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HDAC inhibition may reverse anthracycline resistance in patients with sarcoma
In patients with advanced solid tumors, including sarcoma, the combination of panobinostat, a histone deacetylase (HDAC) inhibitor, and the anthracycline epirubicin demonstrated a correlation between neutropenia, peripheral blood mononucleocyte (PBMC) histone acetylation, and clinical benefit. Acquired topoisomerase resistance was reversed in 8 of 14 patients, suggesting HDAC inhibition reverses resistance.
In 37 evaluable patients, 4 (11%) had partial responses and 17 (46%) had stable disease. The median time to progression and median overall survival were 3.1 (95% CI, 1.8 to 4.6) months and 7.3 (5.9 to 10.3) months, respectively. All four patients with objective partial response had progressed on previous topoisomerase II inhibitors.
“The potential for prolonged treatment with an anthracycline in combination with an HDAC inhibitor speaks to the tolerability of this regimen. This study suggests that further investigation of HDAC inhibition in combination with DNA-damaging agents in defined advanced sarcoma subtypes to validate these preliminary findings is warranted,” wrote Dr. Scott Thomas of the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, and colleagues (Ann Oncol. 2016 Feb 21. doi: 10.1093/annonc/mdw044).
HDACs regulate protein acetylation, thereby modulating protein activity and gene expression. Preclinical studies showed that HDAC inhibitors potentiate DNA damaging activity of anthracyclines in various cancer types, including sarcoma.
The phase I trial enrolled patients with metastatic solid tumors in dose escalation cohorts, and 20 patients with advanced sarcoma in the dose expansion cohort at the maximum tolerated dose of 50 mg/day of panobinostat on days 1, 3, and 5, and 75 mg/m2 of epirubicin on day 5.
In total, 24 patients (60%) had at least one grade 3 or 4 adverse event, including neutropenia (45%), leukopenia (35%), lymphopenia (22.5%), thrombocytopenia (17.5%), anemia (15%), and febrile neutropenia (7.5%). Major nonhematologic toxicities of panobinostat were myelotoxicity, nausea/vomiting, and fatigue, which required dose modification in 26% of patients.
In patients with advanced solid tumors, including sarcoma, the combination of panobinostat, a histone deacetylase (HDAC) inhibitor, and the anthracycline epirubicin demonstrated a correlation between neutropenia, peripheral blood mononucleocyte (PBMC) histone acetylation, and clinical benefit. Acquired topoisomerase resistance was reversed in 8 of 14 patients, suggesting HDAC inhibition reverses resistance.
In 37 evaluable patients, 4 (11%) had partial responses and 17 (46%) had stable disease. The median time to progression and median overall survival were 3.1 (95% CI, 1.8 to 4.6) months and 7.3 (5.9 to 10.3) months, respectively. All four patients with objective partial response had progressed on previous topoisomerase II inhibitors.
“The potential for prolonged treatment with an anthracycline in combination with an HDAC inhibitor speaks to the tolerability of this regimen. This study suggests that further investigation of HDAC inhibition in combination with DNA-damaging agents in defined advanced sarcoma subtypes to validate these preliminary findings is warranted,” wrote Dr. Scott Thomas of the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, and colleagues (Ann Oncol. 2016 Feb 21. doi: 10.1093/annonc/mdw044).
HDACs regulate protein acetylation, thereby modulating protein activity and gene expression. Preclinical studies showed that HDAC inhibitors potentiate DNA damaging activity of anthracyclines in various cancer types, including sarcoma.
The phase I trial enrolled patients with metastatic solid tumors in dose escalation cohorts, and 20 patients with advanced sarcoma in the dose expansion cohort at the maximum tolerated dose of 50 mg/day of panobinostat on days 1, 3, and 5, and 75 mg/m2 of epirubicin on day 5.
In total, 24 patients (60%) had at least one grade 3 or 4 adverse event, including neutropenia (45%), leukopenia (35%), lymphopenia (22.5%), thrombocytopenia (17.5%), anemia (15%), and febrile neutropenia (7.5%). Major nonhematologic toxicities of panobinostat were myelotoxicity, nausea/vomiting, and fatigue, which required dose modification in 26% of patients.
In patients with advanced solid tumors, including sarcoma, the combination of panobinostat, a histone deacetylase (HDAC) inhibitor, and the anthracycline epirubicin demonstrated a correlation between neutropenia, peripheral blood mononucleocyte (PBMC) histone acetylation, and clinical benefit. Acquired topoisomerase resistance was reversed in 8 of 14 patients, suggesting HDAC inhibition reverses resistance.
In 37 evaluable patients, 4 (11%) had partial responses and 17 (46%) had stable disease. The median time to progression and median overall survival were 3.1 (95% CI, 1.8 to 4.6) months and 7.3 (5.9 to 10.3) months, respectively. All four patients with objective partial response had progressed on previous topoisomerase II inhibitors.
“The potential for prolonged treatment with an anthracycline in combination with an HDAC inhibitor speaks to the tolerability of this regimen. This study suggests that further investigation of HDAC inhibition in combination with DNA-damaging agents in defined advanced sarcoma subtypes to validate these preliminary findings is warranted,” wrote Dr. Scott Thomas of the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, and colleagues (Ann Oncol. 2016 Feb 21. doi: 10.1093/annonc/mdw044).
