2018 ASCO Annual Meeting

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.

li_bob_NY_Web.JPG

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.
[embed:render:related:node:202071]

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.
[embed:render:related:node:153287]

“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.

noronha2_vanita_mumbai_web.JPG

“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.

li_bob_NY_Web.JPG

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.
[embed:render:related:node:202071]

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.
[embed:render:related:node:153287]

“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.

noronha2_vanita_mumbai_web.JPG

“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.

li_bob_NY_Web.JPG

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.
[embed:render:related:node:202071]

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.
[embed:render:related:node:153287]

“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.

noronha2_vanita_mumbai_web.JPG

“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.

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.

mdales@mdedge.com

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.

mdales@mdedge.com

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.

mdales@mdedge.com

SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.

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.

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.

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.

CHICAGO – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma 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 – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma 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 – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma 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 – 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 IV_indolent), 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 IV_indolent vs. stage IV_aggressive (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 IV_indolent 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 IV_indolent), 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 IV_indolent vs. stage IV_aggressive (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 IV_indolent 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 IV_indolent), 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 IV_indolent vs. stage IV_aggressive (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 IV_indolent 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 – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, 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.

Thompson_Michael_web.jpg

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.

Socinski_Mark A._web.jpg

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.

Rugo_Hope S_web.jpg

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.

Harbeck_Nadia_web.jpg

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 – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, 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.

Thompson_Michael_web.jpg

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.

Socinski_Mark A._web.jpg

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.

Rugo_Hope S_web.jpg

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.

Harbeck_Nadia_web.jpg

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 – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, 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.

Thompson_Michael_web.jpg

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.

Socinski_Mark A._web.jpg

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.

Rugo_Hope S_web.jpg

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.

Harbeck_Nadia_web.jpg

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 – The biosimilar ABP 980 has efficacy equivalent to that of trastuzumab (Herceptin) in early HER2+ breast cancer, 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.

133856_Kolberg.jpg

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 – The biosimilar ABP 980 has efficacy equivalent to that of trastuzumab (Herceptin) in early HER2+ breast cancer, 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.

133856_Kolberg.jpg

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 – The biosimilar ABP 980 has efficacy equivalent to that of trastuzumab (Herceptin) in early HER2+ breast cancer, 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.

133856_Kolberg.jpg

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.