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Plasma lipoprotein perturbations likely contribute to sickle cell vasculopathy
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
FROM EXPERIMENTAL BIOLOGY AND MEDICINE
Key clinical point:
Major finding: Patients with SCD had reduced levels of HDL3 and altered functionality of HDL2, which were associated with an increased lipoprotein-mediated inflammatory response of endothelial cells.
Data source: An observational cohort study using 31 plasma samples from patients with sickle cell disease and 12 plasma samples from healthy individuals.
Disclosures: Dr. Soupene disclosed that he had no relevant conflicts of interest.
SUNSHINE: High-dose vitamin D boosts PFS in metastatic CRC
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
AT ASCO 2017
Key clinical point:
Major finding: Compared with chemotherapy plus low-dose vitamin D, chemotherapy plus high-dose vitamin D was associated with a reduced risk of progression or death (hazard ratio, 0.67).
Data source: A phase II randomized trial (SUNSHINE) among 139 patients with untreated metastatic colorectal cancer.
Disclosures: Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
Optimizing therapy in relapsed CLL: ibrutinib and beyond
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
AT ASCO 2017
Key clinical point:
Major finding: Long-term progression-free survival was better with ibrutinib than with ofatumumab (hazard ratio, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. Fully 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib.
Data source: An update of a phase III randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL.
Disclosures: Dr. Byrd disclosed that he receives research funding from Genentech, Acerta, and Pharmacyclics. The RESONATE trial was funded by Pharmacyclics. Dr. Nastoupil disclosed that she receives honoraria from Abbvie, Celgene, Genentech/Roche, Gilead Sciences, Pharmacyclics, and TG Therapeutics; receives research funding from Abbvie, Celgene, Janssen Biotech, and TG Therapeutics; and receives travel, accommodations, and/or expenses from Janssen Biotech. The trial was funded by TG Therapeutics. Dr. Gill disclosed that he receives honoraria from Alexion Pharmaceuticals, receives research funding from Novartis (institutional), and has patents for CAR-T cells for acute myeloid leukemia. The trial was funded by Novartis.
PROTECT: Pazopanib falls short as adjuvant therapy for high-risk RCC
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.
Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.
In PROTECT, a phase III randomized controlled trial of more than 1,500 patients who had undergone nephrectomy for high-risk locally advanced RCC, pazopanib started at 600 mg daily did not yield significantly better disease-free survival than placebo, the trial’s primary endpoint. The drug did have a significant benefit when started at 800 mg daily, but that dose had to be lowered partway through because of a high rate of discontinuation due to adverse events.
“The trial did not meet its primary endpoint,” Dr. Motzer concluded. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”
Expert perspective
“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.
“Are these [factors] important or not? I think a lot of this is being overshadowed by things that are going on right now,” Dr. Heng maintained. “There are newer medications, such as PD-1 and PD-L1 inhibitors that are now being studied. And there are now perioperative studies as well – should we be using these drugs before nephrectomy and after nephrectomy to prime the immune system to get better outcomes?”
At the end of the day, identification of a reliable predictive biomarker will be key to using the VEGFR tyrosine kinase inhibitors, he concluded. “I look forward to the future where we can actually use these tests to determine who will benefit most from adjuvant therapy so that we can maximize patient outcomes.”
Study details
The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.
The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.
In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.
In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).
One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.
Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.
Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.
Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.
“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.
A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.
Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.
AT ASCO 2017
Key clinical point:
Major finding: Compared with placebo, pazopanib started at 600 mg daily did not significantly reduce the risk of disease-free survival events (hazard ratio, 0.86; P = .16).
Data source: A phase III randomized controlled trial among 1,538 patients who had undergone nephrectomy for high-risk locally advanced RCC (PROTECT trial).
Disclosures: Dr. Motzer disclosed that he is a consultant to Eisai, Exelixis, Merck, Novartis, and Pfizer, and that he receives research funding from Bristol-Myers Squibb (institutional), Eisai (institutional), Genentech/Roche (institutional), GlaxoSmithKline (institutional), Novartis (institutional), and Pfizer (institutional). The trial was funded by Novartis Oncology.
Hypogonadism after testicular cancer treatment can have lifelong impact
CHICAGO – Hypogonadism may compromise the long-term health outlook for many younger men who have been successfully treated for testicular cancer, according to an analysis conducted by the Platinum Study Group.
“Today, 95% of all testicular cancer patients are cured of their disease thanks to cisplatin-based chemotherapy. Nowadays, testicular cancer survivors can expect to live for over 40 years from the time of their diagnosis,” lead investigator Mohammad Issam Abu Zaid, MBBS, said in a press briefing at the annual meeting of the American Society of Clinical Oncology. “However, they are at risk of other health problems that may be related to their cancer treatment, including late complications from chemotherapy.”
