Sarcoma & GIST

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

BOSTON – In sarcoma as in other cancers, experience counts.

That’s the conclusion of investigators who found that patients with extra-abdominal sarcomas who were treated in high-volume hospitals had half the 30-day mortality rate, higher likelihood of negative surgical margins, and better overall survival, compared with patients treated in low-volume hospitals.

“It appears there is a direct association between hospital volume and short-term as well as long-term outcomes for soft-tissue sarcomas outside the abdomen,” said Dr. Sanjay P. Bagaria of the Mayo Clinic in Jacksonville, Fla.

The findings support centralization of services at the national level in centers specializing in the management of sarcomas, he said at the annual Society of Surgical Oncology Cancer Symposium.

Previous studies have shown that patients treated in high-volume centers for cancers of the esophagus, pancreas, and lung have better outcomes than patients treated in low-volume centers, he noted.

Given the rarity of sarcomas, with an incidence of approximately 12,000 in the U.S. annually, their complexity, with more than 60 histologic subtypes, and the multimodality approach required for them, it seemed likely that a positive association between volume and outcomes could be found, Dr. Bagaria said.

He and colleagues queried the U.S. National Cancer Database, a hospital registry of data from more than 1,500 facilities accredited by the Commission on Cancer.

They drew records on all patients diagnosed with extra-abdominal sarcomas from 2003 through 2007 who underwent surgery at the reporting hospitals, and divided the cases into terciles as either low volume (3 or fewer surgical cases per year), medium volume (3.2-11.6 per year), or high volume (12 or more cases per year).

One third (33%) of all cases were concentrated in just 44 high-volume hospitals, which comprised just 4% of the total hospital sample of 1,163. An additional third (34%) of cases were managed among 196 medium-volume hospitals (17% of the hospital sample), and the remaining third (33%) were spread among 923 low-volume hospitals (79%).

The 30-day mortality rates for low-, medium-, and high-volume hospitals, respectively, were 1.7%, 1.1%, and 0.6% (P less than .0001).

Similarly, the rates of negative margins (R0 resections) were 73.%, 78.2%, and 84.2% (P less than .0001).

Five-year overall survival was identical for low- and medium-volume centers (65% each), but was significantly better for patients treated at high-volume centers (69%, P less than .001)

Compared with low-volume centers, patients treated at high-volume centers had an adjusted odds ratio (OR) for 30-day mortality of 0.46 (P = .01), an adjusted OR for R0 margins of 1.87 (P less than .001), and OR for overall mortality of 0.92 (P = .04).

Dr. Bagaria noted that the study was limited by missing data about disease-specific survival and by possible selection bias associated with the choice of Commission on Cancer-accredited institutions, which account for 70% of cancer cases nationwide but comprise one-third of all hospitals.

BOSTON – In sarcoma as in other cancers, experience counts.

That’s the conclusion of investigators who found that patients with extra-abdominal sarcomas who were treated in high-volume hospitals had half the 30-day mortality rate, higher likelihood of negative surgical margins, and better overall survival, compared with patients treated in low-volume hospitals.

“It appears there is a direct association between hospital volume and short-term as well as long-term outcomes for soft-tissue sarcomas outside the abdomen,” said Dr. Sanjay P. Bagaria of the Mayo Clinic in Jacksonville, Fla.

The findings support centralization of services at the national level in centers specializing in the management of sarcomas, he said at the annual Society of Surgical Oncology Cancer Symposium.

Previous studies have shown that patients treated in high-volume centers for cancers of the esophagus, pancreas, and lung have better outcomes than patients treated in low-volume centers, he noted.

Given the rarity of sarcomas, with an incidence of approximately 12,000 in the U.S. annually, their complexity, with more than 60 histologic subtypes, and the multimodality approach required for them, it seemed likely that a positive association between volume and outcomes could be found, Dr. Bagaria said.

He and colleagues queried the U.S. National Cancer Database, a hospital registry of data from more than 1,500 facilities accredited by the Commission on Cancer.

They drew records on all patients diagnosed with extra-abdominal sarcomas from 2003 through 2007 who underwent surgery at the reporting hospitals, and divided the cases into terciles as either low volume (3 or fewer surgical cases per year), medium volume (3.2-11.6 per year), or high volume (12 or more cases per year).

One third (33%) of all cases were concentrated in just 44 high-volume hospitals, which comprised just 4% of the total hospital sample of 1,163. An additional third (34%) of cases were managed among 196 medium-volume hospitals (17% of the hospital sample), and the remaining third (33%) were spread among 923 low-volume hospitals (79%).

The 30-day mortality rates for low-, medium-, and high-volume hospitals, respectively, were 1.7%, 1.1%, and 0.6% (P less than .0001).

Similarly, the rates of negative margins (R0 resections) were 73.%, 78.2%, and 84.2% (P less than .0001).

Five-year overall survival was identical for low- and medium-volume centers (65% each), but was significantly better for patients treated at high-volume centers (69%, P less than .001)

Compared with low-volume centers, patients treated at high-volume centers had an adjusted odds ratio (OR) for 30-day mortality of 0.46 (P = .01), an adjusted OR for R0 margins of 1.87 (P less than .001), and OR for overall mortality of 0.92 (P = .04).

Dr. Bagaria noted that the study was limited by missing data about disease-specific survival and by possible selection bias associated with the choice of Commission on Cancer-accredited institutions, which account for 70% of cancer cases nationwide but comprise one-third of all hospitals.

BOSTON – In sarcoma as in other cancers, experience counts.

That’s the conclusion of investigators who found that patients with extra-abdominal sarcomas who were treated in high-volume hospitals had half the 30-day mortality rate, higher likelihood of negative surgical margins, and better overall survival, compared with patients treated in low-volume hospitals.

“It appears there is a direct association between hospital volume and short-term as well as long-term outcomes for soft-tissue sarcomas outside the abdomen,” said Dr. Sanjay P. Bagaria of the Mayo Clinic in Jacksonville, Fla.

The findings support centralization of services at the national level in centers specializing in the management of sarcomas, he said at the annual Society of Surgical Oncology Cancer Symposium.

