2012 ASCO Annual Meeting

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

CHICAGO – Bevacizumab extended both progression-free and overall survival when it was added to second-line chemotherapy in patients with advanced colorectal cancer, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In a phase III randomized trial, patients with inoperable colorectal cancer (CRC) and disease progression following first-line chemotherapy who received bevacizumab (Avastin) in addition to a second-line regimen had a 1.4-month advantage in overall survival, and 1.6-month-longer progression-free survival than patients who received second-line chemotherapy alone, reported Dr. Dirk Arnold, director of the Hubertus Wald Tumor Center at University Clinic Eppendorf in Hamburg, Germany,

The findings suggest that bevacizumab, which has had mixed results in the treatment of other cancers, plays a significantly favorable role in CRC, Dr. Arnold said.

"This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. This study confirms that continuing bevacizumab beyond progression while changing chemotherapy is beneficial for patients, and has translated into a significant improvement in overall survival in metastatic colorectal cancer patients, as well as progression-free survival," he said in a briefing.

A total of 820 patients with unresectable metastatic CRC received first-line chemotherapy with either an irinotecan-based or oxaliplatin-based regimen at the treating physician’s discretion plus bevacizumab. At disease progression, the patients were randomly assigned to second-line therapy with the regimen they did not receive up front with or without concomitant bevacizumab.

Median overall survival, the primary end point, was 11.2 months for patients who received bevacizumab, compared with 9.8 months for those who received chemotherapy alone (hazard ratio 0.81, P = .0062). Median progression-free survival was 5.7 months with bevacizumab and 4.1 months without (HR 0.68, P less than .0001).

The overall response rates were 5.4% for the bevacizumab group and 3.9% for the chemotherapy-alone group, a difference that was not statistically significant.

Adverse events with bevacizumab continued in the second line were similar to those of historical controls treated with bevacizumab in either first- or second-line therapy, Dr. Arnold said.

"This provides clearly a new treatment option in the second line for patients who have been pretreated with a bevacizumab combination regimen before," Dr. Arnold said.

"Furthermore, I think these findings indicate that this might also serve as a new model for a treatment approach by multiple treatment lines in metastatic colorectal cancer and across other tumor types, which is currently [being] investigated in other trials," he added.

Dr. Bruce J. Roth, a professor of medicine in the oncology section at Washington University in St. Louis, who was not involved in the study, commented that "medical oncologists have been trained to stop classic cytotoxic therapy at the time of progression, but the issue is a little bit more complicated for anti-VEGF [vascular endothelial growth factor] therapies like bevacizumab, and this issue has been raised in other tumor types."

Dr. Roth moderated the briefing at which Dr. Arnold presented the data.

Dr. Arnold noted that the findings suggest that mechanisms of tumor resistance to cytotoxic agents may be different from those of resistance to antiangiogenic agents, which could explain the additional benefit seen with bevacizumab.

The study, ML 18147, was supported by Roche. Dr. Arnold disclosed serving in a consulting or advisory role for and receiving honoraria from Amgen, Merck Serono, and Roche Diagnostics, and receiving research funding from Roche Diagnostics. Dr. Roth had no disclosures.

CHICAGO – Bevacizumab extended both progression-free and overall survival when it was added to second-line chemotherapy in patients with advanced colorectal cancer, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In a phase III randomized trial, patients with inoperable colorectal cancer (CRC) and disease progression following first-line chemotherapy who received bevacizumab (Avastin) in addition to a second-line regimen had a 1.4-month advantage in overall survival, and 1.6-month-longer progression-free survival than patients who received second-line chemotherapy alone, reported Dr. Dirk Arnold, director of the Hubertus Wald Tumor Center at University Clinic Eppendorf in Hamburg, Germany,

The findings suggest that bevacizumab, which has had mixed results in the treatment of other cancers, plays a significantly favorable role in CRC, Dr. Arnold said.

"This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. This study confirms that continuing bevacizumab beyond progression while changing chemotherapy is beneficial for patients, and has translated into a significant improvement in overall survival in metastatic colorectal cancer patients, as well as progression-free survival," he said in a briefing.

A total of 820 patients with unresectable metastatic CRC received first-line chemotherapy with either an irinotecan-based or oxaliplatin-based regimen at the treating physician’s discretion plus bevacizumab. At disease progression, the patients were randomly assigned to second-line therapy with the regimen they did not receive up front with or without concomitant bevacizumab.

Median overall survival, the primary end point, was 11.2 months for patients who received bevacizumab, compared with 9.8 months for those who received chemotherapy alone (hazard ratio 0.81, P = .0062). Median progression-free survival was 5.7 months with bevacizumab and 4.1 months without (HR 0.68, P less than .0001).

The overall response rates were 5.4% for the bevacizumab group and 3.9% for the chemotherapy-alone group, a difference that was not statistically significant.

Adverse events with bevacizumab continued in the second line were similar to those of historical controls treated with bevacizumab in either first- or second-line therapy, Dr. Arnold said.

"This provides clearly a new treatment option in the second line for patients who have been pretreated with a bevacizumab combination regimen before," Dr. Arnold said.

"Furthermore, I think these findings indicate that this might also serve as a new model for a treatment approach by multiple treatment lines in metastatic colorectal cancer and across other tumor types, which is currently [being] investigated in other trials," he added.

Dr. Bruce J. Roth, a professor of medicine in the oncology section at Washington University in St. Louis, who was not involved in the study, commented that "medical oncologists have been trained to stop classic cytotoxic therapy at the time of progression, but the issue is a little bit more complicated for anti-VEGF [vascular endothelial growth factor] therapies like bevacizumab, and this issue has been raised in other tumor types."

Dr. Roth moderated the briefing at which Dr. Arnold presented the data.

Dr. Arnold noted that the findings suggest that mechanisms of tumor resistance to cytotoxic agents may be different from those of resistance to antiangiogenic agents, which could explain the additional benefit seen with bevacizumab.