HDACs regulate protein acetylation, thereby modulating protein activity and gene expression. Preclinical studies showed that HDAC inhibitors potentiate DNA damaging activity of anthracyclines in various cancer types, including sarcoma.
The phase I trial enrolled patients with metastatic solid tumors in dose escalation cohorts, and 20 patients with advanced sarcoma in the dose expansion cohort at the maximum tolerated dose of 50 mg/day of panobinostat on days 1, 3, and 5, and 75 mg/m2 of epirubicin on day 5.
In total, 24 patients (60%) had at least one grade 3 or 4 adverse event, including neutropenia (45%), leukopenia (35%), lymphopenia (22.5%), thrombocytopenia (17.5%), anemia (15%), and febrile neutropenia (7.5%). Major nonhematologic toxicities of panobinostat were myelotoxicity, nausea/vomiting, and fatigue, which required dose modification in 26% of patients.
FROM ANNALS OF ONCOLOGY
Key clinical point: Despite prior exposure to multiple regimens, clinical benefit was observed in several patients with advanced solid tumors, including some with sarcoma, who received panobinostat and epirubicin.
Major finding: In 37 evaluable patients, 4 (11%) had partial responses and 17 (46%) had stable disease; acquired topoisomerase resistance was reversed in 8 of 14 patients.
Data source: Phase I trial of 20 patients with metastatic solid tumors in dose escalation cohorts, and 20 patients with advanced sarcoma in the dose expansion cohort.
Disclosures: Research was supported in part by Novartis International AG. Dr. Thomas reported having no disclosures. Dr. Munster received research support from Novartis for this and other clinical trials.
FDA approves eribulin for advanced liposarcoma
The Food and Drug Administration has approved eribulin for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
The approval was based on improved overall survival (OS) in an open-label, randomized, multicenter trial of 446 patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma who had received at least two prior systemic chemotherapies (one of which must have included an anthracycline) and had experienced disease progression within 6 months of randomization, according to the Jan. 28 statement issued by the FDA.
Patients were randomized to receive either eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or dacarbazine (at a dose of 850 mg/m2, 1,000 mg/m2, or 1,200 mg/m2 chosen by the investigator prior to randomization) on day 1 of a 21-day cycle.
Eribulin benefit was limited to the subgroup of patients with liposarcoma. The median OS was 15.6 vs. 8.4 months (HR 0.51 [95% CI: 0.35, 0.75]) and the median progression-free survival (PFS) was 2.9 vs. 1.7 months (HR 0.52 [95% CI: 0.35, 0.78]) in patients with liposarcoma treated with eribulin compared to dacarbazine, respectively. There was no evidence of efficacy for eribulin in patients with leiomyosarcoma.
The most common adverse reactions among those who received eribulin in the trial were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common grade 3-4 laboratory abnormalities were neutropenia, hypokalemia, and hypocalcemia.
The most common serious adverse reactions were neutropenia (4.9%) and pyrexia (4.5%). Febrile neutropenia occurred in 0.9% and fatal neutropenic sepsis in 0.9% of patients treated with eribulin. The most frequent adverse reactions leading to discontinuation were fatigue (0.9%) and thrombocytopenia (0.9%), according to the FDA statement.
Eribulin is marketed as Halaven injection by Eisai. The recommended dose and schedule for eribulin is 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.
On Twitter @nikolaideslaura
The Food and Drug Administration has approved eribulin for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
The approval was based on improved overall survival (OS) in an open-label, randomized, multicenter trial of 446 patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma who had received at least two prior systemic chemotherapies (one of which must have included an anthracycline) and had experienced disease progression within 6 months of randomization, according to the Jan. 28 statement issued by the FDA.
Patients were randomized to receive either eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or dacarbazine (at a dose of 850 mg/m2, 1,000 mg/m2, or 1,200 mg/m2 chosen by the investigator prior to randomization) on day 1 of a 21-day cycle.
Eribulin benefit was limited to the subgroup of patients with liposarcoma. The median OS was 15.6 vs. 8.4 months (HR 0.51 [95% CI: 0.35, 0.75]) and the median progression-free survival (PFS) was 2.9 vs. 1.7 months (HR 0.52 [95% CI: 0.35, 0.78]) in patients with liposarcoma treated with eribulin compared to dacarbazine, respectively. There was no evidence of efficacy for eribulin in patients with leiomyosarcoma.
The most common adverse reactions among those who received eribulin in the trial were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common grade 3-4 laboratory abnormalities were neutropenia, hypokalemia, and hypocalcemia.
The most common serious adverse reactions were neutropenia (4.9%) and pyrexia (4.5%). Febrile neutropenia occurred in 0.9% and fatal neutropenic sepsis in 0.9% of patients treated with eribulin. The most frequent adverse reactions leading to discontinuation were fatigue (0.9%) and thrombocytopenia (0.9%), according to the FDA statement.
Eribulin is marketed as Halaven injection by Eisai. The recommended dose and schedule for eribulin is 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.
On Twitter @nikolaideslaura
The Food and Drug Administration has approved eribulin for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
The approval was based on improved overall survival (OS) in an open-label, randomized, multicenter trial of 446 patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma who had received at least two prior systemic chemotherapies (one of which must have included an anthracycline) and had experienced disease progression within 6 months of randomization, according to the Jan. 28 statement issued by the FDA.
