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FDA approves sunitinib malate as adjuvant treatment for RCC
The Food and Drug Administration has approved sunitinib malate for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
“This is the first adjuvant treatment approved for patients with renal cell carcinoma, which is significant because patients with this disease who have a nephrectomy are often at high risk of the cancer returning,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
Approval for adjuvant treatment of RCC was based on median disease-free survival of 6.8 years for patients receiving sunitinib malate, compared with 5.6 years for patients receiving placebo in S-TRAC, a phase III trial of 615 patients with high risk of recurrent RCC following nephrectomy. In the trial, presented at the European Society for Medical Oncology Congress in 2016 and published in the New England Journal of Medicine, patients were randomized 1:1 to receive either 50 mg sunitinib malate once daily, 4 weeks on treatment followed by 2 weeks off, or placebo. Overall survival data were not mature at the time of data analysis.
The most common adverse reactions to sunitinib in the trial were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia, dyspepsia, and thrombocytopenia.
Severe side effects included hepatotoxicity, low left ventricular ejection fraction, myocardial ischemia/infarction, prolonged QT intervals/torsade de pointes, hypertension, hemorrhagic events, tumor lysis syndrome, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome), proteinuria, thyroid dysfunction, hypoglycemia, osteonecrosis, and wound-healing complications. A boxed warning alerts health care professionals and patients about the risk of hepatoxicity, which may result in liver failure or death.
Sunitinib malate is marketed as Sutent by Pfizer. The recommended dose for the adjuvant treatment of RCC is 50 mg orally once daily, with or without food, 4 weeks on treatment followed by 2 weeks off for nine 6-week cycles.
Full prescribing information is available here.
The Food and Drug Administration has approved sunitinib malate for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
“This is the first adjuvant treatment approved for patients with renal cell carcinoma, which is significant because patients with this disease who have a nephrectomy are often at high risk of the cancer returning,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
Approval for adjuvant treatment of RCC was based on median disease-free survival of 6.8 years for patients receiving sunitinib malate, compared with 5.6 years for patients receiving placebo in S-TRAC, a phase III trial of 615 patients with high risk of recurrent RCC following nephrectomy. In the trial, presented at the European Society for Medical Oncology Congress in 2016 and published in the New England Journal of Medicine, patients were randomized 1:1 to receive either 50 mg sunitinib malate once daily, 4 weeks on treatment followed by 2 weeks off, or placebo. Overall survival data were not mature at the time of data analysis.
The most common adverse reactions to sunitinib in the trial were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia, dyspepsia, and thrombocytopenia.
Severe side effects included hepatotoxicity, low left ventricular ejection fraction, myocardial ischemia/infarction, prolonged QT intervals/torsade de pointes, hypertension, hemorrhagic events, tumor lysis syndrome, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome), proteinuria, thyroid dysfunction, hypoglycemia, osteonecrosis, and wound-healing complications. A boxed warning alerts health care professionals and patients about the risk of hepatoxicity, which may result in liver failure or death.
Sunitinib malate is marketed as Sutent by Pfizer. The recommended dose for the adjuvant treatment of RCC is 50 mg orally once daily, with or without food, 4 weeks on treatment followed by 2 weeks off for nine 6-week cycles.
Full prescribing information is available here.
The Food and Drug Administration has approved sunitinib malate for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.
“This is the first adjuvant treatment approved for patients with renal cell carcinoma, which is significant because patients with this disease who have a nephrectomy are often at high risk of the cancer returning,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.
Approval for adjuvant treatment of RCC was based on median disease-free survival of 6.8 years for patients receiving sunitinib malate, compared with 5.6 years for patients receiving placebo in S-TRAC, a phase III trial of 615 patients with high risk of recurrent RCC following nephrectomy. In the trial, presented at the European Society for Medical Oncology Congress in 2016 and published in the New England Journal of Medicine, patients were randomized 1:1 to receive either 50 mg sunitinib malate once daily, 4 weeks on treatment followed by 2 weeks off, or placebo. Overall survival data were not mature at the time of data analysis.
The most common adverse reactions to sunitinib in the trial were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia, dyspepsia, and thrombocytopenia.
Severe side effects included hepatotoxicity, low left ventricular ejection fraction, myocardial ischemia/infarction, prolonged QT intervals/torsade de pointes, hypertension, hemorrhagic events, tumor lysis syndrome, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome), proteinuria, thyroid dysfunction, hypoglycemia, osteonecrosis, and wound-healing complications. A boxed warning alerts health care professionals and patients about the risk of hepatoxicity, which may result in liver failure or death.