Previous studies have shown that patients treated in high-volume centers for cancers of the esophagus, pancreas, and lung have better outcomes than patients treated in low-volume centers, he noted.

Given the rarity of sarcomas, with an incidence of approximately 12,000 in the U.S. annually, their complexity, with more than 60 histologic subtypes, and the multimodality approach required for them, it seemed likely that a positive association between volume and outcomes could be found, Dr. Bagaria said.

He and colleagues queried the U.S. National Cancer Database, a hospital registry of data from more than 1,500 facilities accredited by the Commission on Cancer.

They drew records on all patients diagnosed with extra-abdominal sarcomas from 2003 through 2007 who underwent surgery at the reporting hospitals, and divided the cases into terciles as either low volume (3 or fewer surgical cases per year), medium volume (3.2-11.6 per year), or high volume (12 or more cases per year).

One third (33%) of all cases were concentrated in just 44 high-volume hospitals, which comprised just 4% of the total hospital sample of 1,163. An additional third (34%) of cases were managed among 196 medium-volume hospitals (17% of the hospital sample), and the remaining third (33%) were spread among 923 low-volume hospitals (79%).

The 30-day mortality rates for low-, medium-, and high-volume hospitals, respectively, were 1.7%, 1.1%, and 0.6% (P less than .0001).

Similarly, the rates of negative margins (R0 resections) were 73.%, 78.2%, and 84.2% (P less than .0001).

Five-year overall survival was identical for low- and medium-volume centers (65% each), but was significantly better for patients treated at high-volume centers (69%, P less than .001)

Compared with low-volume centers, patients treated at high-volume centers had an adjusted odds ratio (OR) for 30-day mortality of 0.46 (P = .01), an adjusted OR for R0 margins of 1.87 (P less than .001), and OR for overall mortality of 0.92 (P = .04).

Dr. Bagaria noted that the study was limited by missing data about disease-specific survival and by possible selection bias associated with the choice of Commission on Cancer-accredited institutions, which account for 70% of cancer cases nationwide but comprise one-third of all hospitals.

BOSTON – CT scans appear to be effective for detecting local recurrences and pulmonary metastases in patients treated for soft-tissue sarcomas of the extremities, for about a third less than the cost of follow-up with MRI.

In a retrospective study by Dr. Allison Maciver and her colleagues, among 91 patients with soft-tissue sarcomas of the extremity followed with CT, 11 patients had a total of 14 local recurrences detected on CT, and 11 of the recurrences were in patients who were clinically asymptomatic.

Surveillance CT also identified 15 cases of pulmonary metastases, and 4 incidental second primary malignancies, Dr. Maciver of the Roswell Park Cancer Institute in Buffalo, N.Y., and her coinvestigators found, and there was only one false-positive recurrence.

The benefits of CT over extremity MRI in this population include decreased imaging time, lower cost, and a larger field of view, allowing for detection of second primary malignancies, she noted in a poster session at the annual Society of Surgical Oncology Cancer Symposium.

Many sarcomas of the extremities are highly aggressive, and timely detection of local recurrences could improve chances for limb-sparing salvage therapies. Although MRI has typically been used to follow patients with sarcomas, it is expensive and has a limited field of view, Dr. Maciver said.

In addition, the risk of pulmonary metastases with some soft-tissue sarcomas is high, necessitating the use of chest CT as a surveillance tool.

To see whether CT scans of the chest and extremities could be a cost-effective surveillance strategy for both local recurrences and pulmonary metastases, the investigators did a retrospective study of a prospective database of patients who underwent surgical resection for soft-tissue sarcomas of the extremities from 2001 through 2014 and who had CT as the primary follow-up imaging modality.

They identified a total of 91 high-risk patients followed for a median of 50.5 months. The patients had an estimated 5-year freedom from local recurrence of 82%, and from distant recurrence of 80%. Five-year overall survival was 76%.

Of the 15 patients found on CT to have pulmonary metastases, there were 4 incidentally discovered second primary cancers, including 1 each of non–small cell lung cancer, pancreatic adenocarcinoma, Merkel cell carcinomatosis, and myxofibrosarcoma. There were no false-positive pulmonary metastases.

The estimated cost of 10 years of surveillance, based on 2014 gross technical costs, was $64,969 per patient for chest CT and extremity MRI, compared with $41,595 per patient for chest and extremity CT surveillance, a potential cost savings with the CT-only strategy of $23,374 per patient.

The investigators said that the overall benefits of CT, including the cost savings in an accountable care organization model, “appear to outweigh the slightly increased radiation exposure.”

The study was internally funded. The authors reported having no relevant financial disclosures.

BOSTON – CT scans appear to be effective for detecting local recurrences and pulmonary metastases in patients treated for soft-tissue sarcomas of the extremities, for about a third less than the cost of follow-up with MRI.

In a retrospective study by Dr. Allison Maciver and her colleagues, among 91 patients with soft-tissue sarcomas of the extremity followed with CT, 11 patients had a total of 14 local recurrences detected on CT, and 11 of the recurrences were in patients who were clinically asymptomatic.

Surveillance CT also identified 15 cases of pulmonary metastases, and 4 incidental second primary malignancies, Dr. Maciver of the Roswell Park Cancer Institute in Buffalo, N.Y., and her coinvestigators found, and there was only one false-positive recurrence.

The benefits of CT over extremity MRI in this population include decreased imaging time, lower cost, and a larger field of view, allowing for detection of second primary malignancies, she noted in a poster session at the annual Society of Surgical Oncology Cancer Symposium.

Many sarcomas of the extremities are highly aggressive, and timely detection of local recurrences could improve chances for limb-sparing salvage therapies. Although MRI has typically been used to follow patients with sarcomas, it is expensive and has a limited field of view, Dr. Maciver said.

In addition, the risk of pulmonary metastases with some soft-tissue sarcomas is high, necessitating the use of chest CT as a surveillance tool.

To see whether CT scans of the chest and extremities could be a cost-effective surveillance strategy for both local recurrences and pulmonary metastases, the investigators did a retrospective study of a prospective database of patients who underwent surgical resection for soft-tissue sarcomas of the extremities from 2001 through 2014 and who had CT as the primary follow-up imaging modality.

