2014 ASCO Annual Meeting

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.

CHICAGO – A small study with just nine patients is sparking enormous hope after demonstrating for the first time that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

A single infusion of human papillomavirus (HPV)-targeted T-cell therapy induced complete responses in two women. A third woman had a partial response, with tumor shrinkage of 39% lasting 3 months.

Follow-up performed during the last week of the two women with complete responses showed no sign of disease 15 and 22 months after treatment.

"This study provides proof of principle that an immunotherapy can induce regression of cervical cancer, and that adoptive T-cell therapy can mediate regression of an epithelial cancer," said lead study author Dr. Christian S. Hinrichs, an investigator with the National Cancer Institute.

Patrice Wendling/Frontline Medical News

Cervical cancer harbors attractive targets for immunotherapy in the HPV E6 and E7 oncoproteins, but clinical trials of immunotherapy in this disease have thus far been disappointing.

The goal with vaccines against HPV is to reduce the future incidence of cervical cancer. But new therapies for advanced-stage disease are desperately needed because chemotherapy is not curative and rarely provides durable palliation, he said during a press briefing at the annual meeting of the American Society of Clinical Oncology.

He noted that one of the patients with a complete response had been previously treated with three different combination cytotoxic chemotherapy regimens for her HPV-16–positive squamous cell carcinoma, while the other had aggressive HPV-18–positive adenocarcinoma that had spread to the pelvis and distant sites despite chemoradiation. Both women were only 36 years old.

The best treatment we have commits women to chemotherapy and/or a biologic for the rest of their lives, which is no more than 2 years for most of the young women being treated, commented Dr. Don S. Dizon, director of the Oncology Sexual Health Clinic at the Massachusetts General Hospital Cancer Center, Boston.

"If all the academic centers can standardize this approach and identify the patients most likely to benefit, we could really reduce the deaths from this disease," he said.

Method

Research using adoptive T-cell therapy (ACT) in epithelial cancers, however, has been limited. ACT has been shown to induce dramatic, complete durable regression of melanoma and certain B-cell malignancies through use of T cells genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARS).

"The difference here is that these are not genetically engineered cells," Dr. Hinrichs said in an interview. "These are naturally occurring T cells that are present in the tumors, grown out, and selected out for their reactivity against tumor antigens [HPV-E6 and -E7]."

The HPV-targeted tumor-infiltrating lymphocytes (TILs) are grown in the laboratory until they number in the billions and then are infused back into the patient. The women are pretreated with a lymphocyte-depleting conditioning regimen of cyclophosphamide and fludarabine (Fludara), and given aldesleukin (Proleukin), dosed to tolerance, after cell infusion.

All patients had HPV-positive cervical cancer and received a median of 81 x 10^-9 T cells (range 33-159 x 10^-9), Dr. Hinrichs reported.

The two women with complete responses by RECIST criteria demonstrated prolonged repopulation with the HPV-reactive T cells, detectable after 13 months in one and 6 months in the other. Two patients showed no repopulation of T cells and did not respond to treatment.

The most common severe adverse events seen with the therapy were the hematologic toxicities of the conditioning regimen, which occurred in all nine patients, Dr. Hinrichs said in an interview. Five patients had febrile neutropenia and six had infections, primarily positive blood cultures that were treated with antibiotics. All toxicities were completely reversible, and since it’s a one-time therapy, they were better tolerated than if they were repeated in cycles like traditional chemotherapy infusions, he observed.

Though encouraging, Dr. Hinrichs and others urged caution in interpreting these early data. Dr. Steven O’Day, with the University of Southern California, Los Angeles, said it’s costly and labor intensive to gather and manipulate cells and that questions remain about how to make the process more efficient, the therapy less toxic, and to determine whether cells could possibly be manipulated in vivo.

"There’re many questions, but the science is exciting, and it’s giving us an opportunity to direct the immune system against a cancer that traditionally isn’t seen by the immune system very well at all," he said. "So there are lots more to come."

Dr. Hinrichs said they plan to expand the study to 35 women to better define the response rate and that HPV-TIL is also being tested in a separate cohort of patients with noncervical HPV-positive cancers like oropharyngeal, anal, vulvar, and vaginal cancer. Physicians interested in enrolling patients should contact the National Institutes of Health. Patient referrals should be directed to June Kryk ([email protected], 301-451-1929) or Linda Williams ([email protected], 301-402-4124).

The study was supported by the National Cancer Institute, National Institutes of Health. The authors and Dr. Dizon reported no financial disclosures.

[email protected]

CHICAGO – A small study with just nine patients is sparking enormous hope after demonstrating for the first time that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

A single infusion of human papillomavirus (HPV)-targeted T-cell therapy induced complete responses in two women. A third woman had a partial response, with tumor shrinkage of 39% lasting 3 months.