Sunitinib malate is marketed as Sutent by Pfizer. The recommended dose for the adjuvant treatment of RCC is 50 mg orally once daily, with or without food, 4 weeks on treatment followed by 2 weeks off for nine 6-week cycles.
Full prescribing information is available here.
Cancer patients with TKI-induced hypothyroidism had better survival rates
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: Relative to peers who remained euthyroid, patients who developed overt hypothyroidism had a reduced risk of death (HR, 0.56; P less than .0001).
Data source: A retrospective cohort study of 538 adult patients with mainly advanced nonthyroid cancers treated with a tyrosine kinase inhibitor.
Disclosures: Dr. Angell had no relevant conflicts of interest.
CheckMate 214: Updated results for RCC focus on PD-L1 expression, QOL
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
AT SITC 2017
Key clinical point:
Major finding: Overall response outcomes favored nivo/ipi vs. sunitinib for both PD-L1–positive tumors and PD-L1–negative tumors, but more so for PD-L1–positive tumors (P less than .0001 and P = .252, respectively).
Data source: The 1,096-patient open-label, phase 3 CheckMate 214 trial.
Disclosures: CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical.
Perioperative blood transfusion linked to worse outcomes in renal cell carcinoma
Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.
Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).
Previous research suggests that PBT may be associated with worse oncological outcomes following cancer surgery, although the data have been inconsistent. In this study, Dr. Abu-Ghanem and colleagues conducted a retrospective study that examined effect of PBT on the prognosis of 1,159 patients who underwent radical nephrectomy or partial nephrectomy for RCC, between 1987 to 2013.
Within this cohort, 198 patients (17.1%) received a PBT, and the median follow-up was 63.2 months. Receipt of PBT was associated with a symptomatic presentation (P less than .001) and a higher rate of adverse pathological features that included larger tumors (P less than .001), high nuclear grade (P less than .001), presence of tumor necrosis (P less than .001), and capsular invasion (P less than .001). Patients who received PBT were also more likely to have undergone an open surgical procedure (P less than .05).
The authors found that receipt of a PBT was associated with significantly worse 5-year relapse free survival (81% vs. 92%, P less than .01) as well as metastatic free survival (79% vs. 93%, P less than .001). Receiving a PBT was also associated with a worse 5-year CSS (85% vs. 95%, P less than .001) and OS (73% vs. 81%, P less than .001) versus those who were not transfused.
A subgroup analysis showed that patients who underwent a partial nephrectomy also had worse outcomes if they received a PBT as compared to those who didn’t; 5-year relapse free survival was 81% vs. 90% (P = .014), CSS was 89% vs. 97% (P = .019) and OS was 82% vs. 92%, (P = .016).
There were no funding sources or author disclosures listed in the article.
Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.
Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).
Previous research suggests that PBT may be associated with worse oncological outcomes following cancer surgery, although the data have been inconsistent. In this study, Dr. Abu-Ghanem and colleagues conducted a retrospective study that examined effect of PBT on the prognosis of 1,159 patients who underwent radical nephrectomy or partial nephrectomy for RCC, between 1987 to 2013.
Within this cohort, 198 patients (17.1%) received a PBT, and the median follow-up was 63.2 months. Receipt of PBT was associated with a symptomatic presentation (P less than .001) and a higher rate of adverse pathological features that included larger tumors (P less than .001), high nuclear grade (P less than .001), presence of tumor necrosis (P less than .001), and capsular invasion (P less than .001). Patients who received PBT were also more likely to have undergone an open surgical procedure (P less than .05).
The authors found that receipt of a PBT was associated with significantly worse 5-year relapse free survival (81% vs. 92%, P less than .01) as well as metastatic free survival (79% vs. 93%, P less than .001). Receiving a PBT was also associated with a worse 5-year CSS (85% vs. 95%, P less than .001) and OS (73% vs. 81%, P less than .001) versus those who were not transfused.
A subgroup analysis showed that patients who underwent a partial nephrectomy also had worse outcomes if they received a PBT as compared to those who didn’t; 5-year relapse free survival was 81% vs. 90% (P = .014), CSS was 89% vs. 97% (P = .019) and OS was 82% vs. 92%, (P = .016).
There were no funding sources or author disclosures listed in the article.
Perioperative blood transfusion (PBT) is associated with poorer outcomes among patients who underwent nephrectomy for renal cell carcinoma (RCC), according to a retrospective review of 1,159 patients.
Using multivariate analysis and controlling for potential confounders such as clinical and pathologic features, receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).
Previous research suggests that PBT may be associated with worse oncological outcomes following cancer surgery, although the data have been inconsistent. In this study, Dr. Abu-Ghanem and colleagues conducted a retrospective study that examined effect of PBT on the prognosis of 1,159 patients who underwent radical nephrectomy or partial nephrectomy for RCC, between 1987 to 2013.
