said the majority of adverse events were grades 1/2, generally manageable, and tolerable.
This was reflected in patient-reported lung cancer symptoms and quality of life. Based on the EORTC Quality of Life Questionnaire (QLQ C-30) and QLQ-LC 13, crizotinib patients had greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain as well as global quality of life (both P less than .0001).
"This is a compound with very mild toxicity," commented Dr. Soria.
He said clinicians need to be aware of crizotinib’s distinct side effect profile, including other rare events such as renal cysts, pneumonitis, asymptomatic bradycardia, and low testosterone, "although we don’t really know if it impacts sexual life."
The topic of hypogonadism was raised in a separate session on second-generation ALK inhibitors at the meeting and in a recent report of rapid-onset hypogonadism secondary to crizotinib use in 19 men with metastatic NSCLC (Cancer 2012 [doi:10.1002/cncr.27450]).
Dr. Shaw said in an interview that the study was small and "requires a lot more validation." Although testosterone levels were not checked in PROFILE 1007, it is being done for the next generation of ALK inhibitors, she added.
Dr. Soria said resistance to crizotinib will become a problem with increasing worldwide use, and that strategies to counter this may include the second-generation ALK inhibitors, increased crizotinib dosing, and crizotinib plus ablative therapy given the poor penetration of crizotinib in the brain.
Brain metastases were present in 35% of patients in both arms. Three-fourths of patients were never smokers, roughly 95% had adenocarcinoma, and their median age was about 50 years.
Dr. Shaw reported an advisory relationship with Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo and research funding from AstraZeneca and Novartis. Dr. Soria reported consultancy fees and steering committee activities with several firms including Pfizer, which sponsored the study.
VIENNA – Long-awaited data from the phase III PROFILE 1007 confirm that crizotinib provides superior progression-free survival and responses, compared with second-line chemotherapy in advanced anaplastic lymphoma kinase–positive non–small cell lung cancer.
Median progression-free survival more than doubled from 3.0 months with single-agent chemotherapy to 7.7 months with crizotinib, according to an independent radiologic review (P value less than .0001; hazard ratio, 0.49).
Crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months; P less than .0001) or pemetrexed (Alimta) (7.7 vs. 4.2; P = .0004), an agent previously shown to be effective against ALK-positive NSCLC.
The overall response rate was 65.3% for crizotinib and 19.5% for chemotherapy in the intent to treat population of 347 patients (overall response rate ratio 3.4; P less than .0001).
Crizotinib was also associated with significantly greater improvement in lung cancer symptoms and quality of life, Dr. Alice Shaw reported during a presidential symposium at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
"Taken together, these results establish crizotinib as the standard of care for patients with advanced, previously treated ALK-positive non–small cell lung cancer," she said.
ALK rearrangements are present in about 5% of lung cancers, typically in younger, never smokers.
Overall survival in the study was 22.8 months for chemotherapy and 20.3 months for crizotinib (P = .5394; HR, 1.02).
The interim survival analysis was immature with just 40% of expected deaths reported and likely confounded by the high number (87%) of chemotherapy patients who crossed over to crizotinib after progression, she noted. After adjusting for crossover, the hazard ratio suggests a survival advantage with crizotinib (HR, 0.83).
Discussant Jean-Charles Soria of Institut Gustave Roussy, Villejuif, France, agreed and said the survival times in either arm were impressive, observing that just two years ago survival in second-line ALK-positive NSCLC was just nine months.
"This is really changing the natural history of the disease," he said.
Crizotinib, an oral, first in class ALK inhibitor, was given accelerated approval in 2011 in the United States to treat advanced ALK-positive NSCLC but is not approved in Europe, where regulatory agencies have required data from the randomized trial.
"While the U.S. treats, Europe randomizes," Dr. Soria lamented to a loud round of laughter.
He observed that worldwide use of crizotinib will require that several financial and practical issues surrounding implementation of molecular testing in daily practice be addressed including the optimal technique, type of sample, and tissue availability.
Testing for epidermal growth factor receptor, another molecular alteration that directs targeted therapy in lung cancer, "should not compete with ALK," he said, adding that multiplexing test strategies "are key."