“Testicular cancer survivors, especially those treated with chemotherapy, are at increased risk for hypogonadism, a problem that can be associated with predisposing factors for heart disease,” summarized Dr. Abu Zaid, of Indiana University in Indianapolis. “Mitigating approaches are the usual weight control, exercise, and monitoring of blood pressure and cholesterol levels.”
Expert perspective
“This is an important study, and it sends a loud message to those of us who take care of testis cancer patients, my area of expertise. ... We need to watch for hypogonadism, and we need to ask survivors about it. We need to examine them thinking about it, and, in patients who we are worried [they] might have hypogonadism, we need to do blood tests for testosterone and other hormone levels,” commented ASCO Expert Timothy D. Gilligan, MD, MSc, of the Cleveland Clinic in Ohio. “These are young patients, they have many years of life, so it’s many decades of suffering from consequences of this if it’s undetected.”
The findings were not surprising based on his personal experience and on evidence from the prostate cancer field showing the adverse metabolic effects of withdrawing testosterone, he said. Although the prevalence of hypogonadism found in the study was higher than that found in other studies, given the large size of the cohort, it should be taken seriously. Additionally, even if the true prevalence is somewhat lower, the absolute number of survivors affected would be substantial.
“We need to be cautious though and make sure people don’t misunderstand and think that this means we should test testosterone levels in all patients, which is a risky thing to do because the definition of normal testosterone is very fuzzy,” Dr. Gilligan stressed. “There is a wide range of normal, and what’s normal for me may not be the same as what’s normal for another man. So, looking for symptoms is really what guides this work, and, when there are symptoms, then testing is important.”
Study details
The Platinum Study is a large, ongoing, multicenter North American–based cohort study of testicular cancer survivors who received cisplatin as part of their chemotherapy.
Dr. Abu Zaid and his colleagues analyzed data from 491 participants who were aged 50 years or younger at diagnosis. All completed questionnaires addressing comorbidities, medications, and health behaviors; underwent physical examination; had measurement of testosterone levels; and had a genetic analysis.
The men were by and large young at the time of evaluation, with a mean age of just 38 years, he reported in the press briefing and a poster session at the meeting.
Overall, 38.5% had hypogonadism, defined in the study as a serum testosterone level of 3 ng/mL or lower or as use of testosterone replacement therapy.
In a multivariate analysis, survivors’ odds of hypogonadism increased with age (odds ratio, 1.41 per 10-year increment; P = .007) and were higher for those having a body mass index of 25 kg/m2 or greater, vs. lower (OR, 2.22; P = .003). On the other hand, there was a trend whereby survivors who engaged in any vigorous-intensity physical activity, vs. none, were less likely to have hypogonadism (OR, 0.64; P = .06).
The odds rose with number of risk alleles in the sex hormone–binding globulin gene, but findings were not significant, Dr. Abu Zaid said. They were also statistically indistinguishable across groups differing with respect to the chemotherapy regimen received and socioeconomic factors.
Compared with counterparts having normal testosterone levels, survivors having hypogonadism were up to four times more likely to be taking medication to treat dyslipidemia (20.1% vs. 6.0%; P less than .001), hypertension (18.5% vs. 10.6%; P = .013), erectile dysfunction (19.6% vs. 11.9%; P = .018), diabetes (5.8% vs. 2.6%; P = .067), and anxiety or depression (14.8% vs. 9.3%; P = .060).
Testicular cancer survivors should not universally have testosterone testing, agreed Dr. Abu Zaid. Such a practice might lead to overtreatment, and, in older men at least, use of testosterone itself has been linked to elevated cardiovascular risk.
“You really want to treat somebody who has symptoms related to hypogonadism: constant fatigue, night sweats, and depressed mood and some other symptoms that are well known to the clinician,” he maintained. “At the moment, we have no studies done looking at testosterone replacement in young men. I would hypothesize that we actually help them by giving them testosterone, and that’s what I tell my patients.”
CHICAGO – Hypogonadism may compromise the long-term health outlook for many younger men who have been successfully treated for testicular cancer, according to an analysis conducted by the Platinum Study Group.
“Today, 95% of all testicular cancer patients are cured of their disease thanks to cisplatin-based chemotherapy. Nowadays, testicular cancer survivors can expect to live for over 40 years from the time of their diagnosis,” lead investigator Mohammad Issam Abu Zaid, MBBS, said in a press briefing at the annual meeting of the American Society of Clinical Oncology. “However, they are at risk of other health problems that may be related to their cancer treatment, including late complications from chemotherapy.”