They identified a total of 91 high-risk patients followed for a median of 50.5 months. The patients had an estimated 5-year freedom from local recurrence of 82%, and from distant recurrence of 80%. Five-year overall survival was 76%.

Of the 15 patients found on CT to have pulmonary metastases, there were 4 incidentally discovered second primary cancers, including 1 each of non–small cell lung cancer, pancreatic adenocarcinoma, Merkel cell carcinomatosis, and myxofibrosarcoma. There were no false-positive pulmonary metastases.

The estimated cost of 10 years of surveillance, based on 2014 gross technical costs, was $64,969 per patient for chest CT and extremity MRI, compared with $41,595 per patient for chest and extremity CT surveillance, a potential cost savings with the CT-only strategy of $23,374 per patient.

The investigators said that the overall benefits of CT, including the cost savings in an accountable care organization model, “appear to outweigh the slightly increased radiation exposure.”

The study was internally funded. The authors reported having no relevant financial disclosures.

BOSTON – CT scans appear to be effective for detecting local recurrences and pulmonary metastases in patients treated for soft-tissue sarcomas of the extremities, for about a third less than the cost of follow-up with MRI.

In a retrospective study by Dr. Allison Maciver and her colleagues, among 91 patients with soft-tissue sarcomas of the extremity followed with CT, 11 patients had a total of 14 local recurrences detected on CT, and 11 of the recurrences were in patients who were clinically asymptomatic.

Surveillance CT also identified 15 cases of pulmonary metastases, and 4 incidental second primary malignancies, Dr. Maciver of the Roswell Park Cancer Institute in Buffalo, N.Y., and her coinvestigators found, and there was only one false-positive recurrence.

The benefits of CT over extremity MRI in this population include decreased imaging time, lower cost, and a larger field of view, allowing for detection of second primary malignancies, she noted in a poster session at the annual Society of Surgical Oncology Cancer Symposium.

Many sarcomas of the extremities are highly aggressive, and timely detection of local recurrences could improve chances for limb-sparing salvage therapies. Although MRI has typically been used to follow patients with sarcomas, it is expensive and has a limited field of view, Dr. Maciver said.

In addition, the risk of pulmonary metastases with some soft-tissue sarcomas is high, necessitating the use of chest CT as a surveillance tool.

To see whether CT scans of the chest and extremities could be a cost-effective surveillance strategy for both local recurrences and pulmonary metastases, the investigators did a retrospective study of a prospective database of patients who underwent surgical resection for soft-tissue sarcomas of the extremities from 2001 through 2014 and who had CT as the primary follow-up imaging modality.

They identified a total of 91 high-risk patients followed for a median of 50.5 months. The patients had an estimated 5-year freedom from local recurrence of 82%, and from distant recurrence of 80%. Five-year overall survival was 76%.

Of the 15 patients found on CT to have pulmonary metastases, there were 4 incidentally discovered second primary cancers, including 1 each of non–small cell lung cancer, pancreatic adenocarcinoma, Merkel cell carcinomatosis, and myxofibrosarcoma. There were no false-positive pulmonary metastases.

The estimated cost of 10 years of surveillance, based on 2014 gross technical costs, was $64,969 per patient for chest CT and extremity MRI, compared with $41,595 per patient for chest and extremity CT surveillance, a potential cost savings with the CT-only strategy of $23,374 per patient.

The investigators said that the overall benefits of CT, including the cost savings in an accountable care organization model, “appear to outweigh the slightly increased radiation exposure.”

The study was internally funded. The authors reported having no relevant financial disclosures.

The treatment of bone sarcomas in adults is guided as much by experience as it is by medical evidence, say sarcoma experts who should know.

“[L]arge prospective clinical trials in adults with bone sarcomas are lacking. Although translation of findings in pediatric studies to adults is possible, it is not clear if findings from pediatric studies truly apply to adults,” Dr. Michael J. Wagner and his colleagues from the University of Texas MD Anderson Cancer Center in Houston said.

In a review article in the Journal of Oncology Practice, the investigators outline how they have melded lessons learned from pediatric clinical trials with clinical experience treating adults with bone sarcomas.

Adult osteosarcomas

Although the peak incidence of osteosarcoma occurs in adolescents and young adults, some studies of various chemotherapy regimens have included middle-aged adults and even some patients in their 90s, although many have excluded patients older than 30, the authors noted.

In adults, and in children and adolescents and young adults, chemotherapy and definitive surgical resection are the mainstays of treatment, with the exception of osteosarcomas of the jaw, which are generally treated with resection alone. For the past three decades, adults with high-grade osteosarcomas have been treated with chemotherapy containing doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.

“However, important differences to consider in the treatment of older patients include, but are not limited to, the increased incidence of histologic variants of osteosarcoma (including secondary osteosarcomas) and medical comorbidities that may limit tolerance of older adults to dose-intense chemotherapy,” wrote Dr. Wagner and his colleagues (J Oncol Pract. 2016 Mar. doi: 10.1200/JOP.2015.009944).

High-grade localized osteosarcoma is treated with neoadjuvant chemotherapy, followed by limb-sparing surgery and adjuvant chemotherapy.

A poor response to neoadjuvant chemotherapy, defined as tumor necrosis of less than 90% at resection, is a marker for poor prognosis.

The authors previously reported that for patients with a poor response following a regimen of doxorubicin intravenous infusion at 90 mg/m² over 96 hours plus cisplatin infused intra-arterially at 120-160 mg/m² over 2 to 24 hours, the addition of high-dose methotrexate and ifosfamide resulted in significant improvement in continuous relapse-free survival.

At MD Anderson, adults with osteosarcoma receive preoperative chemotherapy with doxorubicin and cisplatin for three to four cycles and then undergo surgical resection. Those who have a good response go on to receive adjuvant chemotherapy with doxorubicin 75 mg/m2 and ifosfamide 10g/m2 for four cycles. Patients who have a poor response to neoadjuvant chemotherapy receive alternating courses of ifosfamide 14 g/m², high-dose methotrexate 10 to 12 g/m², and doxorubicin 75 mg/m² and ifosfamide 10 g/m² for up to 12 cycles or until intolerable adverse events.