The study, ML 18147, was supported by Roche. Dr. Arnold disclosed serving in a consulting or advisory role for and receiving honoraria from Amgen, Merck Serono, and Roche Diagnostics, and receiving research funding from Roche Diagnostics. Dr. Roth had no disclosures.

CHICAGO – Bevacizumab extended both progression-free and overall survival when it was added to second-line chemotherapy in patients with advanced colorectal cancer, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In a phase III randomized trial, patients with inoperable colorectal cancer (CRC) and disease progression following first-line chemotherapy who received bevacizumab (Avastin) in addition to a second-line regimen had a 1.4-month advantage in overall survival, and 1.6-month-longer progression-free survival than patients who received second-line chemotherapy alone, reported Dr. Dirk Arnold, director of the Hubertus Wald Tumor Center at University Clinic Eppendorf in Hamburg, Germany,

The findings suggest that bevacizumab, which has had mixed results in the treatment of other cancers, plays a significantly favorable role in CRC, Dr. Arnold said.

"This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. This study confirms that continuing bevacizumab beyond progression while changing chemotherapy is beneficial for patients, and has translated into a significant improvement in overall survival in metastatic colorectal cancer patients, as well as progression-free survival," he said in a briefing.

A total of 820 patients with unresectable metastatic CRC received first-line chemotherapy with either an irinotecan-based or oxaliplatin-based regimen at the treating physician’s discretion plus bevacizumab. At disease progression, the patients were randomly assigned to second-line therapy with the regimen they did not receive up front with or without concomitant bevacizumab.

Median overall survival, the primary end point, was 11.2 months for patients who received bevacizumab, compared with 9.8 months for those who received chemotherapy alone (hazard ratio 0.81, P = .0062). Median progression-free survival was 5.7 months with bevacizumab and 4.1 months without (HR 0.68, P less than .0001).

The overall response rates were 5.4% for the bevacizumab group and 3.9% for the chemotherapy-alone group, a difference that was not statistically significant.

Adverse events with bevacizumab continued in the second line were similar to those of historical controls treated with bevacizumab in either first- or second-line therapy, Dr. Arnold said.

"This provides clearly a new treatment option in the second line for patients who have been pretreated with a bevacizumab combination regimen before," Dr. Arnold said.

"Furthermore, I think these findings indicate that this might also serve as a new model for a treatment approach by multiple treatment lines in metastatic colorectal cancer and across other tumor types, which is currently [being] investigated in other trials," he added.

Dr. Bruce J. Roth, a professor of medicine in the oncology section at Washington University in St. Louis, who was not involved in the study, commented that "medical oncologists have been trained to stop classic cytotoxic therapy at the time of progression, but the issue is a little bit more complicated for anti-VEGF [vascular endothelial growth factor] therapies like bevacizumab, and this issue has been raised in other tumor types."

Dr. Roth moderated the briefing at which Dr. Arnold presented the data.

Dr. Arnold noted that the findings suggest that mechanisms of tumor resistance to cytotoxic agents may be different from those of resistance to antiangiogenic agents, which could explain the additional benefit seen with bevacizumab.

The study, ML 18147, was supported by Roche. Dr. Arnold disclosed serving in a consulting or advisory role for and receiving honoraria from Amgen, Merck Serono, and Roche Diagnostics, and receiving research funding from Roche Diagnostics. Dr. Roth had no disclosures.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.

The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).

Patrice Wendling/IMNG Medical Media

"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.

The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).

Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.

Photo Jane S. MacNeil/IMNG Medical Media

Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.

"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."

Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.

The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*

Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.

"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.

"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.

The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.

Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.

Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.

In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.

If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.

Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."

While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.

"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.

"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"

The investigators disclosed numerous relationships with pharmaceutical companies.

* This story was updated with additional analysis from Dr. Oh on 6/6/2012.

CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.

The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).

Patrice Wendling/IMNG Medical Media

"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.

The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).

Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.

Photo Jane S. MacNeil/IMNG Medical Media

Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.

"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."

Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.

The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*

Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.

"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.

"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.

The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.

Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.

Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.

In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.

If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.

Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."

While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.

"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.

"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"

The investigators disclosed numerous relationships with pharmaceutical companies.

* This story was updated with additional analysis from Dr. Oh on 6/6/2012.

CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.

The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).

Patrice Wendling/IMNG Medical Media

"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.

The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).

Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.

Photo Jane S. MacNeil/IMNG Medical Media

Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.

"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."

Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.

The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*

Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.

"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.

"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.

The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.

Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.

Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.

In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.

If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.

Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."

While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.

"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.

"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"

The investigators disclosed numerous relationships with pharmaceutical companies.

* This story was updated with additional analysis from Dr. Oh on 6/6/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Putting adolescent and young adult leukemia patients on pediatric regimens improved their event-free survival rate at 5-years, but they still did not fare as well as younger patients in a clinical study.

The Children’s Oncology Group protocol randomized 2,571 patients up to 30 years of age in a comparison of treatment regimens for high-risk B-precursor acute lymphoblastic leukemia (ALL). Within this population, 501 patients were 16 years or older – an age group that historically has had poorer outcomes than younger patients.

The 5-year event-free survival rate reached 68% among adolescent and young adult (AYA) patients in the randomized phase III trial – better than the 50%-60% consistently reported in previous trials, according to Dr. Eric Larsen, lead author of the study. It fell short of the 80% achieved in younger patients, however (P less than .0001).

The AYA cohort also had lower rates of overall survival (79.8% vs. 88.4%; P less than .0001) and remission (97.2% vs. 98.8%; P = .0134), which investigators defined as less than 5% marrow blasts after induction therapy. They blamed the disparity in large part on a higher rate of marrow relapse in the older patients (15.2% vs. 9.0%; P less than .0007). CNS relapse occurred at a slightly higher rate in the AYA group – 5.2% vs. 3.7%, they noted, but the difference was not significant (P = .5776).