Patients were randomized to receive either eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or dacarbazine (at a dose of 850 mg/m2, 1,000 mg/m2, or 1,200 mg/m2 chosen by the investigator prior to randomization) on day 1 of a 21-day cycle.
Eribulin benefit was limited to the subgroup of patients with liposarcoma. The median OS was 15.6 vs. 8.4 months (HR 0.51 [95% CI: 0.35, 0.75]) and the median progression-free survival (PFS) was 2.9 vs. 1.7 months (HR 0.52 [95% CI: 0.35, 0.78]) in patients with liposarcoma treated with eribulin compared to dacarbazine, respectively. There was no evidence of efficacy for eribulin in patients with leiomyosarcoma.
The most common adverse reactions among those who received eribulin in the trial were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common grade 3-4 laboratory abnormalities were neutropenia, hypokalemia, and hypocalcemia.
The most common serious adverse reactions were neutropenia (4.9%) and pyrexia (4.5%). Febrile neutropenia occurred in 0.9% and fatal neutropenic sepsis in 0.9% of patients treated with eribulin. The most frequent adverse reactions leading to discontinuation were fatigue (0.9%) and thrombocytopenia (0.9%), according to the FDA statement.
Eribulin is marketed as Halaven injection by Eisai. The recommended dose and schedule for eribulin is 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.
On Twitter @nikolaideslaura
IDH1 mutant inhibitor targets gliomas, chondrosarcomas
BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.
In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.
“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.
A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.
IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.
IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.
Early efficacy promising
He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.
There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.
Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.
Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.
The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.
“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.
In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.
For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.
BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.
In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.
“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.
A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.
IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.
IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.
Early efficacy promising
He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.
There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.
Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.
Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.
The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.
“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.
In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.
For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.
BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.
In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.
“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.
A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.
IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.
IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.
Early efficacy promising
He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.
There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.
Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.
Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.
The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.
“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.
In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.
For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.
AT THE AACR–NCI–EORTC
Key clinical point: AG-120 is a first-in-class inhibitor of IDH1 mutations that may drive oncogenesis.
Major finding: 10 of 20 patients with gliomas and 7 of 11 with chondrosarcomas had stable disease on AG-120.
Data source: Phase I dose-escalation trial in 62 patients (55 available for efficacy analysis).
Disclosures: The trial is supported by Agios Pharmaceuticals. Dr. Burris and Dr. Helman reported no conflicts of interest.
Experimental LOXO-101 induces regression in several hard-to-treat cancers
BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.
“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.
The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.
The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.
A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.
“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.
Tumor promoters
The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.
“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.
Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.
LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.
The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.
Well tolerated
At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).
A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.
Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.
The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.
The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.
The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.
Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.
The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.
BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.
“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.
The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.
The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.
A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.
“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.
Tumor promoters
The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.
“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.
Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.
LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.
The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.
Well tolerated
At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).
A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.
Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.
The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.
The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.
The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.
Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.
The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.
BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.
“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.
The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.
The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.
A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.
“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.
Tumor promoters
The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.
“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.
Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.
LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.
The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.
Well tolerated
At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).
A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.
Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.
The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.
The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.
The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.
Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.
The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.
Key clinical point:Inhibition of TRK gene fusion products is a novel strategy for treating cancer.
Major finding: Three of three patients evaluable for response had near-complete responses.
Data source: Phase I dose-finding study in 24 patients, with and without TRK gene fusions.
Disclosures: The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.
Adjuvant imatinib for 3 years better than 1 year in high-risk GIST
After surgery for high-risk gastrointestinal stromal tumor (GIST), patients who received adjuvant imatinib for 3 years achieved longer relapse-free survival (RFS) and overall survival (OS) compared with those treated for 1 year, according to a study published online in Journal of Clinical Oncology.
With a median follow up of 7.5 years, the 5-year survival rates of greater than 90% represent the highest reported to date in high-risk GIST.
“We speculate that, other than adjuvant imatinib, two procedures were crucially important for achieving the high overall survival rates: longitudinal monitoring of the abdomen with CT to detect GIST recurrence early when the tumor bulk was still small and restarting of imatinib after recurrence was detected,” wrote Dr. Heikki Joensuu of the Comprehensive Cancer Center Helsinki and University of Helsinki, Finland, and colleagues.
Five-year RFS rates for 3- and 1-year treatment durations were 71.1% and 52.3%, respectively (hazard ratio, 0.60; 95% CI, 0.44-0.81; P less than .001); 5-year OS rates were 91.9% and 85.3%, respectively (HR, 0.60; 95% CI, 0.37-0.97; P = .036), the investigators reported (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.62.9170).
After a median follow up of 90 months, the second planned analysis of the open-label Scandinavian Sarcoma Group XVIII/AIO study evaluated outcomes of 358 patients, 181 in the 12-month group and 177 in the 36-month group. Earlier results from the SSGXVIII/AIO trial (after a 4.5-year follow up) showed significantly longer survival in patients who received imatinib for 3 years versus 1 year, and these results have informed treatment guidelines.
However, two other large randomized trials evaluated adjuvant imatinib for durations less than 3 years in patients with lower-risk GIST, and neither study found a survival benefit. The investigators point out that because low- or intermediate-risk GIST is cured with surgery alone in the great majority of patients, most do not benefit from adjuvant imatinib.