Patients with metastatic relapsed/refractory osteosarcoma have 5-year overall survival rates ranging from 15% to 20%, the authors noted, adding that chemotherapy has “limited efficacy” in this setting.

Targeted agents, including the tyrosine kinase inhibitor sorafenib (Nexavar) and the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) have been evaluated in phase II trials.

Ewing sarcoma

Evidence from clinical trials of chemotherapy regimens in Ewing sarcoma show that patients 18 and older tend to have less favorable outcomes than younger patients when treated with dose-dense regimens, the authors noted.

Their practice is to treat adults with Ewing sarcoma with upfront vincristine 2 mg on day 1, doxorubicin 75 to 90 mg/m² in a continuous 72-hour infusion, and ifosfamide 2.5 g/m² given over 3 hours daily for four doses, followed by surgery, and adjuvant chemotherapy with an ifosfamide-based regimen.

Giant cell tumors of bone

These rare osteolytic tumors are treated with surgery as the primary therapy if they are resectable. Patients with metastases (which paradoxically, are usually histologically benign) as well as those who have tumors in areas where surgery may cause unacceptable morbidities may be treated with serial embolization, denosumab (Xgeva), interferon, or pegylated interferon.

Chondrosarcoma

The so-called “conventional” sub-type of chondrosarcomas are not generally responsive to cytotoxic chemotherapy and best managed with surgery alone, the authors say. However, patients with mesenchymal chondrosarcoma are treated similarly to patients with Ewing sarcoma, and those with the dedifferentiated subtype are treated with an osteosarcoma regimens.

The authors noted that point mutations in IDH1 and IDH2 have recently been discovered in chondrosarcomas, making them potential targets for an experimental IDH-1 inhibitor.

Dr. Wagner and coauthor Dr. J. Andrew Livingston reported no relevant disclosures. Coauthors Dr. Shreyaskumar R. Patel and Dr. Robert S. Benjamin reported consulting, advisory roles, research funding, or ownership interests in various pharmaceutical companies.

The treatment of bone sarcomas in adults is guided as much by experience as it is by medical evidence, say sarcoma experts who should know.

“[L]arge prospective clinical trials in adults with bone sarcomas are lacking. Although translation of findings in pediatric studies to adults is possible, it is not clear if findings from pediatric studies truly apply to adults,” Dr. Michael J. Wagner and his colleagues from the University of Texas MD Anderson Cancer Center in Houston said.

In a review article in the Journal of Oncology Practice, the investigators outline how they have melded lessons learned from pediatric clinical trials with clinical experience treating adults with bone sarcomas.

Adult osteosarcomas

Although the peak incidence of osteosarcoma occurs in adolescents and young adults, some studies of various chemotherapy regimens have included middle-aged adults and even some patients in their 90s, although many have excluded patients older than 30, the authors noted.

In adults, and in children and adolescents and young adults, chemotherapy and definitive surgical resection are the mainstays of treatment, with the exception of osteosarcomas of the jaw, which are generally treated with resection alone. For the past three decades, adults with high-grade osteosarcomas have been treated with chemotherapy containing doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.

“However, important differences to consider in the treatment of older patients include, but are not limited to, the increased incidence of histologic variants of osteosarcoma (including secondary osteosarcomas) and medical comorbidities that may limit tolerance of older adults to dose-intense chemotherapy,” wrote Dr. Wagner and his colleagues (J Oncol Pract. 2016 Mar. doi: 10.1200/JOP.2015.009944).

High-grade localized osteosarcoma is treated with neoadjuvant chemotherapy, followed by limb-sparing surgery and adjuvant chemotherapy.

A poor response to neoadjuvant chemotherapy, defined as tumor necrosis of less than 90% at resection, is a marker for poor prognosis.

The authors previously reported that for patients with a poor response following a regimen of doxorubicin intravenous infusion at 90 mg/m² over 96 hours plus cisplatin infused intra-arterially at 120-160 mg/m² over 2 to 24 hours, the addition of high-dose methotrexate and ifosfamide resulted in significant improvement in continuous relapse-free survival.

At MD Anderson, adults with osteosarcoma receive preoperative chemotherapy with doxorubicin and cisplatin for three to four cycles and then undergo surgical resection. Those who have a good response go on to receive adjuvant chemotherapy with doxorubicin 75 mg/m2 and ifosfamide 10g/m2 for four cycles. Patients who have a poor response to neoadjuvant chemotherapy receive alternating courses of ifosfamide 14 g/m², high-dose methotrexate 10 to 12 g/m², and doxorubicin 75 mg/m² and ifosfamide 10 g/m² for up to 12 cycles or until intolerable adverse events.

Patients with metastatic relapsed/refractory osteosarcoma have 5-year overall survival rates ranging from 15% to 20%, the authors noted, adding that chemotherapy has “limited efficacy” in this setting.

Targeted agents, including the tyrosine kinase inhibitor sorafenib (Nexavar) and the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) have been evaluated in phase II trials.

Ewing sarcoma

Evidence from clinical trials of chemotherapy regimens in Ewing sarcoma show that patients 18 and older tend to have less favorable outcomes than younger patients when treated with dose-dense regimens, the authors noted.

Their practice is to treat adults with Ewing sarcoma with upfront vincristine 2 mg on day 1, doxorubicin 75 to 90 mg/m² in a continuous 72-hour infusion, and ifosfamide 2.5 g/m² given over 3 hours daily for four doses, followed by surgery, and adjuvant chemotherapy with an ifosfamide-based regimen.

Giant cell tumors of bone

These rare osteolytic tumors are treated with surgery as the primary therapy if they are resectable. Patients with metastases (which paradoxically, are usually histologically benign) as well as those who have tumors in areas where surgery may cause unacceptable morbidities may be treated with serial embolization, denosumab (Xgeva), interferon, or pegylated interferon.

Chondrosarcoma

The so-called “conventional” sub-type of chondrosarcomas are not generally responsive to cytotoxic chemotherapy and best managed with surgery alone, the authors say. However, patients with mesenchymal chondrosarcoma are treated similarly to patients with Ewing sarcoma, and those with the dedifferentiated subtype are treated with an osteosarcoma regimens.