Investigators at 105 sites across 21 countries in Europe, the Americas, and Asia-Pacific, randomized 173 patients to crizotinib 250 mg twice-daily in a 21-day cycle and 174 patients to chemotherapy containing pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle.
Treatment duration varied significantly, with patients receiving a median of 11 cycles of crizotinib vs. 4 cycles of chemotherapy. This may have influenced the higher number of all-cause deaths among crizotinib patients (25 deaths vs. 7 deaths), said Dr. Shaw, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston.
Crizotinib patients were more likely than were chemotherapy patients to experience the now well-known side effect of visual disturbances (any grade 60% vs. 9%), as well as diarrhea, nausea, elevated transaminases (16% grade 3/4 ), edema, upper respiratory infection, dysgeusia, and dizziness.
In contrast, fatigue, alopecia, dyspnea, and rash were more common in those receiving chemotherapy.
Despite the fact that patients on crizotinib experienced more nausea and vomiting, antiemetic use was significantly higher in the chemotherapy arm (67% vs. 20%), observed Dr. Shaw, who said the majority of adverse events were grades 1/2, generally manageable, and tolerable.
This was reflected in patient-reported lung cancer symptoms and quality of life. Based on the EORTC Quality of Life Questionnaire (QLQ C-30) and QLQ-LC 13, crizotinib patients had greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain as well as global quality of life (both P less than .0001).
"This is a compound with very mild toxicity," commented Dr. Soria.
He said clinicians need to be aware of crizotinib’s distinct side effect profile, including other rare events such as renal cysts, pneumonitis, asymptomatic bradycardia, and low testosterone, "although we don’t really know if it impacts sexual life."
The topic of hypogonadism was raised in a separate session on second-generation ALK inhibitors at the meeting and in a recent report of rapid-onset hypogonadism secondary to crizotinib use in 19 men with metastatic NSCLC (Cancer 2012 [doi:10.1002/cncr.27450]).
Dr. Shaw said in an interview that the study was small and "requires a lot more validation." Although testosterone levels were not checked in PROFILE 1007, it is being done for the next generation of ALK inhibitors, she added.
Dr. Soria said resistance to crizotinib will become a problem with increasing worldwide use, and that strategies to counter this may include the second-generation ALK inhibitors, increased crizotinib dosing, and crizotinib plus ablative therapy given the poor penetration of crizotinib in the brain.
Brain metastases were present in 35% of patients in both arms. Three-fourths of patients were never smokers, roughly 95% had adenocarcinoma, and their median age was about 50 years.
Dr. Shaw reported an advisory relationship with Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo and research funding from AstraZeneca and Novartis. Dr. Soria reported consultancy fees and steering committee activities with several firms including Pfizer, which sponsored the study.
VIENNA – Long-awaited data from the phase III PROFILE 1007 confirm that crizotinib provides superior progression-free survival and responses, compared with second-line chemotherapy in advanced anaplastic lymphoma kinase–positive non–small cell lung cancer.
Median progression-free survival more than doubled from 3.0 months with single-agent chemotherapy to 7.7 months with crizotinib, according to an independent radiologic review (P value less than .0001; hazard ratio, 0.49).
Crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months; P less than .0001) or pemetrexed (Alimta) (7.7 vs. 4.2; P = .0004), an agent previously shown to be effective against ALK-positive NSCLC.
The overall response rate was 65.3% for crizotinib and 19.5% for chemotherapy in the intent to treat population of 347 patients (overall response rate ratio 3.4; P less than .0001).
Crizotinib was also associated with significantly greater improvement in lung cancer symptoms and quality of life, Dr. Alice Shaw reported during a presidential symposium at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
"Taken together, these results establish crizotinib as the standard of care for patients with advanced, previously treated ALK-positive non–small cell lung cancer," she said.
ALK rearrangements are present in about 5% of lung cancers, typically in younger, never smokers.
Overall survival in the study was 22.8 months for chemotherapy and 20.3 months for crizotinib (P = .5394; HR, 1.02).
The interim survival analysis was immature with just 40% of expected deaths reported and likely confounded by the high number (87%) of chemotherapy patients who crossed over to crizotinib after progression, she noted. After adjusting for crossover, the hazard ratio suggests a survival advantage with crizotinib (HR, 0.83).