“Hypothetically, these results suggest that obtaining overall survival benefit may require durable administrations of imatinib and that the patients at high risk for recurrence are the optimal target population,” they wrote.
All but two patients reported at least one adverse event, but most events were mild. Previous reports have suggested cardiac toxicity of imatinib, but only one patient had cardiac failure, perhaps due to the low 400 mg adjuvant daily dosage.
Dr. Joensuu reported consulting or advisory roles with Blueprint Medicines, ARIAD Pharmaceuticals, and Orion Pharma. Several of his coauthors reported ties to industry sources.
After surgery for high-risk gastrointestinal stromal tumor (GIST), patients who received adjuvant imatinib for 3 years achieved longer relapse-free survival (RFS) and overall survival (OS) compared with those treated for 1 year, according to a study published online in Journal of Clinical Oncology.
With a median follow up of 7.5 years, the 5-year survival rates of greater than 90% represent the highest reported to date in high-risk GIST.
“We speculate that, other than adjuvant imatinib, two procedures were crucially important for achieving the high overall survival rates: longitudinal monitoring of the abdomen with CT to detect GIST recurrence early when the tumor bulk was still small and restarting of imatinib after recurrence was detected,” wrote Dr. Heikki Joensuu of the Comprehensive Cancer Center Helsinki and University of Helsinki, Finland, and colleagues.
Five-year RFS rates for 3- and 1-year treatment durations were 71.1% and 52.3%, respectively (hazard ratio, 0.60; 95% CI, 0.44-0.81; P less than .001); 5-year OS rates were 91.9% and 85.3%, respectively (HR, 0.60; 95% CI, 0.37-0.97; P = .036), the investigators reported (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.62.9170).
After a median follow up of 90 months, the second planned analysis of the open-label Scandinavian Sarcoma Group XVIII/AIO study evaluated outcomes of 358 patients, 181 in the 12-month group and 177 in the 36-month group. Earlier results from the SSGXVIII/AIO trial (after a 4.5-year follow up) showed significantly longer survival in patients who received imatinib for 3 years versus 1 year, and these results have informed treatment guidelines.
However, two other large randomized trials evaluated adjuvant imatinib for durations less than 3 years in patients with lower-risk GIST, and neither study found a survival benefit. The investigators point out that because low- or intermediate-risk GIST is cured with surgery alone in the great majority of patients, most do not benefit from adjuvant imatinib.
“Hypothetically, these results suggest that obtaining overall survival benefit may require durable administrations of imatinib and that the patients at high risk for recurrence are the optimal target population,” they wrote.
All but two patients reported at least one adverse event, but most events were mild. Previous reports have suggested cardiac toxicity of imatinib, but only one patient had cardiac failure, perhaps due to the low 400 mg adjuvant daily dosage.
Dr. Joensuu reported consulting or advisory roles with Blueprint Medicines, ARIAD Pharmaceuticals, and Orion Pharma. Several of his coauthors reported ties to industry sources.
After surgery for high-risk gastrointestinal stromal tumor (GIST), patients who received adjuvant imatinib for 3 years achieved longer relapse-free survival (RFS) and overall survival (OS) compared with those treated for 1 year, according to a study published online in Journal of Clinical Oncology.
With a median follow up of 7.5 years, the 5-year survival rates of greater than 90% represent the highest reported to date in high-risk GIST.
“We speculate that, other than adjuvant imatinib, two procedures were crucially important for achieving the high overall survival rates: longitudinal monitoring of the abdomen with CT to detect GIST recurrence early when the tumor bulk was still small and restarting of imatinib after recurrence was detected,” wrote Dr. Heikki Joensuu of the Comprehensive Cancer Center Helsinki and University of Helsinki, Finland, and colleagues.
Five-year RFS rates for 3- and 1-year treatment durations were 71.1% and 52.3%, respectively (hazard ratio, 0.60; 95% CI, 0.44-0.81; P less than .001); 5-year OS rates were 91.9% and 85.3%, respectively (HR, 0.60; 95% CI, 0.37-0.97; P = .036), the investigators reported (J Clin Oncol. 2015 Nov. 2. doi: 10.1200/JCO.2015.62.9170).
After a median follow up of 90 months, the second planned analysis of the open-label Scandinavian Sarcoma Group XVIII/AIO study evaluated outcomes of 358 patients, 181 in the 12-month group and 177 in the 36-month group. Earlier results from the SSGXVIII/AIO trial (after a 4.5-year follow up) showed significantly longer survival in patients who received imatinib for 3 years versus 1 year, and these results have informed treatment guidelines.
However, two other large randomized trials evaluated adjuvant imatinib for durations less than 3 years in patients with lower-risk GIST, and neither study found a survival benefit. The investigators point out that because low- or intermediate-risk GIST is cured with surgery alone in the great majority of patients, most do not benefit from adjuvant imatinib.
“Hypothetically, these results suggest that obtaining overall survival benefit may require durable administrations of imatinib and that the patients at high risk for recurrence are the optimal target population,” they wrote.
All but two patients reported at least one adverse event, but most events were mild. Previous reports have suggested cardiac toxicity of imatinib, but only one patient had cardiac failure, perhaps due to the low 400 mg adjuvant daily dosage.