The authors noted that point mutations in IDH1 and IDH2 have recently been discovered in chondrosarcomas, making them potential targets for an experimental IDH-1 inhibitor.

Dr. Wagner and coauthor Dr. J. Andrew Livingston reported no relevant disclosures. Coauthors Dr. Shreyaskumar R. Patel and Dr. Robert S. Benjamin reported consulting, advisory roles, research funding, or ownership interests in various pharmaceutical companies.

The treatment of bone sarcomas in adults is guided as much by experience as it is by medical evidence, say sarcoma experts who should know.

“[L]arge prospective clinical trials in adults with bone sarcomas are lacking. Although translation of findings in pediatric studies to adults is possible, it is not clear if findings from pediatric studies truly apply to adults,” Dr. Michael J. Wagner and his colleagues from the University of Texas MD Anderson Cancer Center in Houston said.

In a review article in the Journal of Oncology Practice, the investigators outline how they have melded lessons learned from pediatric clinical trials with clinical experience treating adults with bone sarcomas.

Adult osteosarcomas

Although the peak incidence of osteosarcoma occurs in adolescents and young adults, some studies of various chemotherapy regimens have included middle-aged adults and even some patients in their 90s, although many have excluded patients older than 30, the authors noted.

In adults, and in children and adolescents and young adults, chemotherapy and definitive surgical resection are the mainstays of treatment, with the exception of osteosarcomas of the jaw, which are generally treated with resection alone. For the past three decades, adults with high-grade osteosarcomas have been treated with chemotherapy containing doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.

“However, important differences to consider in the treatment of older patients include, but are not limited to, the increased incidence of histologic variants of osteosarcoma (including secondary osteosarcomas) and medical comorbidities that may limit tolerance of older adults to dose-intense chemotherapy,” wrote Dr. Wagner and his colleagues (J Oncol Pract. 2016 Mar. doi: 10.1200/JOP.2015.009944).

High-grade localized osteosarcoma is treated with neoadjuvant chemotherapy, followed by limb-sparing surgery and adjuvant chemotherapy.

A poor response to neoadjuvant chemotherapy, defined as tumor necrosis of less than 90% at resection, is a marker for poor prognosis.

The authors previously reported that for patients with a poor response following a regimen of doxorubicin intravenous infusion at 90 mg/m² over 96 hours plus cisplatin infused intra-arterially at 120-160 mg/m² over 2 to 24 hours, the addition of high-dose methotrexate and ifosfamide resulted in significant improvement in continuous relapse-free survival.

At MD Anderson, adults with osteosarcoma receive preoperative chemotherapy with doxorubicin and cisplatin for three to four cycles and then undergo surgical resection. Those who have a good response go on to receive adjuvant chemotherapy with doxorubicin 75 mg/m2 and ifosfamide 10g/m2 for four cycles. Patients who have a poor response to neoadjuvant chemotherapy receive alternating courses of ifosfamide 14 g/m², high-dose methotrexate 10 to 12 g/m², and doxorubicin 75 mg/m² and ifosfamide 10 g/m² for up to 12 cycles or until intolerable adverse events.

Patients with metastatic relapsed/refractory osteosarcoma have 5-year overall survival rates ranging from 15% to 20%, the authors noted, adding that chemotherapy has “limited efficacy” in this setting.

Targeted agents, including the tyrosine kinase inhibitor sorafenib (Nexavar) and the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) have been evaluated in phase II trials.

Ewing sarcoma

Evidence from clinical trials of chemotherapy regimens in Ewing sarcoma show that patients 18 and older tend to have less favorable outcomes than younger patients when treated with dose-dense regimens, the authors noted.

Their practice is to treat adults with Ewing sarcoma with upfront vincristine 2 mg on day 1, doxorubicin 75 to 90 mg/m² in a continuous 72-hour infusion, and ifosfamide 2.5 g/m² given over 3 hours daily for four doses, followed by surgery, and adjuvant chemotherapy with an ifosfamide-based regimen.

Giant cell tumors of bone

These rare osteolytic tumors are treated with surgery as the primary therapy if they are resectable. Patients with metastases (which paradoxically, are usually histologically benign) as well as those who have tumors in areas where surgery may cause unacceptable morbidities may be treated with serial embolization, denosumab (Xgeva), interferon, or pegylated interferon.

Chondrosarcoma

The so-called “conventional” sub-type of chondrosarcomas are not generally responsive to cytotoxic chemotherapy and best managed with surgery alone, the authors say. However, patients with mesenchymal chondrosarcoma are treated similarly to patients with Ewing sarcoma, and those with the dedifferentiated subtype are treated with an osteosarcoma regimens.

The authors noted that point mutations in IDH1 and IDH2 have recently been discovered in chondrosarcomas, making them potential targets for an experimental IDH-1 inhibitor.

Dr. Wagner and coauthor Dr. J. Andrew Livingston reported no relevant disclosures. Coauthors Dr. Shreyaskumar R. Patel and Dr. Robert S. Benjamin reported consulting, advisory roles, research funding, or ownership interests in various pharmaceutical companies.

SAN DIEGO – Among patients with uterine leiomyosarcoma who underwent prior chemotherapy, treatment with trabectedin resulted in superior disease control, with significantly longer progression-free survival, compared with dacarbazine, a phase III trial showed.

“Trabectedin is an important new treatment option for patients with advanced uterine LMS after anthracycline-containing treatment,” lead study author Dr. Martee L. Hensley said at annual meeting of the Society of Gynecologic Oncology.

Trabectedin, which is marketed by Janssen Products and is also known as ET743, has a novel mechanism of action that “distorts DNA structure resulting in the initiation of DNA repair,” explained Dr. Hensley, a surgical oncologist at Memorial Sloan Kettering Cancer Center, New York. “At the same time it binds and inhibits repair mechanisms, thereby activating apoptosis. In addition, trabectedin inhibits transcriptional activation and can modify the tumor microenvironment.”