In another comparison, the AYA patients were more likely to relapse – the 5-year cumulative incidence was 21.3% vs. 13.4% for younger patients (P = .0018). Though induction mortality rates were not significantly different between AYA and younger patients, (2.4% vs. 1.8%; P = .36), postinduction remission deaths were significantly higher at 5 years (5.5% vs. 2.1%; P less than .0001).

After 5 years, survival curves tend to flatten for both age groups but remissions are still possible, Dr. Larsen said, underscoring the importance of the benchmark during a press briefing at the annual meeting of the American Society of Clinical Oncology.

"In clinical practice and in the research world we would never declare someone truly cured, but when you are out 5 years, the number of people who are going to relapse is extraordinarily small," he said.

Dr. Larsen, medical director of the Maine Children’s Cancer Program, Scarborough, and study chair of the Children’s Oncology Group protocol AALL0232, presented the analysis June 2 at the society’s annual meeting. He reported outcomes of the trial – it found that giving patients 50 times the standard methotrexate dose reduces recurrences – last year at ASCO.

The study was the first pediatric ALL trial to include patients up to 30 years, he noted. Typically, pediatric studies enroll patients up to 18 years of age, but investigators hoped to improve the outcomes of the AYA age group by delivering more aggressive regimens than are typically used in adult patients.

"This is an underserved area," commented Dr. Carol Aghajanian, moderator of the news briefing and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

"I do see young adults ... who have pediatric tumors," she said in an interview. "Do I treat them as a typical adult or as a child who is much younger? We have this group that gets lost in the middle because of their unique situation.

"We need to identify these patients and do studies that define the biology of their disease [and] what the right treatments are," she added.

What the current analysis has shown is that "future strategies to improve outcome in AYA patients with ALL should focus on both better leukemia control and reduced treatment toxicity," Dr. Larsen said in a summary of the findings. AYA patients "have more resistant leukemia and they are more susceptible to side effects," he added in an interview.

Many factors are thought to contribute to the poorer outcomes in AYA patients, according to Dr. Larsen. These include differences in disease biology leading to more aggressive cancers and less tolerance of chemotherapy side effects than is seen in pediatric patients. In addition, socioeconomic factors may be involved, as AYA patients are often in college or looking for jobs.

Compliance is an issue as well, he noted. Although parents take charge of administering oral medications for their children, teenagers want to be responsible for themselves – sometimes with less than optimal results.

"It’s pretty clear that adolescent patients have lower rates of compliance," Dr. Larsen said, adding that "lower compliances correlates with lower survival rates."

The authors said that they had no disclosures.

CHICAGO – Putting adolescent and young adult leukemia patients on pediatric regimens improved their event-free survival rate at 5-years, but they still did not fare as well as younger patients in a clinical study.

The Children’s Oncology Group protocol randomized 2,571 patients up to 30 years of age in a comparison of treatment regimens for high-risk B-precursor acute lymphoblastic leukemia (ALL). Within this population, 501 patients were 16 years or older – an age group that historically has had poorer outcomes than younger patients.

The 5-year event-free survival rate reached 68% among adolescent and young adult (AYA) patients in the randomized phase III trial – better than the 50%-60% consistently reported in previous trials, according to Dr. Eric Larsen, lead author of the study. It fell short of the 80% achieved in younger patients, however (P less than .0001).

The AYA cohort also had lower rates of overall survival (79.8% vs. 88.4%; P less than .0001) and remission (97.2% vs. 98.8%; P = .0134), which investigators defined as less than 5% marrow blasts after induction therapy. They blamed the disparity in large part on a higher rate of marrow relapse in the older patients (15.2% vs. 9.0%; P less than .0007). CNS relapse occurred at a slightly higher rate in the AYA group – 5.2% vs. 3.7%, they noted, but the difference was not significant (P = .5776).

In another comparison, the AYA patients were more likely to relapse – the 5-year cumulative incidence was 21.3% vs. 13.4% for younger patients (P = .0018). Though induction mortality rates were not significantly different between AYA and younger patients, (2.4% vs. 1.8%; P = .36), postinduction remission deaths were significantly higher at 5 years (5.5% vs. 2.1%; P less than .0001).

After 5 years, survival curves tend to flatten for both age groups but remissions are still possible, Dr. Larsen said, underscoring the importance of the benchmark during a press briefing at the annual meeting of the American Society of Clinical Oncology.

"In clinical practice and in the research world we would never declare someone truly cured, but when you are out 5 years, the number of people who are going to relapse is extraordinarily small," he said.

Dr. Larsen, medical director of the Maine Children’s Cancer Program, Scarborough, and study chair of the Children’s Oncology Group protocol AALL0232, presented the analysis June 2 at the society’s annual meeting. He reported outcomes of the trial – it found that giving patients 50 times the standard methotrexate dose reduces recurrences – last year at ASCO.

The study was the first pediatric ALL trial to include patients up to 30 years, he noted. Typically, pediatric studies enroll patients up to 18 years of age, but investigators hoped to improve the outcomes of the AYA age group by delivering more aggressive regimens than are typically used in adult patients.

"This is an underserved area," commented Dr. Carol Aghajanian, moderator of the news briefing and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

"I do see young adults ... who have pediatric tumors," she said in an interview. "Do I treat them as a typical adult or as a child who is much younger? We have this group that gets lost in the middle because of their unique situation.

"We need to identify these patients and do studies that define the biology of their disease [and] what the right treatments are," she added.

What the current analysis has shown is that "future strategies to improve outcome in AYA patients with ALL should focus on both better leukemia control and reduced treatment toxicity," Dr. Larsen said in a summary of the findings. AYA patients "have more resistant leukemia and they are more susceptible to side effects," he added in an interview.

Many factors are thought to contribute to the poorer outcomes in AYA patients, according to Dr. Larsen. These include differences in disease biology leading to more aggressive cancers and less tolerance of chemotherapy side effects than is seen in pediatric patients. In addition, socioeconomic factors may be involved, as AYA patients are often in college or looking for jobs.