Dr. Joensuu reported consulting or advisory roles with Blueprint Medicines, ARIAD Pharmaceuticals, and Orion Pharma. Several of his coauthors reported ties to industry sources.
Key clinical point: Patients with high-risk GIST treated with adjuvant imatinib for 3 years had longer relapse-free survival (RFS) and overall survival (OS) than did those treated for 1 year.
Major finding: Five-year RFS rates for 3- and 1-year treatment durations were 71.1% and 52.3%, respectively (hazard ratio, 0.60; 95% CI, 0.44-0.81; P less than .001); 5-year OS rates were 91.9% and 85.3%, respectively (HR, 0.60; 95% CI, 0.37-0.97; P = .036).
Data source: After a median follow up of 90 months, a second planned analysis of the open-label SSGXVIII/AIO study evaluated outcomes of 358 patients, 181 in the 12-month group and 177 in the 36-month group.
Disclosures: Dr. Joensuu reported consulting or advisory roles with Blueprint Medicines, ARIAD Pharmaceuticals, and Orion Pharma. Several of his coauthors reported ties to industry sources.
Dose-intensive, multiagent regimen improves outcomes from low-risk rhabdomyosarcoma
A dose-intensive multiagent regimen including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation resulted in improved outcomes for patients with low-risk stage IV rhabdomyosarcoma (RMS), but not for patients with high-risk disease, according to results from the Children’s Oncology Group study.
For all patients with stage IV rhabdomyosarcoma, the 3-year event-free and overall survival rates were 38% and 56%, respectively. Patients with stage IV RMS with one or fewer Oberlin risk factors had 3-year event-free survival and overall survival rates of 69% and 79%, respectively; patients with two or more Oberlin risk factors had rates of 20% and 14%, respectively (Jour Clin Oncol. 2015 Oct 26. doi: 10.1200/JCO.2015.63.4048).
The study identified an expanded group of patients with low-risk metastatic RMS that included patients with embryonal RMS aged 10 years and older but with an Oberlin score of less than 2. The results in this group represent an improvement over previous study results. However, for the remainder of high-risk patients with alveolar RMS, different approaches are needed, according to Dr. Brenda Weigel of the University of Minnesota, Minneapolis, and her colleagues.
“Unfortunately, alveolar RMS has fewer genetic aberrations than embryonal RMS and no known recurrently mutated cancer consensus genes, which limits genetic targets available for therapeutic approaches,” they wrote.
The Children’s Oncology Group study ARST0431 enrolled 109 patients with metastatic RMS who had no prior chemotherapy or radiation treatment from 2006 to 2008.
The study combined three treatment strategies: dose intensification by interval compression, use of active agents identified in previous phase II window studies, and use of irinotecan as a radiation sensitizer. The 54-week treatment schedule began with two cycles of vincristine/irinotecan followed by interval-compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (cycles began every 14 days), and finished with four cycles of standard vincristine/actinomycin/cyclophosphamide (VAC) and two more cycles of vincristine/irinotecan. The treatment plan also included radiation of primary and metastatic sites at week 19.
The most common nonhematologic adverse event of grade 3 or higher was diarrhea, reported in 20% of patients during the time period when they received irinotecan. Febrile neutropenia occurred in 63% of patients.
Dr. Weigel reported financial relationships with Genentech and Eli Lilly/ImClone System. Several of her coauthors reported having ties to industry sources.
A dose-intensive multiagent regimen including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation resulted in improved outcomes for patients with low-risk stage IV rhabdomyosarcoma (RMS), but not for patients with high-risk disease, according to results from the Children’s Oncology Group study.
For all patients with stage IV rhabdomyosarcoma, the 3-year event-free and overall survival rates were 38% and 56%, respectively. Patients with stage IV RMS with one or fewer Oberlin risk factors had 3-year event-free survival and overall survival rates of 69% and 79%, respectively; patients with two or more Oberlin risk factors had rates of 20% and 14%, respectively (Jour Clin Oncol. 2015 Oct 26. doi: 10.1200/JCO.2015.63.4048).
The study identified an expanded group of patients with low-risk metastatic RMS that included patients with embryonal RMS aged 10 years and older but with an Oberlin score of less than 2. The results in this group represent an improvement over previous study results. However, for the remainder of high-risk patients with alveolar RMS, different approaches are needed, according to Dr. Brenda Weigel of the University of Minnesota, Minneapolis, and her colleagues.
“Unfortunately, alveolar RMS has fewer genetic aberrations than embryonal RMS and no known recurrently mutated cancer consensus genes, which limits genetic targets available for therapeutic approaches,” they wrote.
The Children’s Oncology Group study ARST0431 enrolled 109 patients with metastatic RMS who had no prior chemotherapy or radiation treatment from 2006 to 2008.
The study combined three treatment strategies: dose intensification by interval compression, use of active agents identified in previous phase II window studies, and use of irinotecan as a radiation sensitizer. The 54-week treatment schedule began with two cycles of vincristine/irinotecan followed by interval-compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (cycles began every 14 days), and finished with four cycles of standard vincristine/actinomycin/cyclophosphamide (VAC) and two more cycles of vincristine/irinotecan. The treatment plan also included radiation of primary and metastatic sites at week 19.