Follow-up performed during the last week of the two women with complete responses showed no sign of disease 15 and 22 months after treatment.

"This study provides proof of principle that an immunotherapy can induce regression of cervical cancer, and that adoptive T-cell therapy can mediate regression of an epithelial cancer," said lead study author Dr. Christian S. Hinrichs, an investigator with the National Cancer Institute.

Patrice Wendling/Frontline Medical News

Cervical cancer harbors attractive targets for immunotherapy in the HPV E6 and E7 oncoproteins, but clinical trials of immunotherapy in this disease have thus far been disappointing.

The goal with vaccines against HPV is to reduce the future incidence of cervical cancer. But new therapies for advanced-stage disease are desperately needed because chemotherapy is not curative and rarely provides durable palliation, he said during a press briefing at the annual meeting of the American Society of Clinical Oncology.

He noted that one of the patients with a complete response had been previously treated with three different combination cytotoxic chemotherapy regimens for her HPV-16–positive squamous cell carcinoma, while the other had aggressive HPV-18–positive adenocarcinoma that had spread to the pelvis and distant sites despite chemoradiation. Both women were only 36 years old.

The best treatment we have commits women to chemotherapy and/or a biologic for the rest of their lives, which is no more than 2 years for most of the young women being treated, commented Dr. Don S. Dizon, director of the Oncology Sexual Health Clinic at the Massachusetts General Hospital Cancer Center, Boston.

"If all the academic centers can standardize this approach and identify the patients most likely to benefit, we could really reduce the deaths from this disease," he said.

Method

Research using adoptive T-cell therapy (ACT) in epithelial cancers, however, has been limited. ACT has been shown to induce dramatic, complete durable regression of melanoma and certain B-cell malignancies through use of T cells genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARS).

"The difference here is that these are not genetically engineered cells," Dr. Hinrichs said in an interview. "These are naturally occurring T cells that are present in the tumors, grown out, and selected out for their reactivity against tumor antigens [HPV-E6 and -E7]."

The HPV-targeted tumor-infiltrating lymphocytes (TILs) are grown in the laboratory until they number in the billions and then are infused back into the patient. The women are pretreated with a lymphocyte-depleting conditioning regimen of cyclophosphamide and fludarabine (Fludara), and given aldesleukin (Proleukin), dosed to tolerance, after cell infusion.

All patients had HPV-positive cervical cancer and received a median of 81 x 10^-9 T cells (range 33-159 x 10^-9), Dr. Hinrichs reported.

The two women with complete responses by RECIST criteria demonstrated prolonged repopulation with the HPV-reactive T cells, detectable after 13 months in one and 6 months in the other. Two patients showed no repopulation of T cells and did not respond to treatment.

The most common severe adverse events seen with the therapy were the hematologic toxicities of the conditioning regimen, which occurred in all nine patients, Dr. Hinrichs said in an interview. Five patients had febrile neutropenia and six had infections, primarily positive blood cultures that were treated with antibiotics. All toxicities were completely reversible, and since it’s a one-time therapy, they were better tolerated than if they were repeated in cycles like traditional chemotherapy infusions, he observed.

Though encouraging, Dr. Hinrichs and others urged caution in interpreting these early data. Dr. Steven O’Day, with the University of Southern California, Los Angeles, said it’s costly and labor intensive to gather and manipulate cells and that questions remain about how to make the process more efficient, the therapy less toxic, and to determine whether cells could possibly be manipulated in vivo.

"There’re many questions, but the science is exciting, and it’s giving us an opportunity to direct the immune system against a cancer that traditionally isn’t seen by the immune system very well at all," he said. "So there are lots more to come."

Dr. Hinrichs said they plan to expand the study to 35 women to better define the response rate and that HPV-TIL is also being tested in a separate cohort of patients with noncervical HPV-positive cancers like oropharyngeal, anal, vulvar, and vaginal cancer. Physicians interested in enrolling patients should contact the National Institutes of Health. Patient referrals should be directed to June Kryk ([email protected], 301-451-1929) or Linda Williams ([email protected], 301-402-4124).

The study was supported by the National Cancer Institute, National Institutes of Health. The authors and Dr. Dizon reported no financial disclosures.

[email protected]

CHICAGO – A small study with just nine patients is sparking enormous hope after demonstrating for the first time that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

A single infusion of human papillomavirus (HPV)-targeted T-cell therapy induced complete responses in two women. A third woman had a partial response, with tumor shrinkage of 39% lasting 3 months.

Follow-up performed during the last week of the two women with complete responses showed no sign of disease 15 and 22 months after treatment.

"This study provides proof of principle that an immunotherapy can induce regression of cervical cancer, and that adoptive T-cell therapy can mediate regression of an epithelial cancer," said lead study author Dr. Christian S. Hinrichs, an investigator with the National Cancer Institute.