Compliance is an issue as well, he noted. Although parents take charge of administering oral medications for their children, teenagers want to be responsible for themselves – sometimes with less than optimal results.

"It’s pretty clear that adolescent patients have lower rates of compliance," Dr. Larsen said, adding that "lower compliances correlates with lower survival rates."

The authors said that they had no disclosures.

CHICAGO – Putting adolescent and young adult leukemia patients on pediatric regimens improved their event-free survival rate at 5-years, but they still did not fare as well as younger patients in a clinical study.

The Children’s Oncology Group protocol randomized 2,571 patients up to 30 years of age in a comparison of treatment regimens for high-risk B-precursor acute lymphoblastic leukemia (ALL). Within this population, 501 patients were 16 years or older – an age group that historically has had poorer outcomes than younger patients.

The 5-year event-free survival rate reached 68% among adolescent and young adult (AYA) patients in the randomized phase III trial – better than the 50%-60% consistently reported in previous trials, according to Dr. Eric Larsen, lead author of the study. It fell short of the 80% achieved in younger patients, however (P less than .0001).

The AYA cohort also had lower rates of overall survival (79.8% vs. 88.4%; P less than .0001) and remission (97.2% vs. 98.8%; P = .0134), which investigators defined as less than 5% marrow blasts after induction therapy. They blamed the disparity in large part on a higher rate of marrow relapse in the older patients (15.2% vs. 9.0%; P less than .0007). CNS relapse occurred at a slightly higher rate in the AYA group – 5.2% vs. 3.7%, they noted, but the difference was not significant (P = .5776).

In another comparison, the AYA patients were more likely to relapse – the 5-year cumulative incidence was 21.3% vs. 13.4% for younger patients (P = .0018). Though induction mortality rates were not significantly different between AYA and younger patients, (2.4% vs. 1.8%; P = .36), postinduction remission deaths were significantly higher at 5 years (5.5% vs. 2.1%; P less than .0001).

After 5 years, survival curves tend to flatten for both age groups but remissions are still possible, Dr. Larsen said, underscoring the importance of the benchmark during a press briefing at the annual meeting of the American Society of Clinical Oncology.

"In clinical practice and in the research world we would never declare someone truly cured, but when you are out 5 years, the number of people who are going to relapse is extraordinarily small," he said.

Dr. Larsen, medical director of the Maine Children’s Cancer Program, Scarborough, and study chair of the Children’s Oncology Group protocol AALL0232, presented the analysis June 2 at the society’s annual meeting. He reported outcomes of the trial – it found that giving patients 50 times the standard methotrexate dose reduces recurrences – last year at ASCO.

The study was the first pediatric ALL trial to include patients up to 30 years, he noted. Typically, pediatric studies enroll patients up to 18 years of age, but investigators hoped to improve the outcomes of the AYA age group by delivering more aggressive regimens than are typically used in adult patients.

"This is an underserved area," commented Dr. Carol Aghajanian, moderator of the news briefing and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

"I do see young adults ... who have pediatric tumors," she said in an interview. "Do I treat them as a typical adult or as a child who is much younger? We have this group that gets lost in the middle because of their unique situation.

"We need to identify these patients and do studies that define the biology of their disease [and] what the right treatments are," she added.

What the current analysis has shown is that "future strategies to improve outcome in AYA patients with ALL should focus on both better leukemia control and reduced treatment toxicity," Dr. Larsen said in a summary of the findings. AYA patients "have more resistant leukemia and they are more susceptible to side effects," he added in an interview.

Many factors are thought to contribute to the poorer outcomes in AYA patients, according to Dr. Larsen. These include differences in disease biology leading to more aggressive cancers and less tolerance of chemotherapy side effects than is seen in pediatric patients. In addition, socioeconomic factors may be involved, as AYA patients are often in college or looking for jobs.

Compliance is an issue as well, he noted. Although parents take charge of administering oral medications for their children, teenagers want to be responsible for themselves – sometimes with less than optimal results.

"It’s pretty clear that adolescent patients have lower rates of compliance," Dr. Larsen said, adding that "lower compliances correlates with lower survival rates."

The authors said that they had no disclosures.

CHICAGO – The combination of an anti-angiogenic agent with chemotherapy offers new hope to women with ovarian cancer who are running out of options because their disease has become resistant to platinums, suggests a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

Among the 361 women studied in the trial, known as AURELIA, median progression-free survival was 6.7 months when bevacizumab (Avastin, manufactured by Genentech/La Roche) was added to chemotherapy versus 3.4 months when chemotherapy was given alone, for a 52% relative reduction in risk.

Susan London/IMNG Medical Media

Certain adverse events were more common with the combination but consistent with those observed previously with bevacizumab, according to data presented in a press briefing at the meeting.

"Patients with ovarian cancer in whom chemotherapy is no longer working are a high unmet medical need," commented lead investigator Eric Pujade-Lauraine, M.D., Ph.D., an oncologist at the Hôpital Hôtel-Dieu in Paris and head of the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), a clinical trials cooperative group based in France. Such women make up a large share of the ovarian cancer population.

"AURELIA is a positive trial: It shows that adding bevacizumab to chemotherapy halves the risk of disease getting worse in these patients," he maintained. "Bevacizumab plus chemotherapy should thus be considered as a new standard option in these patients with platinum-resistant disease."

Dr. Carol Aghajanian, press briefing moderator and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York, noted that the trial is the first to show significant improvement in platinum-resistant ovarian cancer. She drew a distinction between the breast cancer setting, in which bevacizumab has ultimately proven somewhat disappointing, and the ovarian cancer setting.

"I think there is a difference there that the VEGF [vascular endothelial growth factor] pathway is very specifically important in ovarian cancer. And in ovarian cancer, we have had three prior trials ... that were positive," she explained, referring to the GOG-0218 and ICON7 trials in the front-line setting and the OCEANS trial in the relapsed platinum-sensitive setting. "And this one is positive as well."