“Testicular cancer survivors, especially those treated with chemotherapy, are at increased risk for hypogonadism, a problem that can be associated with predisposing factors for heart disease,” summarized Dr. Abu Zaid, of Indiana University in Indianapolis. “Mitigating approaches are the usual weight control, exercise, and monitoring of blood pressure and cholesterol levels.”
Expert perspective
“This is an important study, and it sends a loud message to those of us who take care of testis cancer patients, my area of expertise. ... We need to watch for hypogonadism, and we need to ask survivors about it. We need to examine them thinking about it, and, in patients who we are worried [they] might have hypogonadism, we need to do blood tests for testosterone and other hormone levels,” commented ASCO Expert Timothy D. Gilligan, MD, MSc, of the Cleveland Clinic in Ohio. “These are young patients, they have many years of life, so it’s many decades of suffering from consequences of this if it’s undetected.”
The findings were not surprising based on his personal experience and on evidence from the prostate cancer field showing the adverse metabolic effects of withdrawing testosterone, he said. Although the prevalence of hypogonadism found in the study was higher than that found in other studies, given the large size of the cohort, it should be taken seriously. Additionally, even if the true prevalence is somewhat lower, the absolute number of survivors affected would be substantial.
“We need to be cautious though and make sure people don’t misunderstand and think that this means we should test testosterone levels in all patients, which is a risky thing to do because the definition of normal testosterone is very fuzzy,” Dr. Gilligan stressed. “There is a wide range of normal, and what’s normal for me may not be the same as what’s normal for another man. So, looking for symptoms is really what guides this work, and, when there are symptoms, then testing is important.”
Study details
The Platinum Study is a large, ongoing, multicenter North American–based cohort study of testicular cancer survivors who received cisplatin as part of their chemotherapy.
Dr. Abu Zaid and his colleagues analyzed data from 491 participants who were aged 50 years or younger at diagnosis. All completed questionnaires addressing comorbidities, medications, and health behaviors; underwent physical examination; had measurement of testosterone levels; and had a genetic analysis.
The men were by and large young at the time of evaluation, with a mean age of just 38 years, he reported in the press briefing and a poster session at the meeting.
Overall, 38.5% had hypogonadism, defined in the study as a serum testosterone level of 3 ng/mL or lower or as use of testosterone replacement therapy.
In a multivariate analysis, survivors’ odds of hypogonadism increased with age (odds ratio, 1.41 per 10-year increment; P = .007) and were higher for those having a body mass index of 25 kg/m2 or greater, vs. lower (OR, 2.22; P = .003). On the other hand, there was a trend whereby survivors who engaged in any vigorous-intensity physical activity, vs. none, were less likely to have hypogonadism (OR, 0.64; P = .06).
The odds rose with number of risk alleles in the sex hormone–binding globulin gene, but findings were not significant, Dr. Abu Zaid said. They were also statistically indistinguishable across groups differing with respect to the chemotherapy regimen received and socioeconomic factors.
Compared with counterparts having normal testosterone levels, survivors having hypogonadism were up to four times more likely to be taking medication to treat dyslipidemia (20.1% vs. 6.0%; P less than .001), hypertension (18.5% vs. 10.6%; P = .013), erectile dysfunction (19.6% vs. 11.9%; P = .018), diabetes (5.8% vs. 2.6%; P = .067), and anxiety or depression (14.8% vs. 9.3%; P = .060).
Testicular cancer survivors should not universally have testosterone testing, agreed Dr. Abu Zaid. Such a practice might lead to overtreatment, and, in older men at least, use of testosterone itself has been linked to elevated cardiovascular risk.
“You really want to treat somebody who has symptoms related to hypogonadism: constant fatigue, night sweats, and depressed mood and some other symptoms that are well known to the clinician,” he maintained. “At the moment, we have no studies done looking at testosterone replacement in young men. I would hypothesize that we actually help them by giving them testosterone, and that’s what I tell my patients.”
CHICAGO – Hypogonadism may compromise the long-term health outlook for many younger men who have been successfully treated for testicular cancer, according to an analysis conducted by the Platinum Study Group.
“Today, 95% of all testicular cancer patients are cured of their disease thanks to cisplatin-based chemotherapy. Nowadays, testicular cancer survivors can expect to live for over 40 years from the time of their diagnosis,” lead investigator Mohammad Issam Abu Zaid, MBBS, said in a press briefing at the annual meeting of the American Society of Clinical Oncology. “However, they are at risk of other health problems that may be related to their cancer treatment, including late complications from chemotherapy.”