Patrice Wendling/Frontline Medical News

Cervical cancer harbors attractive targets for immunotherapy in the HPV E6 and E7 oncoproteins, but clinical trials of immunotherapy in this disease have thus far been disappointing.

The goal with vaccines against HPV is to reduce the future incidence of cervical cancer. But new therapies for advanced-stage disease are desperately needed because chemotherapy is not curative and rarely provides durable palliation, he said during a press briefing at the annual meeting of the American Society of Clinical Oncology.

He noted that one of the patients with a complete response had been previously treated with three different combination cytotoxic chemotherapy regimens for her HPV-16–positive squamous cell carcinoma, while the other had aggressive HPV-18–positive adenocarcinoma that had spread to the pelvis and distant sites despite chemoradiation. Both women were only 36 years old.

The best treatment we have commits women to chemotherapy and/or a biologic for the rest of their lives, which is no more than 2 years for most of the young women being treated, commented Dr. Don S. Dizon, director of the Oncology Sexual Health Clinic at the Massachusetts General Hospital Cancer Center, Boston.

"If all the academic centers can standardize this approach and identify the patients most likely to benefit, we could really reduce the deaths from this disease," he said.

Method

Research using adoptive T-cell therapy (ACT) in epithelial cancers, however, has been limited. ACT has been shown to induce dramatic, complete durable regression of melanoma and certain B-cell malignancies through use of T cells genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARS).

"The difference here is that these are not genetically engineered cells," Dr. Hinrichs said in an interview. "These are naturally occurring T cells that are present in the tumors, grown out, and selected out for their reactivity against tumor antigens [HPV-E6 and -E7]."

The HPV-targeted tumor-infiltrating lymphocytes (TILs) are grown in the laboratory until they number in the billions and then are infused back into the patient. The women are pretreated with a lymphocyte-depleting conditioning regimen of cyclophosphamide and fludarabine (Fludara), and given aldesleukin (Proleukin), dosed to tolerance, after cell infusion.

All patients had HPV-positive cervical cancer and received a median of 81 x 10^-9 T cells (range 33-159 x 10^-9), Dr. Hinrichs reported.

The two women with complete responses by RECIST criteria demonstrated prolonged repopulation with the HPV-reactive T cells, detectable after 13 months in one and 6 months in the other. Two patients showed no repopulation of T cells and did not respond to treatment.

The most common severe adverse events seen with the therapy were the hematologic toxicities of the conditioning regimen, which occurred in all nine patients, Dr. Hinrichs said in an interview. Five patients had febrile neutropenia and six had infections, primarily positive blood cultures that were treated with antibiotics. All toxicities were completely reversible, and since it’s a one-time therapy, they were better tolerated than if they were repeated in cycles like traditional chemotherapy infusions, he observed.

Though encouraging, Dr. Hinrichs and others urged caution in interpreting these early data. Dr. Steven O’Day, with the University of Southern California, Los Angeles, said it’s costly and labor intensive to gather and manipulate cells and that questions remain about how to make the process more efficient, the therapy less toxic, and to determine whether cells could possibly be manipulated in vivo.

"There’re many questions, but the science is exciting, and it’s giving us an opportunity to direct the immune system against a cancer that traditionally isn’t seen by the immune system very well at all," he said. "So there are lots more to come."

Dr. Hinrichs said they plan to expand the study to 35 women to better define the response rate and that HPV-TIL is also being tested in a separate cohort of patients with noncervical HPV-positive cancers like oropharyngeal, anal, vulvar, and vaginal cancer. Physicians interested in enrolling patients should contact the National Institutes of Health. Patient referrals should be directed to June Kryk ([email protected], 301-451-1929) or Linda Williams ([email protected], 301-402-4124).

The study was supported by the National Cancer Institute, National Institutes of Health. The authors and Dr. Dizon reported no financial disclosures.

[email protected]

CHICAGO – The investigational targeted agent pembrolizumab induced durable treatment responses in a high percentage of patients with advanced metastatic melanoma, in a phase I study.

Of 411 patients, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles, at a media briefing and in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

Neil Osterweil/ Frontline Medical News

"We used to say that melanoma had a median survival of 6-9 months – that wasn’t that long ago. Then we said well, maybe it’s getting closer to 12 months. Here, we have not reached the median overall survival," Dr. Ribas said.

At 18 months of follow-up, overall survival is 62%, and seems to be plateauing, but longer follow-up will be required to see how long the survival benefit can be maintained, he said.

"The remarkable thing is that almost 90% of these patients are having durable responses with a toxicity profile that is almost unheard of in metastatic cancer," commented Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

Grade 3 or 4 toxicities occurred in 12% of patients, making pembrolizumab "one of the most benign therapies that I have ever used in my clinic," he said.