The most common nonhematologic adverse event of grade 3 or higher was diarrhea, reported in 20% of patients during the time period when they received irinotecan. Febrile neutropenia occurred in 63% of patients.
Dr. Weigel reported financial relationships with Genentech and Eli Lilly/ImClone System. Several of her coauthors reported having ties to industry sources.
A dose-intensive multiagent regimen including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation resulted in improved outcomes for patients with low-risk stage IV rhabdomyosarcoma (RMS), but not for patients with high-risk disease, according to results from the Children’s Oncology Group study.
For all patients with stage IV rhabdomyosarcoma, the 3-year event-free and overall survival rates were 38% and 56%, respectively. Patients with stage IV RMS with one or fewer Oberlin risk factors had 3-year event-free survival and overall survival rates of 69% and 79%, respectively; patients with two or more Oberlin risk factors had rates of 20% and 14%, respectively (Jour Clin Oncol. 2015 Oct 26. doi: 10.1200/JCO.2015.63.4048).
The study identified an expanded group of patients with low-risk metastatic RMS that included patients with embryonal RMS aged 10 years and older but with an Oberlin score of less than 2. The results in this group represent an improvement over previous study results. However, for the remainder of high-risk patients with alveolar RMS, different approaches are needed, according to Dr. Brenda Weigel of the University of Minnesota, Minneapolis, and her colleagues.
“Unfortunately, alveolar RMS has fewer genetic aberrations than embryonal RMS and no known recurrently mutated cancer consensus genes, which limits genetic targets available for therapeutic approaches,” they wrote.
The Children’s Oncology Group study ARST0431 enrolled 109 patients with metastatic RMS who had no prior chemotherapy or radiation treatment from 2006 to 2008.
The study combined three treatment strategies: dose intensification by interval compression, use of active agents identified in previous phase II window studies, and use of irinotecan as a radiation sensitizer. The 54-week treatment schedule began with two cycles of vincristine/irinotecan followed by interval-compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (cycles began every 14 days), and finished with four cycles of standard vincristine/actinomycin/cyclophosphamide (VAC) and two more cycles of vincristine/irinotecan. The treatment plan also included radiation of primary and metastatic sites at week 19.
The most common nonhematologic adverse event of grade 3 or higher was diarrhea, reported in 20% of patients during the time period when they received irinotecan. Febrile neutropenia occurred in 63% of patients.
Dr. Weigel reported financial relationships with Genentech and Eli Lilly/ImClone System. Several of her coauthors reported having ties to industry sources.
Key clinical point: A dose-intensive, multiagent regimen including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation resulted in improved outcomes for patients with low-risk stage IV rhabdomyosarcoma (RMS), but not for patients with high-risk disease.
Major finding: Patients with stage IV rhabdomyosarcoma with one or fewer Oberlin risk factors had 3-year event-free survival and overall survival rates of 69% and 79%, respectively; patients with two or more Oberlin risk factors had rates of 20% and 14%, respectively.
Data source: The Children’s Oncology Group study ARST0431 involving 109 patients with metastatic RMS who had no prior chemotherapy or radiation treatment from 2006 to 2008.
Disclosures: Dr. Weigel reported financial relationships with Genentech and Eli Lilly/ImClone System. Several of her coauthors reported having ties to industry sources.
FDA approves trabectedin for some advanced soft tissue sarcomas
The Food and Drug Administration has approved trabectedin for the treatment of advanced or unresectable liposarcomas and leiomyosarcomas that have been previously treated with anthracycline-based regimens.
Approval is based on improvements in progression-free survival in a trial of 518 participants with metastatic or recurrent leiomyosarcoma or liposarcoma, randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients). Median progression-free survival was 4.2 months for those in the trabectedin arm, compared with 1.5 months for those in the dacarbazine arm, according to an Oct. 23 statement issued by the FDA.
The most common side effects for those in the trabectedin arm were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and decreases in albumin.
The drug label carries a warning of the risk of neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis, and cardiomyopathy. Women should be advised of potential risks to a developing fetus, and those who are breastfeeding should not take trabectedin, the FDA said.
Trabectedin, an alkylating drug, is marketed as Yondelis by Janssen Products of Raritan, N.J.
The label is available on the FDA website at drugsatfda.
On Twitter @NikolaidesLaura
The Food and Drug Administration has approved trabectedin for the treatment of advanced or unresectable liposarcomas and leiomyosarcomas that have been previously treated with anthracycline-based regimens.
Approval is based on improvements in progression-free survival in a trial of 518 participants with metastatic or recurrent leiomyosarcoma or liposarcoma, randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients). Median progression-free survival was 4.2 months for those in the trabectedin arm, compared with 1.5 months for those in the dacarbazine arm, according to an Oct. 23 statement issued by the FDA.
The most common side effects for those in the trabectedin arm were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and decreases in albumin.
The drug label carries a warning of the risk of neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis, and cardiomyopathy. Women should be advised of potential risks to a developing fetus, and those who are breastfeeding should not take trabectedin, the FDA said.
Trabectedin, an alkylating drug, is marketed as Yondelis by Janssen Products of Raritan, N.J.
The label is available on the FDA website at drugsatfda.
On Twitter @NikolaidesLaura
The Food and Drug Administration has approved trabectedin for the treatment of advanced or unresectable liposarcomas and leiomyosarcomas that have been previously treated with anthracycline-based regimens.
