The Sarcoma Journal

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

CHICAGO – Six months of maintenance chemotherapy prolongs overall survival in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

Rhabdomyosarcoma is a rare but very aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the annual meeting of the American Society of Clinical Oncology, where the findings were reported. Among pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.

The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.

Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year overall survival rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.

“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr. Bisogno said.

Susan London/MDedge News

Susan London/MDedge News

Study details

Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.

The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr. Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”

SOURCE: Bisogno et al. ASCO 2018 Abstract LBA2.

CHICAGO – Six months of maintenance chemotherapy prolongs overall survival in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

Rhabdomyosarcoma is a rare but very aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the annual meeting of the American Society of Clinical Oncology, where the findings were reported. Among pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.

The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.

Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year overall survival rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.

“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr. Bisogno said.

Susan London/MDedge News

Susan London/MDedge News

Study details

Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.

The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr. Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”

SOURCE: Bisogno et al. ASCO 2018 Abstract LBA2.

CHICAGO – Six months of maintenance chemotherapy prolongs overall survival in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

Rhabdomyosarcoma is a rare but very aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the annual meeting of the American Society of Clinical Oncology, where the findings were reported. Among pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.

The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.

Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year overall survival rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.

“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr. Bisogno said.

Susan London/MDedge News

Susan London/MDedge News

Study details

Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.

The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr. Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”

SOURCE: Bisogno et al. ASCO 2018 Abstract LBA2.

CHICAGO – Maintenance chemotherapy is life-prolonging for youth with high-risk rhabdomyosarcoma, finds a trial of 371 patients aged 0 to 21 years who had completed standard intensive therapy.

The 5-year rate of overall survival was 86.5% for those who received maintenance therapy with the combination of low-dose intravenous vinorelbine and oral cyclophosphamide, compared with 73.7% for those who did not, translating to a near halving of the risk of death (hazard ratio, 0.52; P = .0111). The regimen was well tolerated. The findings represent the first treatment advance for this rare cancer in 30 years.

In an interview at the annual meeting of the American Society of Clinical Oncology, lead study author Gianni Bisogno, MD, PhD, discussed the risk-benefit profile of maintenance chemotherapy and the practice-changing nature of the new data. Dr. Bisogno, a professor at the University Hospital of Padova in Italy and chair of the European Paediatric Soft tissue Sarcoma Study Group, also described plans for a new trial that will explore alternate maintenance schedules and collaboration with colleagues in North America to further improve pediatric rhabdomyosarcoma outcomes.
 

CHICAGO – Maintenance chemotherapy is life-prolonging for youth with high-risk rhabdomyosarcoma, finds a trial of 371 patients aged 0 to 21 years who had completed standard intensive therapy.

The 5-year rate of overall survival was 86.5% for those who received maintenance therapy with the combination of low-dose intravenous vinorelbine and oral cyclophosphamide, compared with 73.7% for those who did not, translating to a near halving of the risk of death (hazard ratio, 0.52; P = .0111). The regimen was well tolerated. The findings represent the first treatment advance for this rare cancer in 30 years.

In an interview at the annual meeting of the American Society of Clinical Oncology, lead study author Gianni Bisogno, MD, PhD, discussed the risk-benefit profile of maintenance chemotherapy and the practice-changing nature of the new data. Dr. Bisogno, a professor at the University Hospital of Padova in Italy and chair of the European Paediatric Soft tissue Sarcoma Study Group, also described plans for a new trial that will explore alternate maintenance schedules and collaboration with colleagues in North America to further improve pediatric rhabdomyosarcoma outcomes.
 

CHICAGO – Maintenance chemotherapy is life-prolonging for youth with high-risk rhabdomyosarcoma, finds a trial of 371 patients aged 0 to 21 years who had completed standard intensive therapy.

The 5-year rate of overall survival was 86.5% for those who received maintenance therapy with the combination of low-dose intravenous vinorelbine and oral cyclophosphamide, compared with 73.7% for those who did not, translating to a near halving of the risk of death (hazard ratio, 0.52; P = .0111). The regimen was well tolerated. The findings represent the first treatment advance for this rare cancer in 30 years.

In an interview at the annual meeting of the American Society of Clinical Oncology, lead study author Gianni Bisogno, MD, PhD, discussed the risk-benefit profile of maintenance chemotherapy and the practice-changing nature of the new data. Dr. Bisogno, a professor at the University Hospital of Padova in Italy and chair of the European Paediatric Soft tissue Sarcoma Study Group, also described plans for a new trial that will explore alternate maintenance schedules and collaboration with colleagues in North America to further improve pediatric rhabdomyosarcoma outcomes.
 

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.