Furthermore, the regulatory pathway for approval in breast cancer differed, according to Dr. Aghajanian. "There, accelerated approval was given, and the follow-up studies were not all showing the same result or the same magnitude of result. So there were some differences in results across trials, which we haven’t seen here in ovarian cancer."

In AURELIA, the investigators enrolled women with epithelial ovarian, fallopian tube, or primary peritoneal cancer who had progression within 6 months of their last dose of a platinum. Given the known adverse effects of bevacizumab, women were excluded if they had a history of bowel obstruction or abdominal fistula, or evidence of rectosigmoid involvement.

They were assigned evenly to receive chemotherapy (one of three standard agents: paclitaxel, topotecan, or liposomal pegylated doxorubicin) alone or with the addition of bevacizumab, which is currently approved by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer. Patients in the former group could receive bevacizumab monotherapy if they experienced progression.

After a median follow-up of 13.5 months, the rate of recurrence was 75% in the bevacizumab-chemotherapy group, compared with 91% in the chemotherapy group, Dr. Pujade-Lauraine reported.

Median progression-free survival, the trial’s primary endpoint, was almost doubled with the combination (6.7 vs. 3.4 months; hazard ratio, 0.48; P less than .001).

"‘Wow!’ – that’s exactly what the investigators said when they saw this graph," he related. "The separation between the two curves clearly indicates that adding bevacizumab to chemotherapy is working very well." Overall survival results are not yet mature.

Adverse events "were very consistent with those already published and reported with bevacizumab," Dr. Pujade-Lauraine noted. Specifically, patients in the bevacizumab-chemotherapy group were more likely to experience grade 2 or higher hypertension (20% vs. 7%), proteinuria (11% vs. 1%), gastrointestinal perforation (2% vs. 0%), and fistula or abscess (2% vs. 0%).

On the flip side, "we saw some side effects which could be related to tumor were decreased in the bevacizumab-plus-chemo arm compared to the chemo arm, such as fatigue, abdominal pain, dyspnea," he pointed out.

"I think [the AURELIA trial] will change practice," Dr. Pujade-Lauraine concluded. "But of course, we need to wait for the approval of the drug in this setting. And I think that is something which will be filed in the next month."

Dr. Pujade-Lauraine disclosed that he is a consultant to and receives honoraria and research funding from Roche Diagnostics. The trial was sponsored by Hoffman-La Roche. Dr. Aghajanian disclosed no relevant conflicts of interest.

CHICAGO – The combination of an anti-angiogenic agent with chemotherapy offers new hope to women with ovarian cancer who are running out of options because their disease has become resistant to platinums, suggests a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

Among the 361 women studied in the trial, known as AURELIA, median progression-free survival was 6.7 months when bevacizumab (Avastin, manufactured by Genentech/La Roche) was added to chemotherapy versus 3.4 months when chemotherapy was given alone, for a 52% relative reduction in risk.

Susan London/IMNG Medical Media

Certain adverse events were more common with the combination but consistent with those observed previously with bevacizumab, according to data presented in a press briefing at the meeting.

"Patients with ovarian cancer in whom chemotherapy is no longer working are a high unmet medical need," commented lead investigator Eric Pujade-Lauraine, M.D., Ph.D., an oncologist at the Hôpital Hôtel-Dieu in Paris and head of the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), a clinical trials cooperative group based in France. Such women make up a large share of the ovarian cancer population.

"AURELIA is a positive trial: It shows that adding bevacizumab to chemotherapy halves the risk of disease getting worse in these patients," he maintained. "Bevacizumab plus chemotherapy should thus be considered as a new standard option in these patients with platinum-resistant disease."

Dr. Carol Aghajanian, press briefing moderator and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York, noted that the trial is the first to show significant improvement in platinum-resistant ovarian cancer. She drew a distinction between the breast cancer setting, in which bevacizumab has ultimately proven somewhat disappointing, and the ovarian cancer setting.

"I think there is a difference there that the VEGF [vascular endothelial growth factor] pathway is very specifically important in ovarian cancer. And in ovarian cancer, we have had three prior trials ... that were positive," she explained, referring to the GOG-0218 and ICON7 trials in the front-line setting and the OCEANS trial in the relapsed platinum-sensitive setting. "And this one is positive as well."

Furthermore, the regulatory pathway for approval in breast cancer differed, according to Dr. Aghajanian. "There, accelerated approval was given, and the follow-up studies were not all showing the same result or the same magnitude of result. So there were some differences in results across trials, which we haven’t seen here in ovarian cancer."

In AURELIA, the investigators enrolled women with epithelial ovarian, fallopian tube, or primary peritoneal cancer who had progression within 6 months of their last dose of a platinum. Given the known adverse effects of bevacizumab, women were excluded if they had a history of bowel obstruction or abdominal fistula, or evidence of rectosigmoid involvement.

They were assigned evenly to receive chemotherapy (one of three standard agents: paclitaxel, topotecan, or liposomal pegylated doxorubicin) alone or with the addition of bevacizumab, which is currently approved by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer. Patients in the former group could receive bevacizumab monotherapy if they experienced progression.

After a median follow-up of 13.5 months, the rate of recurrence was 75% in the bevacizumab-chemotherapy group, compared with 91% in the chemotherapy group, Dr. Pujade-Lauraine reported.

Median progression-free survival, the trial’s primary endpoint, was almost doubled with the combination (6.7 vs. 3.4 months; hazard ratio, 0.48; P less than .001).

"‘Wow!’ – that’s exactly what the investigators said when they saw this graph," he related. "The separation between the two curves clearly indicates that adding bevacizumab to chemotherapy is working very well." Overall survival results are not yet mature.

Adverse events "were very consistent with those already published and reported with bevacizumab," Dr. Pujade-Lauraine noted. Specifically, patients in the bevacizumab-chemotherapy group were more likely to experience grade 2 or higher hypertension (20% vs. 7%), proteinuria (11% vs. 1%), gastrointestinal perforation (2% vs. 0%), and fistula or abscess (2% vs. 0%).

