User login
Ado-trastuzumab highly efficacious for rare HER2-amplified SGCs
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
REPORTING FROM ASCO 2019
Predicting treatment response in leiomyosarcoma, liposarcoma
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
REPORTING FROM ASCO 2018
Key clinical point: Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma.
Major finding: Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
Study details: Archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas in the completed phase 3 randomized trial comparing trabectedin and dacarbazine.
Disclosures: Dr. Kapoor is employed by LabConnect, Seattle. Research funding was supplied by Janssen Research & Development.
Source: Kapoor G et al. ASCO 2018, Abstract 11513.
Rapid drug alteration a bust in metastatic GIST
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
REPORTING FROM ASCO 2018
Key clinical point: The strategy of rapid alteration of drugs to overcome mutations conferring imatinib resistance in gastrointestinal stromal tumor (GIST) was feasible but ineffective.
Major finding: There were no objective responses among 12 patients treated with the strategy.
Study details: A phase Ib clinical trial in 12 patients with heavily pretreated metastatic GIST.
Disclosures: The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
Source: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
ctDNA profiles pre- and posttreatment KIT mutations in GIST
CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.
In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.
“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.
Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.
An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).
Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.
The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.
There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.
“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.
The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.
SOURCE: George S et al. ASCO 2018. Abstract 11511.
CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.
In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.
“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.
Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.
An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).
Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.
The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.
There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.
“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.
The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.
SOURCE: George S et al. ASCO 2018. Abstract 11511.
CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.
In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.
“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.
Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.
An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).
Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.
The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.
There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.
“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.
The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.
SOURCE: George S et al. ASCO 2018. Abstract 11511.
REPORTING FROM ASCO 2018
Key clinical point: Circulating tumor DNA can be used for mutational profiling and responses assessment in patients with advanced imatinib-resistant GIST.
Major finding: Of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point.
Study details: Subanalyses from a phase 1 trial of DCC-2618.
Disclosures: The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.
Source: George S et al. ASCO 2018. Abstract 11511.
Trabectedin bests supportive care in advanced soft-tissue sarcomas
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
REPORTING FROM ASCO 2018
Key clinical point: Trabectedin was superior to best supportive care in delaying disease progression among patients with advanced soft tissue sarcomas.
Major finding: Median progression-free survival for patients with leiomyosarcoma or liposarcoma treated with trabectedin was 5.13 months vs. 1.41 months for patients treated with best supportive care.
Study details: Randomized open-label trial of 103 patients with histologically proven advanced soft-tissue sarcoma who progressed after at least 1 anthracycline-containing regimen.
Disclosures: Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed receiving honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
Source: Le Cesne A et al. ASCO 2018. Abstract 11508.
Phase 2 trial: Dendritic cell vaccine maintenance prolongs PFS in EOC
CHICAGO – who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.
Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.
Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.
“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.
Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.
Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.
Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.
“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.
The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.
The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”
Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.
Dr. Rob reported having no disclosures.
SOURCE: Rob L et al. ASCO 2018, Abstract 5509.
CHICAGO – who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.
Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.
Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.
“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.
Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.
Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.
Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.
“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.
The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.
The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”
Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.
Dr. Rob reported having no disclosures.
SOURCE: Rob L et al. ASCO 2018, Abstract 5509.
CHICAGO – who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.
Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.
Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.
“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.
Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.
Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.
Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.
“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.
The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.
The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”
Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.
Dr. Rob reported having no disclosures.
SOURCE: Rob L et al. ASCO 2018, Abstract 5509.
REPORTING FROM ASCO 2018
Key clinical point: Dendritic cell vaccine maintenance improves progression-free survival in patients with epithelial ovarian carcinoma who have undergone primary debulking surgery.
Major finding: DCVAC maintenance after chemotherapy prolonged progression-free survival by almost 6 months (hazard ratio, 0.43 vs. chemotherapy alone).
Study details: A randomized, phase 2, open-label trial including 99 patients.
Disclosures: Dr. Rob reported having no disclosures.
Source: Rob L et al. ASCO 2018, Abstract 5509.
Lower CTC count IDs indolent MBC disease subset
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
REPORTING FROM ASCO 2018
Key clinical point: A CTC count less than 5 per 7.5 mL of blood in patients with MBC indicates an indolent disease subset.
Major finding: Median OS for stage IVindolent vs. stage IVaggressive disease was 4.0 vs. 17.3 months in HER2-negative patients, 23.8 vs. 9.0 months in TNBC patients, and 36.7 vs. 20.4 months in HER2-positive disease.
Study details: A pooled analysis of data from two cohort studies including 2,436 patients.
Disclosures: This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
Source: Davis A et al. ASCO 2018 Poster 1019.
Trio of biosimilars have good showing
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
REPORTING FROM ASCO 2018
Key clinical point: Biosimilars for bevacizumab, trastuzumab, and filgrastim showed similar efficacy and safety.
Major finding: In patients with advanced nonsquamous NSCLC, the overall response rate was 45.3% with a candidate bevacizumab biosimilar and 44.6% with bevacizumab. In patients with HER2+ advanced breast cancer, 48-week median progression-free survival was 11.1 months for both trastuzumab-dkst and trastuzumab. The rate of chemotherapy-induced febrile neutropenia among breast cancer patients given a biosimilar for filgrastim was 5.1% in a trial population and 6.2% in a real-world population.
Study details: Randomized, controlled trials of first-line therapy among 719 patients with advanced nonsquamous NSCLC (REFLECTIONS trial) and among 458 patients with HER2+ advanced breast cancer (HERITAGE trial). Comparison of outcomes in a randomized, controlled trial among 217 patients with nonmetastatic breast cancer (PIONEER trial) and a real-world cohort study of 466 patients with any-stage breast cancer (MONITOR-GCSF).
Disclosures: Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were sponsored by Sandoz.
Source: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
Trastuzumab biosimilar is equivalent on central review
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
REPORTING FROM THE ASCO ANNUAL MEETING
Key clinical point: Central review determined that ABP 980 was neither inferior nor superior to trastuzumab in breast cancer patients.
Major finding: The centrally determined pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab, with bounds of the confidence intervals for risk difference and for risk ratio falling within the predefined equivalence margins.
Study details: An analysis of a phase 3 randomized controlled trial of neoadjuvant (and adjuvant) therapy among 725 patients with HER2+ early breast cancer (LILAC trial).
Disclosures: Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
Source: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
DESMOPAZ: Pazopanib slows disease progression of desmoid tumors
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
FROM ASCO 2018