“Testicular cancer survivors, especially those treated with chemotherapy, are at increased risk for hypogonadism, a problem that can be associated with predisposing factors for heart disease,” summarized Dr. Abu Zaid, of Indiana University in Indianapolis. “Mitigating approaches are the usual weight control, exercise, and monitoring of blood pressure and cholesterol levels.”
Expert perspective
“This is an important study, and it sends a loud message to those of us who take care of testis cancer patients, my area of expertise. ... We need to watch for hypogonadism, and we need to ask survivors about it. We need to examine them thinking about it, and, in patients who we are worried [they] might have hypogonadism, we need to do blood tests for testosterone and other hormone levels,” commented ASCO Expert Timothy D. Gilligan, MD, MSc, of the Cleveland Clinic in Ohio. “These are young patients, they have many years of life, so it’s many decades of suffering from consequences of this if it’s undetected.”
The findings were not surprising based on his personal experience and on evidence from the prostate cancer field showing the adverse metabolic effects of withdrawing testosterone, he said. Although the prevalence of hypogonadism found in the study was higher than that found in other studies, given the large size of the cohort, it should be taken seriously. Additionally, even if the true prevalence is somewhat lower, the absolute number of survivors affected would be substantial.
“We need to be cautious though and make sure people don’t misunderstand and think that this means we should test testosterone levels in all patients, which is a risky thing to do because the definition of normal testosterone is very fuzzy,” Dr. Gilligan stressed. “There is a wide range of normal, and what’s normal for me may not be the same as what’s normal for another man. So, looking for symptoms is really what guides this work, and, when there are symptoms, then testing is important.”
Study details
The Platinum Study is a large, ongoing, multicenter North American–based cohort study of testicular cancer survivors who received cisplatin as part of their chemotherapy.
Dr. Abu Zaid and his colleagues analyzed data from 491 participants who were aged 50 years or younger at diagnosis. All completed questionnaires addressing comorbidities, medications, and health behaviors; underwent physical examination; had measurement of testosterone levels; and had a genetic analysis.
The men were by and large young at the time of evaluation, with a mean age of just 38 years, he reported in the press briefing and a poster session at the meeting.
Overall, 38.5% had hypogonadism, defined in the study as a serum testosterone level of 3 ng/mL or lower or as use of testosterone replacement therapy.
In a multivariate analysis, survivors’ odds of hypogonadism increased with age (odds ratio, 1.41 per 10-year increment; P = .007) and were higher for those having a body mass index of 25 kg/m2 or greater, vs. lower (OR, 2.22; P = .003). On the other hand, there was a trend whereby survivors who engaged in any vigorous-intensity physical activity, vs. none, were less likely to have hypogonadism (OR, 0.64; P = .06).
The odds rose with number of risk alleles in the sex hormone–binding globulin gene, but findings were not significant, Dr. Abu Zaid said. They were also statistically indistinguishable across groups differing with respect to the chemotherapy regimen received and socioeconomic factors.
Compared with counterparts having normal testosterone levels, survivors having hypogonadism were up to four times more likely to be taking medication to treat dyslipidemia (20.1% vs. 6.0%; P less than .001), hypertension (18.5% vs. 10.6%; P = .013), erectile dysfunction (19.6% vs. 11.9%; P = .018), diabetes (5.8% vs. 2.6%; P = .067), and anxiety or depression (14.8% vs. 9.3%; P = .060).
Testicular cancer survivors should not universally have testosterone testing, agreed Dr. Abu Zaid. Such a practice might lead to overtreatment, and, in older men at least, use of testosterone itself has been linked to elevated cardiovascular risk.
“You really want to treat somebody who has symptoms related to hypogonadism: constant fatigue, night sweats, and depressed mood and some other symptoms that are well known to the clinician,” he maintained. “At the moment, we have no studies done looking at testosterone replacement in young men. I would hypothesize that we actually help them by giving them testosterone, and that’s what I tell my patients.”
AT ASCO 2017
Key clinical point:
Major finding: Fully 38.5% of survivors had low testosterone levels, and men in this group were more likely to be taking medications for dyslipidemia, hypertension, diabetes, erectile dysfunction, and anxiety or depression.
Data source: A cohort study of 491 testicular cancer survivors who had been treated with cisplatin-based chemotherapy (Platinum Study).
Disclosures: Dr. Abu Zaid reported that he had no relevant disclosures.
OlympiAD’s positive results spell good news for olaparib in breast cancer
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
AT ASCO 2017
Key clinical point:
Major finding: Progression-free survival was superior with olaparib as compared with standard single-agent chemotherapy (7.0 vs. 4.2 months; hazard ratio, 0.58; P = .0009).