On the flip side, "we saw some side effects which could be related to tumor were decreased in the bevacizumab-plus-chemo arm compared to the chemo arm, such as fatigue, abdominal pain, dyspnea," he pointed out.

"I think [the AURELIA trial] will change practice," Dr. Pujade-Lauraine concluded. "But of course, we need to wait for the approval of the drug in this setting. And I think that is something which will be filed in the next month."

Dr. Pujade-Lauraine disclosed that he is a consultant to and receives honoraria and research funding from Roche Diagnostics. The trial was sponsored by Hoffman-La Roche. Dr. Aghajanian disclosed no relevant conflicts of interest.

CHICAGO – The combination of an anti-angiogenic agent with chemotherapy offers new hope to women with ovarian cancer who are running out of options because their disease has become resistant to platinums, suggests a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

Among the 361 women studied in the trial, known as AURELIA, median progression-free survival was 6.7 months when bevacizumab (Avastin, manufactured by Genentech/La Roche) was added to chemotherapy versus 3.4 months when chemotherapy was given alone, for a 52% relative reduction in risk.

Susan London/IMNG Medical Media

Certain adverse events were more common with the combination but consistent with those observed previously with bevacizumab, according to data presented in a press briefing at the meeting.

"Patients with ovarian cancer in whom chemotherapy is no longer working are a high unmet medical need," commented lead investigator Eric Pujade-Lauraine, M.D., Ph.D., an oncologist at the Hôpital Hôtel-Dieu in Paris and head of the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), a clinical trials cooperative group based in France. Such women make up a large share of the ovarian cancer population.

"AURELIA is a positive trial: It shows that adding bevacizumab to chemotherapy halves the risk of disease getting worse in these patients," he maintained. "Bevacizumab plus chemotherapy should thus be considered as a new standard option in these patients with platinum-resistant disease."

Dr. Carol Aghajanian, press briefing moderator and chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York, noted that the trial is the first to show significant improvement in platinum-resistant ovarian cancer. She drew a distinction between the breast cancer setting, in which bevacizumab has ultimately proven somewhat disappointing, and the ovarian cancer setting.

"I think there is a difference there that the VEGF [vascular endothelial growth factor] pathway is very specifically important in ovarian cancer. And in ovarian cancer, we have had three prior trials ... that were positive," she explained, referring to the GOG-0218 and ICON7 trials in the front-line setting and the OCEANS trial in the relapsed platinum-sensitive setting. "And this one is positive as well."

Furthermore, the regulatory pathway for approval in breast cancer differed, according to Dr. Aghajanian. "There, accelerated approval was given, and the follow-up studies were not all showing the same result or the same magnitude of result. So there were some differences in results across trials, which we haven’t seen here in ovarian cancer."

In AURELIA, the investigators enrolled women with epithelial ovarian, fallopian tube, or primary peritoneal cancer who had progression within 6 months of their last dose of a platinum. Given the known adverse effects of bevacizumab, women were excluded if they had a history of bowel obstruction or abdominal fistula, or evidence of rectosigmoid involvement.

They were assigned evenly to receive chemotherapy (one of three standard agents: paclitaxel, topotecan, or liposomal pegylated doxorubicin) alone or with the addition of bevacizumab, which is currently approved by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer. Patients in the former group could receive bevacizumab monotherapy if they experienced progression.

After a median follow-up of 13.5 months, the rate of recurrence was 75% in the bevacizumab-chemotherapy group, compared with 91% in the chemotherapy group, Dr. Pujade-Lauraine reported.

Median progression-free survival, the trial’s primary endpoint, was almost doubled with the combination (6.7 vs. 3.4 months; hazard ratio, 0.48; P less than .001).

"‘Wow!’ – that’s exactly what the investigators said when they saw this graph," he related. "The separation between the two curves clearly indicates that adding bevacizumab to chemotherapy is working very well." Overall survival results are not yet mature.

Adverse events "were very consistent with those already published and reported with bevacizumab," Dr. Pujade-Lauraine noted. Specifically, patients in the bevacizumab-chemotherapy group were more likely to experience grade 2 or higher hypertension (20% vs. 7%), proteinuria (11% vs. 1%), gastrointestinal perforation (2% vs. 0%), and fistula or abscess (2% vs. 0%).

On the flip side, "we saw some side effects which could be related to tumor were decreased in the bevacizumab-plus-chemo arm compared to the chemo arm, such as fatigue, abdominal pain, dyspnea," he pointed out.

"I think [the AURELIA trial] will change practice," Dr. Pujade-Lauraine concluded. "But of course, we need to wait for the approval of the drug in this setting. And I think that is something which will be filed in the next month."

Dr. Pujade-Lauraine disclosed that he is a consultant to and receives honoraria and research funding from Roche Diagnostics. The trial was sponsored by Hoffman-La Roche. Dr. Aghajanian disclosed no relevant conflicts of interest.

The recently approved cancer drug crizotinib draws strong responses in children whose cancers have mutations in the gene targeted by the drug, according to early data from a phase I dose-escalating study.

The most dramatic improvements occurred in anaplastic large-cell lymphoma, with complete and durable responses observed in 7 of 8 children with the ALK mutation, which is common in the disease. Crizotinib (Xalkori) also appeared to be active in subsets of children with inflammatory myofibroblastic tumor and neuroblastoma, though the early data were less clear in these cancers.

"Crizotinib appears to have a high degree of activity in children with anaplastic large-cell lymphoma – the majority of whom are driven by the ALK oncogene," lead author Dr. Yael P. Mosse said during a press briefing in advance of the annual meeting of the American Society of Clinical Oncology. She noted that these are phase I results and should be taken with caution.

"Certainly for the eight patients that we enrolled with anaplastic large cell lymphoma – seven of whom have had a complete response and a durable response – I think that this is dramatic activity and has already met the bar for what you would look for in a phase-II trial ... for neuroblastoma there is still a lot of work to be done," said Dr. Mosse of Children’s Hospital of Philadelphia and the University of Pennsylvania.

