Sarcoma & GIST

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.

"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.

In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.

In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.

The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.

As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.

"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.

The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.

An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).

Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.

Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).

An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.

The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).

In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.

"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.

"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.

Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."

"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.

RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.

The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.

MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.

The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.

Mitchel Zoler/Frontline Medical News

Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.

"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.

The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.

"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.

The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.

The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."

The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.

Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.

GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.

Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.

[email protected]

On Twitter @mitchelzoler

MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.

The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.

Mitchel Zoler/Frontline Medical News

Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.

"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.

The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.

"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.

The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.

The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."

The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.

Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.

GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.

Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.

[email protected]

On Twitter @mitchelzoler

MILAN – An ongoing phase III trial launched in 2012 that is testing whether adjuvant therapy aids women following removal of high-risk uterine leiomyosarcomas has also blazed a path for the International Rare Cancer Initiative, which has launched two other trials in rare cancers and is planning to start several more.

The advanced uterine leiomyosarcoma trial, which is testing an adjuvant regimen of up to four courses of gemcitabine (Gemzar) plus docetaxel (Taxotere) followed by doxorubicin (Adriamycin) for four courses should "answer the adjuvant chemotherapy question" for these patients, Dr. Martee L. Hensley said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

The trial, known as Gynecologic Oncology Group (GOG) 0277, was the first study organized by the International Rare Cancer Initiative (IRCI) to activate. The study involves more than 200 U.S. centers and will open in many more European centers once regulatory approvals occur, said Dr. Hensley, professor of medicine at Weill Cornell Medical College and a gynecologic medical oncologist at Memorial Sloan- Kettering Cancer Center, New York.

Mitchel Zoler/Frontline Medical News

Oncologists diagnose about 1,200 uterine sarcomas annually in the United States, most of which are uterine-limited and histologically high grade. "Successful conduct of this study in this rare but high-risk disease will establish the standard of care for managing women who have undergone complete resection," she said in an interview.

"Conducting prospective randomized trials in rare cancers is a significant challenge. International collaboration is considered a key factor in success" by speeding patient accrual, identifying research questions of international importance, and designing a trial that is internationally accepted and generalizable, Dr. Hensley said. In 2011, five cancer organizations formed the IRCI: the U.S. National Cancer Institute, the European Organization for the Research and Treatment of Cancer, Cancer Research UK, the U.K. National Cancer Research Network, and the French Institut National du Cancer.

The IRCI defines rare cancers as generally having an incidence below 2 cases per 100,000 population, and it is charged to develop intervention trials for these cancers, especially randomized trials.

"Creation of the IRCI has provided some needed infrastructure and has been critical to the success of GOG 0277," Dr. Hensley said. "But one could also say that GOG 0277 is also key to the IRCI’s success. The work we have done for GOG 0277 will inform the design and conduct of future international studies" in rare cancers.

The IRCI includes nine committees, each of which develops trials for different rare-cancer types. These include the gynecologic sarcoma committee that Dr. Hensley serves on and which helped organize GOG 0277, and other committees for small bowel adenocarcinoma, salivary gland cancer, thymoma, ocular melanoma, relapsed or metastatic anal cancer, rare brain cancer, desmoplastic small-round-cell tumor, and penile cancer. The committees include representatives appointed by the founding organizations, which also appoint the members of the IRCI board, the body that determines which committees to form, explained Nicola Keat, a staffer at Cancer Research UK in London who serves as the IRCI coordinator.

The gynecologic sarcoma committee decided that the question of whether adjuvant chemotherapy following complete resection helps patients with uterus-limited, high-grade leiomyosarcoma had "primary importance," said Dr. Hensley. "We recognized that the IRCI provided an ideal opportunity."

The gynecologic sarcoma group also plans to open a prospective study of doxorubicin for chemotherapy-naive patients with advanced, high-grade undifferentiated sarcoma of the uterus, a rare and aggressive cancer with no standard treatment. The study would also assess whether cabozantinib (Cometriq) can further prolong progression-free survival, compared with placebo, in patients with stable disease or an objective response to doxorubicin. In addition, the committee would like to launch a trial of aromatase inhibition for patients with low-grade endometrial stromal sarcoma through the IRCI, she said.

Following the launch of GOG 0277, the IRCI opened enrollment of patients into a trial focused on advanced uveal melanoma at U.S. centers, with U.K. recruitment anticipated to start later this year, Ms. Keat said in an interview. A third IRCI-organized trial, for patients with advanced anal cancer, recently opened for enrollment at participating U.K. centers, she added.

GOG 0277 began in June 2012 and aims to enroll 216 patients. As of February 2014, it had accrued seven patients, but Dr. Hensley said she believed the study was on track to its targeted finish date in 2018, as patients will soon start to enroll in Europe. "We expect the study to open in the U.K. in the next couple of months," Ms. Keat said in late March.

Dr. Hensley said that her spouse is a Sanofi employee. Ms. Keat had no disclosures.

[email protected]

On Twitter @mitchelzoler

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

[email protected]

On Twitter @mitchelzoler

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

[email protected]

On Twitter @mitchelzoler

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

[email protected]

On Twitter @mitchelzoler

MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.

The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).

But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.

"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.

"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.

"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.

The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.

"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.

The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.

"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.

The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.

The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).

But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.

"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.

"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.

"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.

The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.

"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.

The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.

"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.

The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.

The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).

But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.

"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.

"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.

"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.

The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.

"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.

The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.

"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.

The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

[email protected]

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

[email protected]

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

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