Data source: An open-label randomized phase III trial among 302 patients with HER2-negative metastatic breast cancer and a germline BRCA mutation (OlympiAD trial).
Disclosures: Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; and receives research funding (institutional) from AstraZeneca, AbbVie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
TRK inhibitor shows ‘striking’ activity, durability across diverse adult and pediatric cancers
CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.
Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.
Dr. Hyman and his colleagues analyzed data from 55 patients having 17 discrete types of advanced cancer harboring TRK fusions who were treated with larotrectinib in phase I and II trials. Results showed an overall response rate of 76%, and the large majority of responses were still ongoing at 12 months.
“I believe these data support larotrectinib as a potential new standard of care for these patients,” he said. “However, I want to emphasize that really recognizing this benefit in the community will require that we test patients more universally for the presence of TRK fusions or other tumor-agnostic biomarkers, such as microsatellite instability.”
On the basis of these promising data, the drug’s manufacturer, Loxo Oncology, plans to submit a New Drug Application to the Food and Drug Administration later this year or early next year. Larotrectinib has already been granted both orphan drug designation (for drugs used to treat rare conditions) and breakthrough therapy designation (for drugs used to treat serious conditions showing greater efficacy than available therapies).
A randomized trial pitting larotrectinib against other therapies is unlikely given the low prevalence of TRK fusions, the lack of treatment options for the fairly heavily pretreated trial patients, and the drug’s impressive performance, according to Dr. Hyman.
“The efficacy is so striking that it really exceeds almost any existing standard of care for solid tumors,” he elaborated. “There is hardly any chemotherapy or targeted therapy that has a response rate or durability that looks like larotrectinib in these patients.”
Expert perspective
The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.
TRK testing
Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.
“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.
Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”
Study details
For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).
“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”
In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.
Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.
With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.
The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.
It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.
Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.
Dr. Hyman and his colleagues analyzed data from 55 patients having 17 discrete types of advanced cancer harboring TRK fusions who were treated with larotrectinib in phase I and II trials. Results showed an overall response rate of 76%, and the large majority of responses were still ongoing at 12 months.
“I believe these data support larotrectinib as a potential new standard of care for these patients,” he said. “However, I want to emphasize that really recognizing this benefit in the community will require that we test patients more universally for the presence of TRK fusions or other tumor-agnostic biomarkers, such as microsatellite instability.”
On the basis of these promising data, the drug’s manufacturer, Loxo Oncology, plans to submit a New Drug Application to the Food and Drug Administration later this year or early next year. Larotrectinib has already been granted both orphan drug designation (for drugs used to treat rare conditions) and breakthrough therapy designation (for drugs used to treat serious conditions showing greater efficacy than available therapies).
A randomized trial pitting larotrectinib against other therapies is unlikely given the low prevalence of TRK fusions, the lack of treatment options for the fairly heavily pretreated trial patients, and the drug’s impressive performance, according to Dr. Hyman.
“The efficacy is so striking that it really exceeds almost any existing standard of care for solid tumors,” he elaborated. “There is hardly any chemotherapy or targeted therapy that has a response rate or durability that looks like larotrectinib in these patients.”
Expert perspective
The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.
TRK testing
Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.
“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.
Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”
Study details
For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).
“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”
In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.
Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.
With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.
The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.
It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.
Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.
Dr. Hyman and his colleagues analyzed data from 55 patients having 17 discrete types of advanced cancer harboring TRK fusions who were treated with larotrectinib in phase I and II trials. Results showed an overall response rate of 76%, and the large majority of responses were still ongoing at 12 months.
“I believe these data support larotrectinib as a potential new standard of care for these patients,” he said. “However, I want to emphasize that really recognizing this benefit in the community will require that we test patients more universally for the presence of TRK fusions or other tumor-agnostic biomarkers, such as microsatellite instability.”
On the basis of these promising data, the drug’s manufacturer, Loxo Oncology, plans to submit a New Drug Application to the Food and Drug Administration later this year or early next year. Larotrectinib has already been granted both orphan drug designation (for drugs used to treat rare conditions) and breakthrough therapy designation (for drugs used to treat serious conditions showing greater efficacy than available therapies).
A randomized trial pitting larotrectinib against other therapies is unlikely given the low prevalence of TRK fusions, the lack of treatment options for the fairly heavily pretreated trial patients, and the drug’s impressive performance, according to Dr. Hyman.
“The efficacy is so striking that it really exceeds almost any existing standard of care for solid tumors,” he elaborated. “There is hardly any chemotherapy or targeted therapy that has a response rate or durability that looks like larotrectinib in these patients.”
Expert perspective
The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.