Within this cohort, 198 patients (17.1%) received a PBT, and the median follow-up was 63.2 months. Receipt of PBT was associated with a symptomatic presentation (P less than .001) and a higher rate of adverse pathological features that included larger tumors (P less than .001), high nuclear grade (P less than .001), presence of tumor necrosis (P less than .001), and capsular invasion (P less than .001). Patients who received PBT were also more likely to have undergone an open surgical procedure (P less than .05).
The authors found that receipt of a PBT was associated with significantly worse 5-year relapse free survival (81% vs. 92%, P less than .01) as well as metastatic free survival (79% vs. 93%, P less than .001). Receiving a PBT was also associated with a worse 5-year CSS (85% vs. 95%, P less than .001) and OS (73% vs. 81%, P less than .001) versus those who were not transfused.
A subgroup analysis showed that patients who underwent a partial nephrectomy also had worse outcomes if they received a PBT as compared to those who didn’t; 5-year relapse free survival was 81% vs. 90% (P = .014), CSS was 89% vs. 97% (P = .019) and OS was 82% vs. 92%, (P = .016).
There were no funding sources or author disclosures listed in the article.
FROM UROLOGIC ONCOLOGY
Key clinical point: Major finding: Receipt of PBT was associated with significantly increased risk of tumor recurrence (HR = 2, P = .02, metastatic progression (HR = 2.5, P = .007), and death from RCC (HR = 2.5, P = .02).
Data source: Retrospective study that included 1,159 patients with RCC who underwent nephrectomy and evaluated outcomes in those who received a PBT versus those who did not.
Disclosures: There are no funding sources or author disclosures listed.
High EZH2 expression a marker for death risk in RCC
In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.
Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.
Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).
“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.
EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.
In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.
In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).
When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).
They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).
The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.
“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.
The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.
In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.
Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.
Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).
“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.
EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.
In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.
In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).
When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).
They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).
The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.
“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.
The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.
In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.
Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.
Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238).
“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.
EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.
In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.
In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).
When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).
They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).
The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat.
“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.
The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: High levels of EZH2 were associated with worse survival of clear cell renal cell carcinoma (RCC).
Major finding: Patients with RCC who had high levels of EZH2 expression in tumors had about a 1.5-fold risk for all-cause mortality, and twofold risk for RCC-specific death.
Data source: Analysis of EZH2 gene and protein expression in tumors from 1,192 patients with RCC in three cohorts.
Disclosures: The study was supported by the Mayo Clinic, Gerstner Family Career Development Award National Cancer Institute and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.
PFS better with first-line pazopanib vs. sorafenib in mRCC
MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.
The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.
The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.
However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.
SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.
In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.
A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.
After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.
For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.
Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.
An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).
In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).
A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.
In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.
Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.
He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.
The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.
MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.
The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.
The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.
However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.
SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.
In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.
A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.
After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.
For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.
Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.
An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).
In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).
A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.
In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.
Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.
He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.
The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.
MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.
The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.
The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.
However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.
SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.
In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.
A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.
After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.
For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.
Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.
An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).
In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).
A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.
In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.
Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.
He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.
The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.
AT ESMO 2017
Key clinical point: than when the drug sequence was reversed.
Major finding: Total PFS with sorafenib-pazopanib did not meet its primary endpoint of noninferiority to pazopanib-sorafenib.
Data source: Randomized, sequential open-label, phase 3 trial in 377 patients with advanced/metastatic RCC.
Disclosures: The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.
Checkmate 214: Upfront nivo/ipi bests TKI in advanced RCC
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
AT ESMO 2017
Key clinical point: The combination of the PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab was efficacious in frontline therapyfor advanced or metastatic renal cell carcinoma.
Major finding: The trial met its coprimary endpoints of overall response rate and progression-free survival, as well as its secondary endpoint of overall survival.
Data source: Randomized open-label study in 1096 patients with advanced/metastatic RCC, including 847 with intermediate- to poor-risk disease.
Disclosures: The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
FDA approves biosimilar to bevacizumab
The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.
Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.
Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.
• Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product–containing regimen.
• Non-squamous non–small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent, or metastatic disease.
• Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate.
• Metastatic renal cell carcinoma, in combination with interferon alfa.
• Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
Common expected side effects of the biosimilar include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Serious expected side effects include perforation or fistula, arterial and venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion-related reactions, and ovarian failure. Women who are pregnant should not take bevacizumab-awwb.