New name, same PD-1 antibody

Pembrolizumab, formerly known as lambrolizumab or MK-3475, is a humanized monoclonal antibody targeted against the PD-1 immune system checkpoint. By binding to and inhibiting what Dr. Ribas called the "do not kill me" signal, the antibody allows the immune system to recognize and mount a more potent T-cell–mediated defense against melanoma.

The Food and Drug Administration previously granted permbrolizumab a breakthrough therapy designation, and in May 2014 gave it a priority review designation under the agency’s accelerated approval program.

At the 2013 ASCO annual meeting, Dr. Ribas and colleagues reported a 41% overall response rate (ORR) in the first 135 patients with metastatic melanoma treated with the antibody in the phase I study KEYNOTE 001.

The data he presented at this year’s ASCO meeting on the melanoma expansion cohort from that trial support the earlier findings from the study, showing an overall ORR of 34%, with responses seen in 44% of treatment-naive patients, 28% of those who had previously been treated with a different checkpoint inhibitor, ipilimumab (Yervoy), and 40% in patients who had received prior therapies other than ipilimumab.

The current study is an analysis of pooled data on 411 patients, 221 of whom had disease progression on ipilimumab and 190 of whom had never received ipilimumab. All patients had melanoma metastatic to the lungs or other organs.

Neil Osterweil/ Frontline Medical News

The patients received pembrolizumab in one of three dosing schedules: 10 mg/kg every 2 weeks (57 patients) or every 3 weeks (192), or 2 mg/kg every 3 weeks (162).

As noted, the overall survival rate at 1 year was 69% (74% for ipilimumab-naive patients and 65% for ipilimumab-treated patients), with the median overall survival not yet reached.

Dr. O’Day said it was encouraging that prior exposure to ipilimumab did not appear to dramatically decrease the benefit from pembrolizumab.

"This is critical to us understanding whether to combine or sequence these drugs, because there does not seem to be a lot of cross-resistance between ipilimumab and PD-1 [inhibition]," he said.

The most common adverse event of any grade was fatigue, occurring in 36% of patients, but only 2% of patients had grade 3 or 4 fatigue. Other common events were pruritus (24%), rash (20%), diarrhea (16%), arthralgia (16%), nausea (12%), and vitiligo (11%). The overall rate of any adverse events was 83%, but as noted before, only 12% of patients had a grade 3 or 4 adverse event. These events were manageable across all doses and in both ipilmumab-naive and experienced patients.

Pembrolizumab is currently being investigated in international, randomized controlled clinical trials, Dr. Ribas noted.

The study was supported by Merck. Dr. Ribas disclosed serving as a consultant/adviser to the company. Dr. O’Day reported having no relevant disclosures.

CHICAGO – The investigational targeted agent pembrolizumab induced durable treatment responses in a high percentage of patients with advanced metastatic melanoma, in a phase I study.

Of 411 patients, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles, at a media briefing and in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

Neil Osterweil/ Frontline Medical News

"We used to say that melanoma had a median survival of 6-9 months – that wasn’t that long ago. Then we said well, maybe it’s getting closer to 12 months. Here, we have not reached the median overall survival," Dr. Ribas said.

At 18 months of follow-up, overall survival is 62%, and seems to be plateauing, but longer follow-up will be required to see how long the survival benefit can be maintained, he said.

"The remarkable thing is that almost 90% of these patients are having durable responses with a toxicity profile that is almost unheard of in metastatic cancer," commented Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

Grade 3 or 4 toxicities occurred in 12% of patients, making pembrolizumab "one of the most benign therapies that I have ever used in my clinic," he said.

New name, same PD-1 antibody

Pembrolizumab, formerly known as lambrolizumab or MK-3475, is a humanized monoclonal antibody targeted against the PD-1 immune system checkpoint. By binding to and inhibiting what Dr. Ribas called the "do not kill me" signal, the antibody allows the immune system to recognize and mount a more potent T-cell–mediated defense against melanoma.

The Food and Drug Administration previously granted permbrolizumab a breakthrough therapy designation, and in May 2014 gave it a priority review designation under the agency’s accelerated approval program.

At the 2013 ASCO annual meeting, Dr. Ribas and colleagues reported a 41% overall response rate (ORR) in the first 135 patients with metastatic melanoma treated with the antibody in the phase I study KEYNOTE 001.

The data he presented at this year’s ASCO meeting on the melanoma expansion cohort from that trial support the earlier findings from the study, showing an overall ORR of 34%, with responses seen in 44% of treatment-naive patients, 28% of those who had previously been treated with a different checkpoint inhibitor, ipilimumab (Yervoy), and 40% in patients who had received prior therapies other than ipilimumab.

The current study is an analysis of pooled data on 411 patients, 221 of whom had disease progression on ipilimumab and 190 of whom had never received ipilimumab. All patients had melanoma metastatic to the lungs or other organs.