TRK testing
Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.
“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.
Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”
Study details
For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).
“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”
In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.
Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.
With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.
The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.
It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
AT ASCO 2017
Key clinical point:
Major finding: The overall response rate was 76%, and 79% of responses were still ongoing at 12 months.
Data source: An integrated analysis of phase I and II trials among 55 children and adults having 17 discrete types of advanced cancer with TRK fusions.
Disclosures: Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
VIDEO: Olaparib improves outlook in women with BRCA-related HER2-negative MBC
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: TRK inhibitor shows 76% ORR across diverse cancers harboring TRK fusions
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
Single-dose RT suffices for treatment of spinal cord compression due to mets
CHICAGO – A single dose of radiation therapy appears to work as well as multiple doses given over a week for treating spinal cord compression due to metastatic cancer, according to findings of the SCORAD III trial reported at the annual meeting of the American Society of Clinical Oncology.
“There is no standard radiotherapy schedule,” first author Peter Hoskin, MD, FCRP, FRCR, an oncologist at the Mount Vernon Cancer Centre in Middlesex, England, noted in a press briefing. “A range of radiation doses are used internationally, from single doses of 8 to 10 Gy ranging up to 4 weeks of treatment delivering 40 Gy.”
The noninferiority phase III trial enrolled nearly 700 patients in the United Kingdom and Australia with spinal cord compression due to metastases, the majority of whom were able to walk at baseline. They were randomized evenly to receive either 8 Gy of radiation in a single fraction or 20 Gy split into five fractions given over consecutive days.
Results showed that at 8 weeks, more than two-thirds of patients in each group were able to walk, the trial’s primary endpoint. The lower bound of the confidence interval for the difference between groups fell just outside the trial’s margin for noninferiority.
Additionally, the two groups were statistically indistinguishable with respect to median overall survival, bowel and bladder function, and the rate of grade 3 or 4 toxicity.
“A single dose of 8 Gy is as effective as 20 Gy in five fractions for a range of clinically relevant endpoints, particularly ambulatory status, both at 8 weeks and indeed at all time points between 1 week and 12 weeks,” Dr. Hoskin summarized. The trial also underscores the importance of early diagnosis, as the majority of patients who were ambulatory initially remained so with radiation therapy, regardless of dosing schedule.
“A single dose of radiotherapy in our minds is now recommended in this setting. It has major advantages for these patients,” he maintained. “An important thing to realize is that these patients had a very short survival; median survival in this study was only 13 weeks. A single dose has enormous advantages in those patients with short survival times, and of course, it is increasingly cost effective.”
Findings in context
The trial population was not fully representative of all patients with spinal cord compression due to metastases, with underrepresentation of some cancers, such as breast cancer, and the modest survival, Dr. Hoskin acknowledged.
Some patients on the trial have survived for many months and even years, he noted. “We have looked at patients at longer times, although it was not in the protocol, and there was no obvious difference [in outcomes]. But there is some evidence to suggest that for the longer-surviving patients, a more prolonged fractionation may be appropriate, although clearly that needs to be investigated properly in a formal randomized trial.”
“This is the first study that really shows equal outcomes in terms of meaningful benefits for patients with a single dose of radiotherapy versus a much longer course, allowing patients to spend more time with their families, more time doing the things they want to do,” commented ASCO Expert Joshua A. Jones, MD, MA, of the Hospital of the University of Pennsylvania in Philadelphia.
“We still have work to do to figure out for patients who have longer than this average survival of 3 months what is the most appropriate regimen,” he agreed. “But for many patients, this is going to provide tremendous benefit with the idea that sometimes, less really is more.”
Study details
SCORAD III, which was funded by Cancer Research UK, enrolled 688 patients with metastatic prostate (44%), lung (18%), breast (11%), and gastrointestinal (11%) cancers.
At baseline, 66% were able to walk without or with an aid (ambulatory status 1 or 2), whereas the rest were unable to walk but still had some limb power (ambulatory status 3) or had flaccid paraplegia (ambulatory status 4).
At 8 weeks, the proportion of patients with ambulatory status 1 or 2 was 69.5% in the group who received the 8-Gy single-dose radiation therapy and 73.3% in the group who received the 20-Gy multidose radiation therapy, for a risk difference of –3.78%, reported Dr. Hoskin.
The 90% confidence interval for the difference between groups of –11.85% to 4.28% slightly exceeded the trial’s predefined 11% margin for noninferiority.
Among patients having ambulatory status 1 or 2 at baseline, the proportion maintaining that status at 8 weeks was 62.20% with the single dose and 63.07% with multiple doses. Median overall survival was 12.4 weeks and 13.7 weeks, respectively, a nonsignificant difference.