ET743-SAR-3007 was the largest randomized, phase III study in soft tissue sarcoma. It found that trabectedin demonstrated a statistically significant improvement in progression-free survival (PFS), compared with dacarbazine (4.2 months vs. 1.5 months; hazard ratio = .55; P less than .001). The results led to FDA approval of trabectedin for the treatment of patients with leiomyosarcoma (LMS) or liposarcoma (LPS), after prior anthracycline therapy. In addition, a previously reported subgroup analysis demonstrated equivalent PFS benefit in patients with either LMS (HR = .56) or LPS HR = .55). However, the majority of that study population (73%) had LMS, and most of those (40%) were uterine LMS. The purpose of the current analysis was the subgroup of patients 232 with uterine LMS who were enrolled in ET743-SAR-3007, which was conducted in 90 sites on four different countries.

Dr. Hensley reported that of the 232 women, 144 were randomized to receive a 24-hour infusion of trabectedin 1.5 mg/m² every three weeks and 88 to receive a 20- to-120-minute infusion of dacarbazine 1 g/m² every three weeks. “It’s interesting to note that the vast majority of these patients are enrolling in this study for either a third or fourth-line therapy, and nearly 20% are enrolling for fifth-line therapy for metastatic sarcoma,” she said. The primary endpoint was overall survival, while secondary endpoints were progression-free survival, overall response rate, duration of response, safety, and patient-reported outcomes.

The median number of treatment cycles was four in the trabectedin arm, compared with two in the dacarbazine arm. Nearly 40% of patients in the trabectedin arm received at least six cycles of therapy, compared with 19% in the dacarbazine arm. “There is probably a lack of cumulative toxicity that allows patients that have good disease control to remain trabectedin for a prolonged period of time,” Dr. Hensley said.

The researchers found that in patients with uterine LMS, trabectedin significantly improved progression-free survival, compared with those who received dacarbazine (4.01 months vs. 1.54 months, respectively; HR: .57; P = .0012). “Because progression-free survival can be a soft endpoint, the study was designed to collect radiographic images for central review,” Dr. Hensley said. “That was achieved in 60% of the study population in order to corroborate the PFS endpoint.”

The overall survival benefit observed with trabectedin treatment did not differ from that of dacarbazine (a median of 13.4 months vs. 12.9 months, respectively; HR = .89; P = .5107). Dr. Hensley characterized the overall response rate of both agents as “modest” (11% in the trabectedin arm, vs. 9% in the dacarbazine arm; P = .816).

Median time to response was similar between both arms (about three months) as was median duration of response (about four months for the dacarbazine arm vs. six months for the trabectedin arm). However, she pointed out that those two comparisons were based on a total of 22 patients: seven in the dacarbazine arm and 15 in the trabectedin arm.

Grade 3-4 adverse events such as increased ALT and neutropenia were more common in the trabectedin arm, compared with the dacarbazine arm (69% vs. 42%). There were two treatment-related deaths within 30 days of last dose in the trabectedin arm (1.4%) and no deaths on the dacarbazine arm.

[email protected]

SAN DIEGO – Among patients with uterine leiomyosarcoma who underwent prior chemotherapy, treatment with trabectedin resulted in superior disease control, with significantly longer progression-free survival, compared with dacarbazine, a phase III trial showed.

“Trabectedin is an important new treatment option for patients with advanced uterine LMS after anthracycline-containing treatment,” lead study author Dr. Martee L. Hensley said at annual meeting of the Society of Gynecologic Oncology.

Trabectedin, which is marketed by Janssen Products and is also known as ET743, has a novel mechanism of action that “distorts DNA structure resulting in the initiation of DNA repair,” explained Dr. Hensley, a surgical oncologist at Memorial Sloan Kettering Cancer Center, New York. “At the same time it binds and inhibits repair mechanisms, thereby activating apoptosis. In addition, trabectedin inhibits transcriptional activation and can modify the tumor microenvironment.”

ET743-SAR-3007 was the largest randomized, phase III study in soft tissue sarcoma. It found that trabectedin demonstrated a statistically significant improvement in progression-free survival (PFS), compared with dacarbazine (4.2 months vs. 1.5 months; hazard ratio = .55; P less than .001). The results led to FDA approval of trabectedin for the treatment of patients with leiomyosarcoma (LMS) or liposarcoma (LPS), after prior anthracycline therapy. In addition, a previously reported subgroup analysis demonstrated equivalent PFS benefit in patients with either LMS (HR = .56) or LPS HR = .55). However, the majority of that study population (73%) had LMS, and most of those (40%) were uterine LMS. The purpose of the current analysis was the subgroup of patients 232 with uterine LMS who were enrolled in ET743-SAR-3007, which was conducted in 90 sites on four different countries.

Dr. Hensley reported that of the 232 women, 144 were randomized to receive a 24-hour infusion of trabectedin 1.5 mg/m² every three weeks and 88 to receive a 20- to-120-minute infusion of dacarbazine 1 g/m² every three weeks. “It’s interesting to note that the vast majority of these patients are enrolling in this study for either a third or fourth-line therapy, and nearly 20% are enrolling for fifth-line therapy for metastatic sarcoma,” she said. The primary endpoint was overall survival, while secondary endpoints were progression-free survival, overall response rate, duration of response, safety, and patient-reported outcomes.

The median number of treatment cycles was four in the trabectedin arm, compared with two in the dacarbazine arm. Nearly 40% of patients in the trabectedin arm received at least six cycles of therapy, compared with 19% in the dacarbazine arm. “There is probably a lack of cumulative toxicity that allows patients that have good disease control to remain trabectedin for a prolonged period of time,” Dr. Hensley said.

The researchers found that in patients with uterine LMS, trabectedin significantly improved progression-free survival, compared with those who received dacarbazine (4.01 months vs. 1.54 months, respectively; HR: .57; P = .0012). “Because progression-free survival can be a soft endpoint, the study was designed to collect radiographic images for central review,” Dr. Hensley said. “That was achieved in 60% of the study population in order to corroborate the PFS endpoint.”

The overall survival benefit observed with trabectedin treatment did not differ from that of dacarbazine (a median of 13.4 months vs. 12.9 months, respectively; HR = .89; P = .5107). Dr. Hensley characterized the overall response rate of both agents as “modest” (11% in the trabectedin arm, vs. 9% in the dacarbazine arm; P = .816).