Neil Osterweil/ Frontline Medical News

The patients received pembrolizumab in one of three dosing schedules: 10 mg/kg every 2 weeks (57 patients) or every 3 weeks (192), or 2 mg/kg every 3 weeks (162).

As noted, the overall survival rate at 1 year was 69% (74% for ipilimumab-naive patients and 65% for ipilimumab-treated patients), with the median overall survival not yet reached.

Dr. O’Day said it was encouraging that prior exposure to ipilimumab did not appear to dramatically decrease the benefit from pembrolizumab.

"This is critical to us understanding whether to combine or sequence these drugs, because there does not seem to be a lot of cross-resistance between ipilimumab and PD-1 [inhibition]," he said.

The most common adverse event of any grade was fatigue, occurring in 36% of patients, but only 2% of patients had grade 3 or 4 fatigue. Other common events were pruritus (24%), rash (20%), diarrhea (16%), arthralgia (16%), nausea (12%), and vitiligo (11%). The overall rate of any adverse events was 83%, but as noted before, only 12% of patients had a grade 3 or 4 adverse event. These events were manageable across all doses and in both ipilmumab-naive and experienced patients.

Pembrolizumab is currently being investigated in international, randomized controlled clinical trials, Dr. Ribas noted.

The study was supported by Merck. Dr. Ribas disclosed serving as a consultant/adviser to the company. Dr. O’Day reported having no relevant disclosures.

CHICAGO – The investigational targeted agent pembrolizumab induced durable treatment responses in a high percentage of patients with advanced metastatic melanoma, in a phase I study.

Of 411 patients, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles, at a media briefing and in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

Neil Osterweil/ Frontline Medical News

"We used to say that melanoma had a median survival of 6-9 months – that wasn’t that long ago. Then we said well, maybe it’s getting closer to 12 months. Here, we have not reached the median overall survival," Dr. Ribas said.

At 18 months of follow-up, overall survival is 62%, and seems to be plateauing, but longer follow-up will be required to see how long the survival benefit can be maintained, he said.

"The remarkable thing is that almost 90% of these patients are having durable responses with a toxicity profile that is almost unheard of in metastatic cancer," commented Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

Grade 3 or 4 toxicities occurred in 12% of patients, making pembrolizumab "one of the most benign therapies that I have ever used in my clinic," he said.

New name, same PD-1 antibody

Pembrolizumab, formerly known as lambrolizumab or MK-3475, is a humanized monoclonal antibody targeted against the PD-1 immune system checkpoint. By binding to and inhibiting what Dr. Ribas called the "do not kill me" signal, the antibody allows the immune system to recognize and mount a more potent T-cell–mediated defense against melanoma.

The Food and Drug Administration previously granted permbrolizumab a breakthrough therapy designation, and in May 2014 gave it a priority review designation under the agency’s accelerated approval program.

At the 2013 ASCO annual meeting, Dr. Ribas and colleagues reported a 41% overall response rate (ORR) in the first 135 patients with metastatic melanoma treated with the antibody in the phase I study KEYNOTE 001.

The data he presented at this year’s ASCO meeting on the melanoma expansion cohort from that trial support the earlier findings from the study, showing an overall ORR of 34%, with responses seen in 44% of treatment-naive patients, 28% of those who had previously been treated with a different checkpoint inhibitor, ipilimumab (Yervoy), and 40% in patients who had received prior therapies other than ipilimumab.

The current study is an analysis of pooled data on 411 patients, 221 of whom had disease progression on ipilimumab and 190 of whom had never received ipilimumab. All patients had melanoma metastatic to the lungs or other organs.

Neil Osterweil/ Frontline Medical News

The patients received pembrolizumab in one of three dosing schedules: 10 mg/kg every 2 weeks (57 patients) or every 3 weeks (192), or 2 mg/kg every 3 weeks (162).

As noted, the overall survival rate at 1 year was 69% (74% for ipilimumab-naive patients and 65% for ipilimumab-treated patients), with the median overall survival not yet reached.

Dr. O’Day said it was encouraging that prior exposure to ipilimumab did not appear to dramatically decrease the benefit from pembrolizumab.

"This is critical to us understanding whether to combine or sequence these drugs, because there does not seem to be a lot of cross-resistance between ipilimumab and PD-1 [inhibition]," he said.

The most common adverse event of any grade was fatigue, occurring in 36% of patients, but only 2% of patients had grade 3 or 4 fatigue. Other common events were pruritus (24%), rash (20%), diarrhea (16%), arthralgia (16%), nausea (12%), and vitiligo (11%). The overall rate of any adverse events was 83%, but as noted before, only 12% of patients had a grade 3 or 4 adverse event. These events were manageable across all doses and in both ipilmumab-naive and experienced patients.

Pembrolizumab is currently being investigated in international, randomized controlled clinical trials, Dr. Ribas noted.