The biosimilar to bevacizumab carries a similar boxed warning regarding the increased risk of gastrointestinal perforations; surgery and wound healing complications; and severe or fatal pulmonary, gastrointestinal, central nervous system, and vaginal hemorrhage.
The biosimilar approval was granted to Amgen, which will market the drug under the trade name Mvasi.
The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.
Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.
Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.
• Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product–containing regimen.
• Non-squamous non–small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent, or metastatic disease.
• Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate.
• Metastatic renal cell carcinoma, in combination with interferon alfa.
• Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
Common expected side effects of the biosimilar include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Serious expected side effects include perforation or fistula, arterial and venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion-related reactions, and ovarian failure. Women who are pregnant should not take bevacizumab-awwb.
The biosimilar to bevacizumab carries a similar boxed warning regarding the increased risk of gastrointestinal perforations; surgery and wound healing complications; and severe or fatal pulmonary, gastrointestinal, central nervous system, and vaginal hemorrhage.
The biosimilar approval was granted to Amgen, which will market the drug under the trade name Mvasi.
The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.
Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.
Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.
• Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product–containing regimen.
• Non-squamous non–small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent, or metastatic disease.
• Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate.
• Metastatic renal cell carcinoma, in combination with interferon alfa.
• Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
Common expected side effects of the biosimilar include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Serious expected side effects include perforation or fistula, arterial and venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion-related reactions, and ovarian failure. Women who are pregnant should not take bevacizumab-awwb.
The biosimilar to bevacizumab carries a similar boxed warning regarding the increased risk of gastrointestinal perforations; surgery and wound healing complications; and severe or fatal pulmonary, gastrointestinal, central nervous system, and vaginal hemorrhage.
The biosimilar approval was granted to Amgen, which will market the drug under the trade name Mvasi.
PROTECT trial: No DFS benefit with adjuvant pazopanib for high-risk RCC
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
Adjuvant pazopanib provided no disease-free survival benefit compared with placebo in the randomized phase 3 PROTECT trial of patients with locally advanced renal cell carcinoma at high risk for relapse after nephrectomy.
In the primary analysis for disease-free survival among 571 patients treated for 1 year with 600 mg of pazopanib and 564 who received placebo, no significant improvement was seen with pazopanib (hazard ratio, 0.86). In a follow-up analysis 12 months later, the hazard ratio was 0.94. Secondary analysis in 403 additional patients who were treated with 800 mg of pazopanib before the dose was lowered to 600 mg due to intolerance and toxicity attrition showed a benefit with pazopanib (HR, 0.69), but this group represented only a third of the study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and his colleagues. The study results were published online in the Journal of Clinical Oncology.
Common adverse events leading to treatment discontinuation included increased alanine transaminase and aspartate transaminase levels, which occurred in 16% and 5% of patients treated with 600 mg, respectively, and in 18% and 7% of patients treated with 800 mg, respectively. Four grade 5 adverse events occurred in the pazopanib groups (vs. 2 in the placebo group), and one of the deaths (in a patient who received 800 mg dosing) involved cardiomyopathy that was considered to be related to treatment, the investigators said (J Clin Oncol. 2017 Sep 13. doi: 10.1200/JCO.2017.73.5324).
The study comprised adults with resected pT2 or pT3 and greater disease, including N1, clear cell renal cell carcinoma, who were enrolled between Dec. 9, 2010, and Sept. 10, 2013, from 263 centers in 26 countries. Primary analysis was done after 350 disease-free events occurred in the intent-to-treat population receiving 600 mg.
The difference in treatment effect between those receiving 600 mg and 800 mg of pazopanib could be explained by the different starting dose, or by better performance of the placebo arm in the 600 mg group, the investigators noted.
As for overall survival, the results are inconclusive, because the data are not mature, they said.
Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: In the primary analysis for disease-free survival, no significant improvement was seen with pazopanib vs. placebo (hazard ratio, 0.86).
Data source: The phase 3 PROTECT study of 1,538 patients.
Disclosures: Novartis supported the study. Dr. Mercer reported consulting or advisory roles with Pfizer, Novartis, Eisai, and Exelixis, and research funding to his institution from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech. Numerous coauthors also reported financial relationships with pharmaceutical companies.
Pembrolizumab, nivolumab linked to 3% rate of neurologic events
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
FROM JAMA NEUROLOGY
Key clinical point: Watch for immune-related adverse effects of nivolumab and pembrolizumab.
Major finding: Ten of 347 patients (2.9%) developed subacute neurologic immune-related adverse events, typically neuromuscular syndromes.
Data source: A single-center, retrospective cohort study of 347 patients who received pembrolizumab or nivolumab for metastatic melanoma or solid tumors.
Disclosures: The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.