Median time to response was similar between both arms (about three months) as was median duration of response (about four months for the dacarbazine arm vs. six months for the trabectedin arm). However, she pointed out that those two comparisons were based on a total of 22 patients: seven in the dacarbazine arm and 15 in the trabectedin arm.

Grade 3-4 adverse events such as increased ALT and neutropenia were more common in the trabectedin arm, compared with the dacarbazine arm (69% vs. 42%). There were two treatment-related deaths within 30 days of last dose in the trabectedin arm (1.4%) and no deaths on the dacarbazine arm.

[email protected]

SAN DIEGO – Among patients with uterine leiomyosarcoma who underwent prior chemotherapy, treatment with trabectedin resulted in superior disease control, with significantly longer progression-free survival, compared with dacarbazine, a phase III trial showed.

“Trabectedin is an important new treatment option for patients with advanced uterine LMS after anthracycline-containing treatment,” lead study author Dr. Martee L. Hensley said at annual meeting of the Society of Gynecologic Oncology.

Trabectedin, which is marketed by Janssen Products and is also known as ET743, has a novel mechanism of action that “distorts DNA structure resulting in the initiation of DNA repair,” explained Dr. Hensley, a surgical oncologist at Memorial Sloan Kettering Cancer Center, New York. “At the same time it binds and inhibits repair mechanisms, thereby activating apoptosis. In addition, trabectedin inhibits transcriptional activation and can modify the tumor microenvironment.”

ET743-SAR-3007 was the largest randomized, phase III study in soft tissue sarcoma. It found that trabectedin demonstrated a statistically significant improvement in progression-free survival (PFS), compared with dacarbazine (4.2 months vs. 1.5 months; hazard ratio = .55; P less than .001). The results led to FDA approval of trabectedin for the treatment of patients with leiomyosarcoma (LMS) or liposarcoma (LPS), after prior anthracycline therapy. In addition, a previously reported subgroup analysis demonstrated equivalent PFS benefit in patients with either LMS (HR = .56) or LPS HR = .55). However, the majority of that study population (73%) had LMS, and most of those (40%) were uterine LMS. The purpose of the current analysis was the subgroup of patients 232 with uterine LMS who were enrolled in ET743-SAR-3007, which was conducted in 90 sites on four different countries.

Dr. Hensley reported that of the 232 women, 144 were randomized to receive a 24-hour infusion of trabectedin 1.5 mg/m² every three weeks and 88 to receive a 20- to-120-minute infusion of dacarbazine 1 g/m² every three weeks. “It’s interesting to note that the vast majority of these patients are enrolling in this study for either a third or fourth-line therapy, and nearly 20% are enrolling for fifth-line therapy for metastatic sarcoma,” she said. The primary endpoint was overall survival, while secondary endpoints were progression-free survival, overall response rate, duration of response, safety, and patient-reported outcomes.

The median number of treatment cycles was four in the trabectedin arm, compared with two in the dacarbazine arm. Nearly 40% of patients in the trabectedin arm received at least six cycles of therapy, compared with 19% in the dacarbazine arm. “There is probably a lack of cumulative toxicity that allows patients that have good disease control to remain trabectedin for a prolonged period of time,” Dr. Hensley said.

The researchers found that in patients with uterine LMS, trabectedin significantly improved progression-free survival, compared with those who received dacarbazine (4.01 months vs. 1.54 months, respectively; HR: .57; P = .0012). “Because progression-free survival can be a soft endpoint, the study was designed to collect radiographic images for central review,” Dr. Hensley said. “That was achieved in 60% of the study population in order to corroborate the PFS endpoint.”

The overall survival benefit observed with trabectedin treatment did not differ from that of dacarbazine (a median of 13.4 months vs. 12.9 months, respectively; HR = .89; P = .5107). Dr. Hensley characterized the overall response rate of both agents as “modest” (11% in the trabectedin arm, vs. 9% in the dacarbazine arm; P = .816).

Median time to response was similar between both arms (about three months) as was median duration of response (about four months for the dacarbazine arm vs. six months for the trabectedin arm). However, she pointed out that those two comparisons were based on a total of 22 patients: seven in the dacarbazine arm and 15 in the trabectedin arm.

Grade 3-4 adverse events such as increased ALT and neutropenia were more common in the trabectedin arm, compared with the dacarbazine arm (69% vs. 42%). There were two treatment-related deaths within 30 days of last dose in the trabectedin arm (1.4%) and no deaths on the dacarbazine arm.

[email protected]

The use of progression-free survival and response rate as surrogates for overall survival were supported by significant correlations between the endpoints, in randomized trials of advanced soft tissue sarcoma.

However, 3-month progression-free survival (PFS) and 6-month PFS were not significantly correlated with overall survival (OS) and were not recommended as surrogates for OS, according to the researchers.

Significant correlations were observed between overall survival and PFS (correlation coefficient, 0.61) and overall survival and response rate (0.51). Correlations between 3-month PFS and 6-month PFS with overall survival (0.27 and 0.31, respectively) were not significant.

“In soft tissue sarcoma, trial design is particularly challenging, owing to the rarity and heterogeneity of this disease. Time-based endpoints including PFS, 3-month PFS, and 6-month PFS are gaining popularity as primary endpoints in phase III RCTs [randomized controlled trials], despite the fact that current data support their use only to screen for effective drugs in phase II trials,” wrote Dr. Alona Zer of Princess Margaret Cancer Centre and the University of Toronto and colleagues (J Clin Oncol. 2016 March 7. Doi: 10.1200/JCO.2016.66.4581).

“Data show that the assessment of outcomes as a single point in time … only rarely mirrors the hazards of the same endpoint. … As such, the odds ratio for 3-month PFS or 6-month PFS likely do not approximate the hazard ratio for PFS, making it difficult to justify the use of these endpoints in definitive phase III trials.”

PFS and overall survival have shown poor correlation in other cancer types, and evidence suggests that survival post progression may influence the association, with weaker correlations at longer survival post progression. The majority of soft tissue sarcoma reports had survival post progression of less than 12 months, likely explaining the high correlation between PFS and overall survival.

The investigators performed a systematic review of 52 randomized controlled trials, published from 1974 to 2014, that included 9,762 patients who received systemic therapy for advanced/metastatic soft tissue sarcoma.