The study was supported by Merck. Dr. Ribas disclosed serving as a consultant/adviser to the company. Dr. O’Day reported having no relevant disclosures.

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

[email protected]

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

[email protected]

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

[email protected]

CHICAGO –The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, discusses the implications of the results before presenting the phase III study at the annual meeting of the American Society of Clinical Oncology.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in consulting or advisory roles to Astellas Pharma, BIND Biosciences, and other companies. One of his coauthors disclosed consulting/advising or receiving research funding from Astellas, Bayer, and other companies, and another coauthor served as a Data and Safety Monitoring Board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.

CHICAGO –The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, discusses the implications of the results before presenting the phase III study at the annual meeting of the American Society of Clinical Oncology.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in consulting or advisory roles to Astellas Pharma, BIND Biosciences, and other companies. One of his coauthors disclosed consulting/advising or receiving research funding from Astellas, Bayer, and other companies, and another coauthor served as a Data and Safety Monitoring Board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.

CHICAGO –The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, discusses the implications of the results before presenting the phase III study at the annual meeting of the American Society of Clinical Oncology.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in consulting or advisory roles to Astellas Pharma, BIND Biosciences, and other companies. One of his coauthors disclosed consulting/advising or receiving research funding from Astellas, Bayer, and other companies, and another coauthor served as a Data and Safety Monitoring Board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.

CHICAGO – The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

In a randomized phase III trial, median overall survival for men who received upfront androgen deprivation therapy (ADT) alone for 18 weeks was 44 months, compared with 57.6 months for men who received ADT plus docetaxel (Taxotere), reported Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston.

Neil Osterweil/Frontline Medical News

"The certainty of the data is strong for patients with a high volume of metastatic disease and clearly justifies the treatment burden. This is one of the biggest improvements in survival we have seen involving patients with an adult, node-metastatic solid tumor," said Dr. Sweeney, who presented the data at a media briefing and in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"In prostate cancer, I’m not aware of an historical study that ever offered up quite this magnitude of improvement in survival," commented Dr. Clifford Hudis, who moderated the briefing and the plenary session.

Dr. Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, was not involved in the study.

In this study of 790 men with newly diagnosed metastatic prostate cancer, those with more extensive disease at study entry (520 patients) experienced the greatest benefit from the docetaxel-ADT combination, with a median overall survival of 49.2 months, compared with 32.2 months for men with extensive disease who received ADT alone.

Median overall survival for men with less invasive disease, has not yet been reached, Dr. Sweeney noted.

Start docetaxel earlier?

The CHAARTED (Chemo Hormonal Therapy vs. Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study began enrolling patients in 2006. Because there was evidence to show that docetaxel improves overall survival of men with metastatic prostate cancer who had disease progression while on ADT, the investigators wanted to see whether starting docetaxel earlier might provide additional benefit.

They randomly assigned men on a 1:1 basis to receive either ADT alone, or ADT plus docetaxel 75 mg/m² every 3 weeks for six cycles within 4 months of starting ADT. Patients were stratified by low- vs. high volume disease, with high-volume defined as visceral metastases and/or four or more metastatic bone lesions; antiandrogen therapy use beyond 30 days, age, ECOG (Eastern Cooperative Oncology Group) performance status, prior adjuvant ADT for less than or more than 1 year, and whether they had used a Food and Drug Administration–approved drug for preventing skeletal events, such as a bisphosphonate.

Of the patients assigned to ADT only, 124 received docetaxel at the time of disease progression. Of those in the combination group, 45 who had disease progression received additional docetaxel.

Data released early

Neil Osterweil/Frontline Medical News

At the fourth planned interim analysis in September 2013, when 53% of planned information had been accrued, the data-monitoring committee determined that the ADT-docetaxel combination had crossed the O’Brien-Fleming upper boundary, signaling statistically significant efficacy, and decided to release all available data.

As of Jan. 16, 2014, with a median follow-up of 29 months, there had been 137 deaths among patients treated with ADT alone, compared with 104 treated with ADT-docetaxel.

As noted before, median overall survival was 44 months for those on ADT alone, compared with 57.6 months for those on the combination (P = .0006). This translated into a hazard ratio for death of 0.61 (P = .0003).

The hazard ratio was similar for the subset of men with high-volume disease, at 0.60 (P = .0006), who received both ADT and docetaxel. The hazard ratio for men with low-volume disease was not significant, but as noted before, median overall survival in this group has not yet been reached, likely because men with low-volume disease tend to derive greater benefit from ADT, suggesting that it may take longer follow-up for an added effect of docetaxel to be seen.