"The story is really a glimpse at the new paradigm for understanding of cancer and drug development," said ASCO President Dr. Michael Link, comoderator of the press briefing.

"It’s no longer adequate to identify a tumor based on histology organ of origin. It’s now understood that tumors are heterogeneous and it’s key to understand the particular molecular driver," said Dr. Link of Stanford (Calif.) University.

"If you understand the molecular driver of the tumor and pick an appropriate inhibitor – in this case crizotinib for ALK-driven tumors – we have the prospect of seeing dramatic responses."

The ALK (anaplastic lymphoma receptor tyrosine kinase) gene is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the cell surface into the cell via signal transduction. Though the specific function of ALK is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.

ALK is involved in the formation of several human cancers, including anaplastic large cell lymphoma (ALCL), which typically occurs in childhood. Activating mutations in the ALK gene "are the leading cause for most cases of the hereditary form of neuroblastoma and ... these mutations are also somatically acquired in 14% of patients with the aggressive form of this disease," Dr. Mosse said.

Crizotinib, an oral small-molecule inhibitor of ALK, was approved in August 2011 for the treatment of patients with locally-advanced or metastatic non–small cell lung cancer (NSCLC) that is ALK positive based on a diagnostic test approved concurrently by the Food and Drug Administration.

Dr. Mosse and colleagues conducted the phase I study to assess the safety and efficacy of crizotinib in pediatric patients aged 1-21 years with relapsed or refractory cancer. The children received the drug orally, twice daily for 28-day cycles. Based on the results, the recommended phase II dose for children is 280 mg/m² per day. This is roughly twice the recommended phase II dose for adults, according to Dr. Mosse.

Eight patients with anaplastic large-cell lymphoma were enrolled in the current study. All had an ALK translocation and were heavily pretreated. Seven children had a complete response with doses ranging from 165 mg/m² per day to 280 mg/m² per day. They remain on the drug, with no progression observed for as long as 18 months.

Investigators also enrolled seven patients with inflammatory myofibroblastic tumor – all had an ALK translocation. Of these, one had a minor response and remains on the drug after 2 years. One patient had a partial response and remains on the drug after 10 cycles. It is too early to determine response for five patients.

Lastly, the researchers enrolled 35 patients with neuroblastoma; 27 were evaluable. Eight of these patients had known ALK mutations. Two of these patients have germline mutations. One of these patients had a complete response to therapy and remains on treatment (more than 6 months). The second patient with a germline mutation had a minor response and continues treatment (more than 15 months). A third patient with a somatic ALK mutation has had stable disease for more than eight cycles.

There were 19 neuroblastoma patients who had unknown ALK status. One patient had a complete response and remains on treatment (more than 24 cycles). Six patients have had prolonged stable disease and remain on treatment (7-29 cycles).

Overall, the drug was "exceedingly well tolerated," Dr. Mosse said. "Most of the toxicities were extremely low-grade and did not affect overall quality of life. At the highest dose level that we tested, we saw irritation of the liver enzymes that were reversible."

The study was sponsored by the Children’s Oncology Group with collaboration from the National Cancer Institute. Dr. Mosse reported receiving research funding from Pfizer, which makes Xalkori.

The recently approved cancer drug crizotinib draws strong responses in children whose cancers have mutations in the gene targeted by the drug, according to early data from a phase I dose-escalating study.

The most dramatic improvements occurred in anaplastic large-cell lymphoma, with complete and durable responses observed in 7 of 8 children with the ALK mutation, which is common in the disease. Crizotinib (Xalkori) also appeared to be active in subsets of children with inflammatory myofibroblastic tumor and neuroblastoma, though the early data were less clear in these cancers.

"Crizotinib appears to have a high degree of activity in children with anaplastic large-cell lymphoma – the majority of whom are driven by the ALK oncogene," lead author Dr. Yael P. Mosse said during a press briefing in advance of the annual meeting of the American Society of Clinical Oncology. She noted that these are phase I results and should be taken with caution.

"Certainly for the eight patients that we enrolled with anaplastic large cell lymphoma – seven of whom have had a complete response and a durable response – I think that this is dramatic activity and has already met the bar for what you would look for in a phase-II trial ... for neuroblastoma there is still a lot of work to be done," said Dr. Mosse of Children’s Hospital of Philadelphia and the University of Pennsylvania.

"The story is really a glimpse at the new paradigm for understanding of cancer and drug development," said ASCO President Dr. Michael Link, comoderator of the press briefing.

"It’s no longer adequate to identify a tumor based on histology organ of origin. It’s now understood that tumors are heterogeneous and it’s key to understand the particular molecular driver," said Dr. Link of Stanford (Calif.) University.

"If you understand the molecular driver of the tumor and pick an appropriate inhibitor – in this case crizotinib for ALK-driven tumors – we have the prospect of seeing dramatic responses."

The ALK (anaplastic lymphoma receptor tyrosine kinase) gene is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the cell surface into the cell via signal transduction. Though the specific function of ALK is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.

ALK is involved in the formation of several human cancers, including anaplastic large cell lymphoma (ALCL), which typically occurs in childhood. Activating mutations in the ALK gene "are the leading cause for most cases of the hereditary form of neuroblastoma and ... these mutations are also somatically acquired in 14% of patients with the aggressive form of this disease," Dr. Mosse said.

Crizotinib, an oral small-molecule inhibitor of ALK, was approved in August 2011 for the treatment of patients with locally-advanced or metastatic non–small cell lung cancer (NSCLC) that is ALK positive based on a diagnostic test approved concurrently by the Food and Drug Administration.

Dr. Mosse and colleagues conducted the phase I study to assess the safety and efficacy of crizotinib in pediatric patients aged 1-21 years with relapsed or refractory cancer. The children received the drug orally, twice daily for 28-day cycles. Based on the results, the recommended phase II dose for children is 280 mg/m² per day. This is roughly twice the recommended phase II dose for adults, according to Dr. Mosse.