Approval is based on improvements in progression-free survival in a trial of 518 participants with metastatic or recurrent leiomyosarcoma or liposarcoma, randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients). Median progression-free survival was 4.2 months for those in the trabectedin arm, compared with 1.5 months for those in the dacarbazine arm, according to an Oct. 23 statement issued by the FDA.
The most common side effects for those in the trabectedin arm were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and decreases in albumin.
The drug label carries a warning of the risk of neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis, and cardiomyopathy. Women should be advised of potential risks to a developing fetus, and those who are breastfeeding should not take trabectedin, the FDA said.
Trabectedin, an alkylating drug, is marketed as Yondelis by Janssen Products of Raritan, N.J.
The label is available on the FDA website at drugsatfda.
On Twitter @NikolaidesLaura
Trabectedin superior for advanced liposarcoma, leiomyosarcoma
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
This study confirms what we originally heard a decade ago from European investigators: Trabectedin shows clinical activity against liposarcomas and leiomyosarcomas. But the benefits demonstrated here still seem small, and it is not yet clear whether the data are now sufficient to make trabectedin the standard of care for all patients who have these sarcomas.
The primary end point – improving overall survival to a greater degree than dacarbazine – was not met. However, in the investigators’ defense, this was partly because the dacarbazine group survived much longer than expected. This, in turn, may be because more patients who had disease progression with dacarbazine (56%) than with trabectedin (47%) crossed over to other anticancer drugs, including the receptor tyrosine kinase inhibitor pazopanib, which was approved during the course of this study.
Dr. Gary K. Schwartz is at the Herbert Irving Comprehensive Cancer Center and Columbia University, New York. He reported ties to Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Schwartz made these remarks in an editorial accompanying Dr. Demetri’s report (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.63.5938]).
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Trabectedin was superior to standard dacarbazine by most measures in advanced, refractory liposarcoma and leiomyosarcoma, though not for overall survival.
Major finding: Trabectedin reduced the risk of disease progression by 45% (HR, 0.55).
Data source: An international industry-sponsored open-label randomized phase III clinical trial involving 518 patients.
Disclosures: This study was supported by Janssen Pharmaceuticals and the Adelson Medical Research Foundation. Dr. Demetri and his associates reported ties to numerous industry sources.
Preop chemo feasible for high-risk soft-tissue sarcomas
Preoperative chemotherapy is feasible for high-risk localized soft-tissue sarcomas of the limbs or superficial trunk, even with concurrent radiotherapy and even in selected elderly patients, investigators reported online Sept. 7 in Journal of Clinical Oncology.
Full-dose preoperative chemotherapy now can be offered and an excellent chemotherapeutic dose intensity now can be achieved with concomitant radiotherapy in cases “when surgical reasons suggest that major preoperative shrinkage may help,” said Dr. Elena Palassini of Istituto Nazionale dei Tumori, Bologna (Italy), and her associates in the Italian Sarcoma Group and Spanish Sarcoma Group.
The investigators already reported the efficacy results of their international phase III randomized clinical trial assessing preoperative chemotherapy (with or without radiotherapy, at the treating physician’s discretion). In the current analysis, they focused on the toxicity data for 303 of the trial participants, all of whom had high-grade, deep, large, adult-type soft-tissue sarcomas arising from the extremities or trunk wall.
The median patient age was 48 years (range, 15-79 years), and 13% of the study population was aged 65 years or older. A total of 152 received preoperative radiotherapy along with epirubicin plus ifosfamide.
“The most interesting clinical finding was the tolerability of the combination of preoperative chemotherapy and radiotherapy,” which is particularly remarkable because patients chosen for combination treatment had the largest tumors and the most challenging presentations, the investigators wrote.
Participants who received combination preoperative therapy showed “only limited worsening of toxicities” compared with those who had preoperative chemotherapy alone, Dr. Palassini and her associates said (J Clin Oncol. 2015 Sept. 7. doi: 10.1200/JCO.2015.62.9394).
Grade 3 or 4 thrombocytopenia was more frequent with combined therapy than with chemotherapy alone, but grade 4 leukopenia and grade 3 or 4 anemia were not. There were no cases of fatal toxicity, and the rate of wound complications was not significantly higher when radiotherapy was added to chemotherapy (17.1%) than when it was not (9.9%).
Even though some patients failed to complete all planned cycles of chemotherapy or experienced dose reductions or interruptions because of toxic effects, the overall median chemotherapeutic dose index remained “excellent” at greater than 90%. This was true even in patients aged 65 years and older, which “clearly suggests the possibility of selecting and treating at least a proportion of [older] patients in the adjuvant setting with full-dose regimens.” This finding is especially important because older patients comprise 30% of those newly diagnosed as having soft-tissue sarcoma, the investigators noted.
The authors did not identify a sponsor of this study. Dr. Palassini reported having no relevant financial disclosures, and her associates reported ties to numerous industry sources.
Preoperative chemotherapy is feasible for high-risk localized soft-tissue sarcomas of the limbs or superficial trunk, even with concurrent radiotherapy and even in selected elderly patients, investigators reported online Sept. 7 in Journal of Clinical Oncology.