Discussant Jean-Charles Soria of Institut Gustave Roussy, Villejuif, France, agreed and said the survival times in either arm were impressive, observing that just two years ago survival in second-line ALK-positive NSCLC was just nine months.
"This is really changing the natural history of the disease," he said.
Crizotinib, an oral, first in class ALK inhibitor, was given accelerated approval in 2011 in the United States to treat advanced ALK-positive NSCLC but is not approved in Europe, where regulatory agencies have required data from the randomized trial.
"While the U.S. treats, Europe randomizes," Dr. Soria lamented to a loud round of laughter.
He observed that worldwide use of crizotinib will require that several financial and practical issues surrounding implementation of molecular testing in daily practice be addressed including the optimal technique, type of sample, and tissue availability.
Testing for epidermal growth factor receptor, another molecular alteration that directs targeted therapy in lung cancer, "should not compete with ALK," he said, adding that multiplexing test strategies "are key."
Investigators at 105 sites across 21 countries in Europe, the Americas, and Asia-Pacific, randomized 173 patients to crizotinib 250 mg twice-daily in a 21-day cycle and 174 patients to chemotherapy containing pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle.
Treatment duration varied significantly, with patients receiving a median of 11 cycles of crizotinib vs. 4 cycles of chemotherapy. This may have influenced the higher number of all-cause deaths among crizotinib patients (25 deaths vs. 7 deaths), said Dr. Shaw, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston.
Crizotinib patients were more likely than were chemotherapy patients to experience the now well-known side effect of visual disturbances (any grade 60% vs. 9%), as well as diarrhea, nausea, elevated transaminases (16% grade 3/4 ), edema, upper respiratory infection, dysgeusia, and dizziness.
In contrast, fatigue, alopecia, dyspnea, and rash were more common in those receiving chemotherapy.
Despite the fact that patients on crizotinib experienced more nausea and vomiting, antiemetic use was significantly higher in the chemotherapy arm (67% vs. 20%), observed Dr. Shaw, who said the majority of adverse events were grades 1/2, generally manageable, and tolerable.
This was reflected in patient-reported lung cancer symptoms and quality of life. Based on the EORTC Quality of Life Questionnaire (QLQ C-30) and QLQ-LC 13, crizotinib patients had greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain as well as global quality of life (both P less than .0001).
"This is a compound with very mild toxicity," commented Dr. Soria.
He said clinicians need to be aware of crizotinib’s distinct side effect profile, including other rare events such as renal cysts, pneumonitis, asymptomatic bradycardia, and low testosterone, "although we don’t really know if it impacts sexual life."
The topic of hypogonadism was raised in a separate session on second-generation ALK inhibitors at the meeting and in a recent report of rapid-onset hypogonadism secondary to crizotinib use in 19 men with metastatic NSCLC (Cancer 2012 [doi:10.1002/cncr.27450]).
Dr. Shaw said in an interview that the study was small and "requires a lot more validation." Although testosterone levels were not checked in PROFILE 1007, it is being done for the next generation of ALK inhibitors, she added.
Dr. Soria said resistance to crizotinib will become a problem with increasing worldwide use, and that strategies to counter this may include the second-generation ALK inhibitors, increased crizotinib dosing, and crizotinib plus ablative therapy given the poor penetration of crizotinib in the brain.
Brain metastases were present in 35% of patients in both arms. Three-fourths of patients were never smokers, roughly 95% had adenocarcinoma, and their median age was about 50 years.
Dr. Shaw reported an advisory relationship with Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo and research funding from AstraZeneca and Novartis. Dr. Soria reported consultancy fees and steering committee activities with several firms including Pfizer, which sponsored the study.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
Major Finding: Median progression-free survival was 3.0 months with chemotherapy and 7.7 months with crizotinib (P less than .0001; hazard ratio 0.49).
Data Source: Results came from a phase III study involving 318 patients with advanced ALK-positive non–small cell lung cancer.
Disclosures: Dr. Shaw reported an advisory relationship with Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo and research funding from AstraZeneca and Novartis.