Eight patients with anaplastic large-cell lymphoma were enrolled in the current study. All had an ALK translocation and were heavily pretreated. Seven children had a complete response with doses ranging from 165 mg/m² per day to 280 mg/m² per day. They remain on the drug, with no progression observed for as long as 18 months.

Investigators also enrolled seven patients with inflammatory myofibroblastic tumor – all had an ALK translocation. Of these, one had a minor response and remains on the drug after 2 years. One patient had a partial response and remains on the drug after 10 cycles. It is too early to determine response for five patients.

Lastly, the researchers enrolled 35 patients with neuroblastoma; 27 were evaluable. Eight of these patients had known ALK mutations. Two of these patients have germline mutations. One of these patients had a complete response to therapy and remains on treatment (more than 6 months). The second patient with a germline mutation had a minor response and continues treatment (more than 15 months). A third patient with a somatic ALK mutation has had stable disease for more than eight cycles.

There were 19 neuroblastoma patients who had unknown ALK status. One patient had a complete response and remains on treatment (more than 24 cycles). Six patients have had prolonged stable disease and remain on treatment (7-29 cycles).

Overall, the drug was "exceedingly well tolerated," Dr. Mosse said. "Most of the toxicities were extremely low-grade and did not affect overall quality of life. At the highest dose level that we tested, we saw irritation of the liver enzymes that were reversible."

The study was sponsored by the Children’s Oncology Group with collaboration from the National Cancer Institute. Dr. Mosse reported receiving research funding from Pfizer, which makes Xalkori.

The recently approved cancer drug crizotinib draws strong responses in children whose cancers have mutations in the gene targeted by the drug, according to early data from a phase I dose-escalating study.

The most dramatic improvements occurred in anaplastic large-cell lymphoma, with complete and durable responses observed in 7 of 8 children with the ALK mutation, which is common in the disease. Crizotinib (Xalkori) also appeared to be active in subsets of children with inflammatory myofibroblastic tumor and neuroblastoma, though the early data were less clear in these cancers.

"Crizotinib appears to have a high degree of activity in children with anaplastic large-cell lymphoma – the majority of whom are driven by the ALK oncogene," lead author Dr. Yael P. Mosse said during a press briefing in advance of the annual meeting of the American Society of Clinical Oncology. She noted that these are phase I results and should be taken with caution.

"Certainly for the eight patients that we enrolled with anaplastic large cell lymphoma – seven of whom have had a complete response and a durable response – I think that this is dramatic activity and has already met the bar for what you would look for in a phase-II trial ... for neuroblastoma there is still a lot of work to be done," said Dr. Mosse of Children’s Hospital of Philadelphia and the University of Pennsylvania.

"The story is really a glimpse at the new paradigm for understanding of cancer and drug development," said ASCO President Dr. Michael Link, comoderator of the press briefing.

"It’s no longer adequate to identify a tumor based on histology organ of origin. It’s now understood that tumors are heterogeneous and it’s key to understand the particular molecular driver," said Dr. Link of Stanford (Calif.) University.

"If you understand the molecular driver of the tumor and pick an appropriate inhibitor – in this case crizotinib for ALK-driven tumors – we have the prospect of seeing dramatic responses."

The ALK (anaplastic lymphoma receptor tyrosine kinase) gene is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the cell surface into the cell via signal transduction. Though the specific function of ALK is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.

ALK is involved in the formation of several human cancers, including anaplastic large cell lymphoma (ALCL), which typically occurs in childhood. Activating mutations in the ALK gene "are the leading cause for most cases of the hereditary form of neuroblastoma and ... these mutations are also somatically acquired in 14% of patients with the aggressive form of this disease," Dr. Mosse said.

Crizotinib, an oral small-molecule inhibitor of ALK, was approved in August 2011 for the treatment of patients with locally-advanced or metastatic non–small cell lung cancer (NSCLC) that is ALK positive based on a diagnostic test approved concurrently by the Food and Drug Administration.

Dr. Mosse and colleagues conducted the phase I study to assess the safety and efficacy of crizotinib in pediatric patients aged 1-21 years with relapsed or refractory cancer. The children received the drug orally, twice daily for 28-day cycles. Based on the results, the recommended phase II dose for children is 280 mg/m² per day. This is roughly twice the recommended phase II dose for adults, according to Dr. Mosse.

Eight patients with anaplastic large-cell lymphoma were enrolled in the current study. All had an ALK translocation and were heavily pretreated. Seven children had a complete response with doses ranging from 165 mg/m² per day to 280 mg/m² per day. They remain on the drug, with no progression observed for as long as 18 months.

Investigators also enrolled seven patients with inflammatory myofibroblastic tumor – all had an ALK translocation. Of these, one had a minor response and remains on the drug after 2 years. One patient had a partial response and remains on the drug after 10 cycles. It is too early to determine response for five patients.

Lastly, the researchers enrolled 35 patients with neuroblastoma; 27 were evaluable. Eight of these patients had known ALK mutations. Two of these patients have germline mutations. One of these patients had a complete response to therapy and remains on treatment (more than 6 months). The second patient with a germline mutation had a minor response and continues treatment (more than 15 months). A third patient with a somatic ALK mutation has had stable disease for more than eight cycles.

There were 19 neuroblastoma patients who had unknown ALK status. One patient had a complete response and remains on treatment (more than 24 cycles). Six patients have had prolonged stable disease and remain on treatment (7-29 cycles).

Overall, the drug was "exceedingly well tolerated," Dr. Mosse said. "Most of the toxicities were extremely low-grade and did not affect overall quality of life. At the highest dose level that we tested, we saw irritation of the liver enzymes that were reversible."

The study was sponsored by the Children’s Oncology Group with collaboration from the National Cancer Institute. Dr. Mosse reported receiving research funding from Pfizer, which makes Xalkori.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.