Full-dose preoperative chemotherapy now can be offered and an excellent chemotherapeutic dose intensity now can be achieved with concomitant radiotherapy in cases “when surgical reasons suggest that major preoperative shrinkage may help,” said Dr. Elena Palassini of Istituto Nazionale dei Tumori, Bologna (Italy), and her associates in the Italian Sarcoma Group and Spanish Sarcoma Group.
The investigators already reported the efficacy results of their international phase III randomized clinical trial assessing preoperative chemotherapy (with or without radiotherapy, at the treating physician’s discretion). In the current analysis, they focused on the toxicity data for 303 of the trial participants, all of whom had high-grade, deep, large, adult-type soft-tissue sarcomas arising from the extremities or trunk wall.
The median patient age was 48 years (range, 15-79 years), and 13% of the study population was aged 65 years or older. A total of 152 received preoperative radiotherapy along with epirubicin plus ifosfamide.
“The most interesting clinical finding was the tolerability of the combination of preoperative chemotherapy and radiotherapy,” which is particularly remarkable because patients chosen for combination treatment had the largest tumors and the most challenging presentations, the investigators wrote.
Participants who received combination preoperative therapy showed “only limited worsening of toxicities” compared with those who had preoperative chemotherapy alone, Dr. Palassini and her associates said (J Clin Oncol. 2015 Sept. 7. doi: 10.1200/JCO.2015.62.9394).
Grade 3 or 4 thrombocytopenia was more frequent with combined therapy than with chemotherapy alone, but grade 4 leukopenia and grade 3 or 4 anemia were not. There were no cases of fatal toxicity, and the rate of wound complications was not significantly higher when radiotherapy was added to chemotherapy (17.1%) than when it was not (9.9%).
Even though some patients failed to complete all planned cycles of chemotherapy or experienced dose reductions or interruptions because of toxic effects, the overall median chemotherapeutic dose index remained “excellent” at greater than 90%. This was true even in patients aged 65 years and older, which “clearly suggests the possibility of selecting and treating at least a proportion of [older] patients in the adjuvant setting with full-dose regimens.” This finding is especially important because older patients comprise 30% of those newly diagnosed as having soft-tissue sarcoma, the investigators noted.
The authors did not identify a sponsor of this study. Dr. Palassini reported having no relevant financial disclosures, and her associates reported ties to numerous industry sources.
Preoperative chemotherapy is feasible for high-risk localized soft-tissue sarcomas of the limbs or superficial trunk, even with concurrent radiotherapy and even in selected elderly patients, investigators reported online Sept. 7 in Journal of Clinical Oncology.
Full-dose preoperative chemotherapy now can be offered and an excellent chemotherapeutic dose intensity now can be achieved with concomitant radiotherapy in cases “when surgical reasons suggest that major preoperative shrinkage may help,” said Dr. Elena Palassini of Istituto Nazionale dei Tumori, Bologna (Italy), and her associates in the Italian Sarcoma Group and Spanish Sarcoma Group.
The investigators already reported the efficacy results of their international phase III randomized clinical trial assessing preoperative chemotherapy (with or without radiotherapy, at the treating physician’s discretion). In the current analysis, they focused on the toxicity data for 303 of the trial participants, all of whom had high-grade, deep, large, adult-type soft-tissue sarcomas arising from the extremities or trunk wall.
The median patient age was 48 years (range, 15-79 years), and 13% of the study population was aged 65 years or older. A total of 152 received preoperative radiotherapy along with epirubicin plus ifosfamide.
“The most interesting clinical finding was the tolerability of the combination of preoperative chemotherapy and radiotherapy,” which is particularly remarkable because patients chosen for combination treatment had the largest tumors and the most challenging presentations, the investigators wrote.
Participants who received combination preoperative therapy showed “only limited worsening of toxicities” compared with those who had preoperative chemotherapy alone, Dr. Palassini and her associates said (J Clin Oncol. 2015 Sept. 7. doi: 10.1200/JCO.2015.62.9394).
Grade 3 or 4 thrombocytopenia was more frequent with combined therapy than with chemotherapy alone, but grade 4 leukopenia and grade 3 or 4 anemia were not. There were no cases of fatal toxicity, and the rate of wound complications was not significantly higher when radiotherapy was added to chemotherapy (17.1%) than when it was not (9.9%).
Even though some patients failed to complete all planned cycles of chemotherapy or experienced dose reductions or interruptions because of toxic effects, the overall median chemotherapeutic dose index remained “excellent” at greater than 90%. This was true even in patients aged 65 years and older, which “clearly suggests the possibility of selecting and treating at least a proportion of [older] patients in the adjuvant setting with full-dose regimens.” This finding is especially important because older patients comprise 30% of those newly diagnosed as having soft-tissue sarcoma, the investigators noted.
The authors did not identify a sponsor of this study. Dr. Palassini reported having no relevant financial disclosures, and her associates reported ties to numerous industry sources.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Preoperative chemotherapy is feasible for high-risk localized soft-tissue sarcomas, even with concurrent radiotherapy.
Major finding: The overall median chemotherapeutic dose index was “excellent” at greater than 90%.
Data source: An analysis of toxicity data from a 5-year international phase III randomized trial involving 303 patients.
Disclosures: The authors did not identify a sponsor of this study. Dr. Palassini reported having no relevant financial disclosures, and her associates reported ties to numerous industry sources.
Genomic oncology: moving beyond the tip of the iceberg
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2