In addition to the survival advantage, the combination was better than ADT alone at driving down prostate-specific antigen (PSA) levels, with 27.5% of patients on the ADT-docetaxel arm having a PSA below 0.2 ng/mL at 6 months, compared with 14% of patients treated with ADT alone (P less than .0001). At 12 months, the respective percentages were 22.7% and 11.7% (P less than .0001)

The combination was also better at delaying the median time to development of castration-resistant prostate cancer (20.7 vs. 14.7 months; P less than .0001), and the median time to clinical progression (32.7 vs. 19.8 months).

The most serious adverse events were febrile neutropenia and neuropathy. Of the 101 patients in the combination group who died, 84 of the deaths (83.2%) were from prostate cancer, 8 were from unknown causes, and 1 was attributed to the study protocol. Of the 136 in the ADT-alone arm who died, 112 deaths (83.6%) were from prostate cancers, and 22 were from other or unknown causes; data on the causes of death in 2 patients were missing.

"The clinical interpretation of the data is that six cycles of docetaxel in addition to ADT represents an appropriate option for men with metastatic prostate cancer commencing ADT who are suitable for docetaxel therapy," Dr. Sweeney said in the plenary session.

Dr. Michael J, Morris, the invited discussant, pointed out that the superior overall survival seen with the combination in this study far outstrips that of other drugs tried in this population, with median overall survival benefits ranging from 2.2 to 5.2 months.

"The investigators have adequately shown that high-volume patients with castration-sensitive metastatic disease can benefit from upfront docetaxel," he said. "But there is insufficient data at this after 29 months of median follow-up to recommend that low-volume patients with castration-sensitive disease undergo chemotherapy. We need to optimize the distinction between those who benefit from chemotherapy and those who don’t."

Dr. Morris of Memorial Sloan–Kettering Cancer Center and of Weill Cornell Medical College in New York was not involved in the study.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in a consulting or advisory role to Astellas Pharma, BIND Biosciences; Bionomics, Exelixis, Genentech, Janssen Pharmaceuticals, Roche and Sanofi. Dr. Morris disclosed consulting/advising Astellas, Bayer, Janssen, Millennium, and Progenics, stock ownership in Biogen Idec, Procter & Gamble, and Teva, and research funding from Agensys, Algeta, Bayer, Medivation, and Sanofi. Dr. Hudis served as a DSMB Chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck & Co.

CHICAGO – The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

In a randomized phase III trial, median overall survival for men who received upfront androgen deprivation therapy (ADT) alone for 18 weeks was 44 months, compared with 57.6 months for men who received ADT plus docetaxel (Taxotere), reported Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston.

Neil Osterweil/Frontline Medical News

"The certainty of the data is strong for patients with a high volume of metastatic disease and clearly justifies the treatment burden. This is one of the biggest improvements in survival we have seen involving patients with an adult, node-metastatic solid tumor," said Dr. Sweeney, who presented the data at a media briefing and in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"In prostate cancer, I’m not aware of an historical study that ever offered up quite this magnitude of improvement in survival," commented Dr. Clifford Hudis, who moderated the briefing and the plenary session.

Dr. Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, was not involved in the study.

In this study of 790 men with newly diagnosed metastatic prostate cancer, those with more extensive disease at study entry (520 patients) experienced the greatest benefit from the docetaxel-ADT combination, with a median overall survival of 49.2 months, compared with 32.2 months for men with extensive disease who received ADT alone.

Median overall survival for men with less invasive disease, has not yet been reached, Dr. Sweeney noted.

Start docetaxel earlier?

The CHAARTED (Chemo Hormonal Therapy vs. Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study began enrolling patients in 2006. Because there was evidence to show that docetaxel improves overall survival of men with metastatic prostate cancer who had disease progression while on ADT, the investigators wanted to see whether starting docetaxel earlier might provide additional benefit.

They randomly assigned men on a 1:1 basis to receive either ADT alone, or ADT plus docetaxel 75 mg/m² every 3 weeks for six cycles within 4 months of starting ADT. Patients were stratified by low- vs. high volume disease, with high-volume defined as visceral metastases and/or four or more metastatic bone lesions; antiandrogen therapy use beyond 30 days, age, ECOG (Eastern Cooperative Oncology Group) performance status, prior adjuvant ADT for less than or more than 1 year, and whether they had used a Food and Drug Administration–approved drug for preventing skeletal events, such as a bisphosphonate.

Of the patients assigned to ADT only, 124 received docetaxel at the time of disease progression. Of those in the combination group, 45 who had disease progression received additional docetaxel.

Data released early

Neil Osterweil/Frontline Medical News

At the fourth planned interim analysis in September 2013, when 53% of planned information had been accrued, the data-monitoring committee determined that the ADT-docetaxel combination had crossed the O’Brien-Fleming upper boundary, signaling statistically significant efficacy, and decided to release all available data.

As of Jan. 16, 2014, with a median follow-up of 29 months, there had been 137 deaths among patients treated with ADT alone, compared with 104 treated with ADT-docetaxel.