Patients in the single-dose and multidose groups had similar rates of grade 3 or 4 toxicity (20.6% vs. 20.4%), but the former had a lower rate of grade 1 or 2 toxicity (51.0% vs. 56.9%).
CHICAGO – A single dose of radiation therapy appears to work as well as multiple doses given over a week for treating spinal cord compression due to metastatic cancer, according to findings of the SCORAD III trial reported at the annual meeting of the American Society of Clinical Oncology.
“There is no standard radiotherapy schedule,” first author Peter Hoskin, MD, FCRP, FRCR, an oncologist at the Mount Vernon Cancer Centre in Middlesex, England, noted in a press briefing. “A range of radiation doses are used internationally, from single doses of 8 to 10 Gy ranging up to 4 weeks of treatment delivering 40 Gy.”
The noninferiority phase III trial enrolled nearly 700 patients in the United Kingdom and Australia with spinal cord compression due to metastases, the majority of whom were able to walk at baseline. They were randomized evenly to receive either 8 Gy of radiation in a single fraction or 20 Gy split into five fractions given over consecutive days.
Results showed that at 8 weeks, more than two-thirds of patients in each group were able to walk, the trial’s primary endpoint. The lower bound of the confidence interval for the difference between groups fell just outside the trial’s margin for noninferiority.
Additionally, the two groups were statistically indistinguishable with respect to median overall survival, bowel and bladder function, and the rate of grade 3 or 4 toxicity.
“A single dose of 8 Gy is as effective as 20 Gy in five fractions for a range of clinically relevant endpoints, particularly ambulatory status, both at 8 weeks and indeed at all time points between 1 week and 12 weeks,” Dr. Hoskin summarized. The trial also underscores the importance of early diagnosis, as the majority of patients who were ambulatory initially remained so with radiation therapy, regardless of dosing schedule.
“A single dose of radiotherapy in our minds is now recommended in this setting. It has major advantages for these patients,” he maintained. “An important thing to realize is that these patients had a very short survival; median survival in this study was only 13 weeks. A single dose has enormous advantages in those patients with short survival times, and of course, it is increasingly cost effective.”
Findings in context
The trial population was not fully representative of all patients with spinal cord compression due to metastases, with underrepresentation of some cancers, such as breast cancer, and the modest survival, Dr. Hoskin acknowledged.
Some patients on the trial have survived for many months and even years, he noted. “We have looked at patients at longer times, although it was not in the protocol, and there was no obvious difference [in outcomes]. But there is some evidence to suggest that for the longer-surviving patients, a more prolonged fractionation may be appropriate, although clearly that needs to be investigated properly in a formal randomized trial.”
“This is the first study that really shows equal outcomes in terms of meaningful benefits for patients with a single dose of radiotherapy versus a much longer course, allowing patients to spend more time with their families, more time doing the things they want to do,” commented ASCO Expert Joshua A. Jones, MD, MA, of the Hospital of the University of Pennsylvania in Philadelphia.
“We still have work to do to figure out for patients who have longer than this average survival of 3 months what is the most appropriate regimen,” he agreed. “But for many patients, this is going to provide tremendous benefit with the idea that sometimes, less really is more.”
Study details
SCORAD III, which was funded by Cancer Research UK, enrolled 688 patients with metastatic prostate (44%), lung (18%), breast (11%), and gastrointestinal (11%) cancers.
At baseline, 66% were able to walk without or with an aid (ambulatory status 1 or 2), whereas the rest were unable to walk but still had some limb power (ambulatory status 3) or had flaccid paraplegia (ambulatory status 4).
At 8 weeks, the proportion of patients with ambulatory status 1 or 2 was 69.5% in the group who received the 8-Gy single-dose radiation therapy and 73.3% in the group who received the 20-Gy multidose radiation therapy, for a risk difference of –3.78%, reported Dr. Hoskin.
The 90% confidence interval for the difference between groups of –11.85% to 4.28% slightly exceeded the trial’s predefined 11% margin for noninferiority.
Among patients having ambulatory status 1 or 2 at baseline, the proportion maintaining that status at 8 weeks was 62.20% with the single dose and 63.07% with multiple doses. Median overall survival was 12.4 weeks and 13.7 weeks, respectively, a nonsignificant difference.
Patients in the single-dose and multidose groups had similar rates of grade 3 or 4 toxicity (20.6% vs. 20.4%), but the former had a lower rate of grade 1 or 2 toxicity (51.0% vs. 56.9%).