Comprehensive toxicity assessment was included in just 20 studies (47%) and poorly reported in 6 studies (14%). Few studies included quality of life as a secondary endpoint. The authors noted that in the soft tissue sarcoma setting in which the purpose of systemic treatment may be palliation of symptoms, this is a concern.

Over the 4 decades represented by the systematic review, several trends appeared. Overall, a low proportion of studies included intent-to-treat analyses and clearly defined primary endpoints, but these characteristics improved over time. Endpoint selection has shifted away from response rate in favor of time-based events, including PFS, 3-month PFS, and 6-month PFS. Overall survival was the primary endpoint in just 4% of studies. Studies published in the last 2 decades were more likely to be supported by industry (5% vs. 35%).

Dr. Zer and coauthors reported having no relevant financial disclosures.

The use of progression-free survival and response rate as surrogates for overall survival were supported by significant correlations between the endpoints, in randomized trials of advanced soft tissue sarcoma.

However, 3-month progression-free survival (PFS) and 6-month PFS were not significantly correlated with overall survival (OS) and were not recommended as surrogates for OS, according to the researchers.

Significant correlations were observed between overall survival and PFS (correlation coefficient, 0.61) and overall survival and response rate (0.51). Correlations between 3-month PFS and 6-month PFS with overall survival (0.27 and 0.31, respectively) were not significant.

“In soft tissue sarcoma, trial design is particularly challenging, owing to the rarity and heterogeneity of this disease. Time-based endpoints including PFS, 3-month PFS, and 6-month PFS are gaining popularity as primary endpoints in phase III RCTs [randomized controlled trials], despite the fact that current data support their use only to screen for effective drugs in phase II trials,” wrote Dr. Alona Zer of Princess Margaret Cancer Centre and the University of Toronto and colleagues (J Clin Oncol. 2016 March 7. Doi: 10.1200/JCO.2016.66.4581).

“Data show that the assessment of outcomes as a single point in time … only rarely mirrors the hazards of the same endpoint. … As such, the odds ratio for 3-month PFS or 6-month PFS likely do not approximate the hazard ratio for PFS, making it difficult to justify the use of these endpoints in definitive phase III trials.”

PFS and overall survival have shown poor correlation in other cancer types, and evidence suggests that survival post progression may influence the association, with weaker correlations at longer survival post progression. The majority of soft tissue sarcoma reports had survival post progression of less than 12 months, likely explaining the high correlation between PFS and overall survival.

The investigators performed a systematic review of 52 randomized controlled trials, published from 1974 to 2014, that included 9,762 patients who received systemic therapy for advanced/metastatic soft tissue sarcoma.

Comprehensive toxicity assessment was included in just 20 studies (47%) and poorly reported in 6 studies (14%). Few studies included quality of life as a secondary endpoint. The authors noted that in the soft tissue sarcoma setting in which the purpose of systemic treatment may be palliation of symptoms, this is a concern.

Over the 4 decades represented by the systematic review, several trends appeared. Overall, a low proportion of studies included intent-to-treat analyses and clearly defined primary endpoints, but these characteristics improved over time. Endpoint selection has shifted away from response rate in favor of time-based events, including PFS, 3-month PFS, and 6-month PFS. Overall survival was the primary endpoint in just 4% of studies. Studies published in the last 2 decades were more likely to be supported by industry (5% vs. 35%).

Dr. Zer and coauthors reported having no relevant financial disclosures.

The use of progression-free survival and response rate as surrogates for overall survival were supported by significant correlations between the endpoints, in randomized trials of advanced soft tissue sarcoma.

However, 3-month progression-free survival (PFS) and 6-month PFS were not significantly correlated with overall survival (OS) and were not recommended as surrogates for OS, according to the researchers.

Significant correlations were observed between overall survival and PFS (correlation coefficient, 0.61) and overall survival and response rate (0.51). Correlations between 3-month PFS and 6-month PFS with overall survival (0.27 and 0.31, respectively) were not significant.

“In soft tissue sarcoma, trial design is particularly challenging, owing to the rarity and heterogeneity of this disease. Time-based endpoints including PFS, 3-month PFS, and 6-month PFS are gaining popularity as primary endpoints in phase III RCTs [randomized controlled trials], despite the fact that current data support their use only to screen for effective drugs in phase II trials,” wrote Dr. Alona Zer of Princess Margaret Cancer Centre and the University of Toronto and colleagues (J Clin Oncol. 2016 March 7. Doi: 10.1200/JCO.2016.66.4581).

“Data show that the assessment of outcomes as a single point in time … only rarely mirrors the hazards of the same endpoint. … As such, the odds ratio for 3-month PFS or 6-month PFS likely do not approximate the hazard ratio for PFS, making it difficult to justify the use of these endpoints in definitive phase III trials.”

PFS and overall survival have shown poor correlation in other cancer types, and evidence suggests that survival post progression may influence the association, with weaker correlations at longer survival post progression. The majority of soft tissue sarcoma reports had survival post progression of less than 12 months, likely explaining the high correlation between PFS and overall survival.

The investigators performed a systematic review of 52 randomized controlled trials, published from 1974 to 2014, that included 9,762 patients who received systemic therapy for advanced/metastatic soft tissue sarcoma.

Comprehensive toxicity assessment was included in just 20 studies (47%) and poorly reported in 6 studies (14%). Few studies included quality of life as a secondary endpoint. The authors noted that in the soft tissue sarcoma setting in which the purpose of systemic treatment may be palliation of symptoms, this is a concern.

Over the 4 decades represented by the systematic review, several trends appeared. Overall, a low proportion of studies included intent-to-treat analyses and clearly defined primary endpoints, but these characteristics improved over time. Endpoint selection has shifted away from response rate in favor of time-based events, including PFS, 3-month PFS, and 6-month PFS. Overall survival was the primary endpoint in just 4% of studies. Studies published in the last 2 decades were more likely to be supported by industry (5% vs. 35%).

Dr. Zer and coauthors reported having no relevant financial disclosures.

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.

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.

[email protected]

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.

[email protected]

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.

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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.

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.