CHICAGO – A single dose of radiation therapy appears to work as well as multiple doses given over a week for treating spinal cord compression due to metastatic cancer, according to findings of the SCORAD III trial reported at the annual meeting of the American Society of Clinical Oncology.
“There is no standard radiotherapy schedule,” first author Peter Hoskin, MD, FCRP, FRCR, an oncologist at the Mount Vernon Cancer Centre in Middlesex, England, noted in a press briefing. “A range of radiation doses are used internationally, from single doses of 8 to 10 Gy ranging up to 4 weeks of treatment delivering 40 Gy.”
The noninferiority phase III trial enrolled nearly 700 patients in the United Kingdom and Australia with spinal cord compression due to metastases, the majority of whom were able to walk at baseline. They were randomized evenly to receive either 8 Gy of radiation in a single fraction or 20 Gy split into five fractions given over consecutive days.
Results showed that at 8 weeks, more than two-thirds of patients in each group were able to walk, the trial’s primary endpoint. The lower bound of the confidence interval for the difference between groups fell just outside the trial’s margin for noninferiority.
Additionally, the two groups were statistically indistinguishable with respect to median overall survival, bowel and bladder function, and the rate of grade 3 or 4 toxicity.
“A single dose of 8 Gy is as effective as 20 Gy in five fractions for a range of clinically relevant endpoints, particularly ambulatory status, both at 8 weeks and indeed at all time points between 1 week and 12 weeks,” Dr. Hoskin summarized. The trial also underscores the importance of early diagnosis, as the majority of patients who were ambulatory initially remained so with radiation therapy, regardless of dosing schedule.
“A single dose of radiotherapy in our minds is now recommended in this setting. It has major advantages for these patients,” he maintained. “An important thing to realize is that these patients had a very short survival; median survival in this study was only 13 weeks. A single dose has enormous advantages in those patients with short survival times, and of course, it is increasingly cost effective.”
Findings in context
The trial population was not fully representative of all patients with spinal cord compression due to metastases, with underrepresentation of some cancers, such as breast cancer, and the modest survival, Dr. Hoskin acknowledged.
Some patients on the trial have survived for many months and even years, he noted. “We have looked at patients at longer times, although it was not in the protocol, and there was no obvious difference [in outcomes]. But there is some evidence to suggest that for the longer-surviving patients, a more prolonged fractionation may be appropriate, although clearly that needs to be investigated properly in a formal randomized trial.”
“This is the first study that really shows equal outcomes in terms of meaningful benefits for patients with a single dose of radiotherapy versus a much longer course, allowing patients to spend more time with their families, more time doing the things they want to do,” commented ASCO Expert Joshua A. Jones, MD, MA, of the Hospital of the University of Pennsylvania in Philadelphia.
“We still have work to do to figure out for patients who have longer than this average survival of 3 months what is the most appropriate regimen,” he agreed. “But for many patients, this is going to provide tremendous benefit with the idea that sometimes, less really is more.”
Study details
SCORAD III, which was funded by Cancer Research UK, enrolled 688 patients with metastatic prostate (44%), lung (18%), breast (11%), and gastrointestinal (11%) cancers.
At baseline, 66% were able to walk without or with an aid (ambulatory status 1 or 2), whereas the rest were unable to walk but still had some limb power (ambulatory status 3) or had flaccid paraplegia (ambulatory status 4).
At 8 weeks, the proportion of patients with ambulatory status 1 or 2 was 69.5% in the group who received the 8-Gy single-dose radiation therapy and 73.3% in the group who received the 20-Gy multidose radiation therapy, for a risk difference of –3.78%, reported Dr. Hoskin.
The 90% confidence interval for the difference between groups of –11.85% to 4.28% slightly exceeded the trial’s predefined 11% margin for noninferiority.
Among patients having ambulatory status 1 or 2 at baseline, the proportion maintaining that status at 8 weeks was 62.20% with the single dose and 63.07% with multiple doses. Median overall survival was 12.4 weeks and 13.7 weeks, respectively, a nonsignificant difference.
Patients in the single-dose and multidose groups had similar rates of grade 3 or 4 toxicity (20.6% vs. 20.4%), but the former had a lower rate of grade 1 or 2 toxicity (51.0% vs. 56.9%).
At ASCO 2017
Key clinical point:
Major finding: At 8 weeks, the proportion of patients able to walk was 69.5% with 8 Gy given in a single dose and 73.3% with 20 Gy given in five doses.
Data source: A randomized phase III noninferiority trial among 688 patients with spinal cord compression due to metastatic cancer (SCORAD III trial).
Disclosures: Dr. Hoskin disclosed that he receives research funding (institutional) from Varian Medical Systems. The trial was funded by Cancer Research UK.