As noted before, median overall survival was 44 months for those on ADT alone, compared with 57.6 months for those on the combination (P = .0006). This translated into a hazard ratio for death of 0.61 (P = .0003).

The hazard ratio was similar for the subset of men with high-volume disease, at 0.60 (P = .0006), who received both ADT and docetaxel. The hazard ratio for men with low-volume disease was not significant, but as noted before, median overall survival in this group has not yet been reached, likely because men with low-volume disease tend to derive greater benefit from ADT, suggesting that it may take longer follow-up for an added effect of docetaxel to be seen.

In addition to the survival advantage, the combination was better than ADT alone at driving down prostate-specific antigen (PSA) levels, with 27.5% of patients on the ADT-docetaxel arm having a PSA below 0.2 ng/mL at 6 months, compared with 14% of patients treated with ADT alone (P less than .0001). At 12 months, the respective percentages were 22.7% and 11.7% (P less than .0001)

The combination was also better at delaying the median time to development of castration-resistant prostate cancer (20.7 vs. 14.7 months; P less than .0001), and the median time to clinical progression (32.7 vs. 19.8 months).

The most serious adverse events were febrile neutropenia and neuropathy. Of the 101 patients in the combination group who died, 84 of the deaths (83.2%) were from prostate cancer, 8 were from unknown causes, and 1 was attributed to the study protocol. Of the 136 in the ADT-alone arm who died, 112 deaths (83.6%) were from prostate cancers, and 22 were from other or unknown causes; data on the causes of death in 2 patients were missing.

"The clinical interpretation of the data is that six cycles of docetaxel in addition to ADT represents an appropriate option for men with metastatic prostate cancer commencing ADT who are suitable for docetaxel therapy," Dr. Sweeney said in the plenary session.

Dr. Michael J, Morris, the invited discussant, pointed out that the superior overall survival seen with the combination in this study far outstrips that of other drugs tried in this population, with median overall survival benefits ranging from 2.2 to 5.2 months.

"The investigators have adequately shown that high-volume patients with castration-sensitive metastatic disease can benefit from upfront docetaxel," he said. "But there is insufficient data at this after 29 months of median follow-up to recommend that low-volume patients with castration-sensitive disease undergo chemotherapy. We need to optimize the distinction between those who benefit from chemotherapy and those who don’t."

Dr. Morris of Memorial Sloan–Kettering Cancer Center and of Weill Cornell Medical College in New York was not involved in the study.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in a consulting or advisory role to Astellas Pharma, BIND Biosciences; Bionomics, Exelixis, Genentech, Janssen Pharmaceuticals, Roche and Sanofi. Dr. Morris disclosed consulting/advising Astellas, Bayer, Janssen, Millennium, and Progenics, stock ownership in Biogen Idec, Procter & Gamble, and Teva, and research funding from Agensys, Algeta, Bayer, Medivation, and Sanofi. Dr. Hudis served as a DSMB Chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck & Co.

CHICAGO – The answer was nearly a decade in coming, but worth the wait: Adding docetaxel to initial hormonal therapy in men with metastatic, hormone-sensitive prostate cancer can extend overall survival by more than a year.

In a randomized phase III trial, median overall survival for men who received upfront androgen deprivation therapy (ADT) alone for 18 weeks was 44 months, compared with 57.6 months for men who received ADT plus docetaxel (Taxotere), reported Dr. Christopher Sweeney of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston.

Neil Osterweil/Frontline Medical News

"The certainty of the data is strong for patients with a high volume of metastatic disease and clearly justifies the treatment burden. This is one of the biggest improvements in survival we have seen involving patients with an adult, node-metastatic solid tumor," said Dr. Sweeney, who presented the data at a media briefing and in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"In prostate cancer, I’m not aware of an historical study that ever offered up quite this magnitude of improvement in survival," commented Dr. Clifford Hudis, who moderated the briefing and the plenary session.

Dr. Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, was not involved in the study.

In this study of 790 men with newly diagnosed metastatic prostate cancer, those with more extensive disease at study entry (520 patients) experienced the greatest benefit from the docetaxel-ADT combination, with a median overall survival of 49.2 months, compared with 32.2 months for men with extensive disease who received ADT alone.

Median overall survival for men with less invasive disease, has not yet been reached, Dr. Sweeney noted.

Start docetaxel earlier?

The CHAARTED (Chemo Hormonal Therapy vs. Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study began enrolling patients in 2006. Because there was evidence to show that docetaxel improves overall survival of men with metastatic prostate cancer who had disease progression while on ADT, the investigators wanted to see whether starting docetaxel earlier might provide additional benefit.

They randomly assigned men on a 1:1 basis to receive either ADT alone, or ADT plus docetaxel 75 mg/m² every 3 weeks for six cycles within 4 months of starting ADT. Patients were stratified by low- vs. high volume disease, with high-volume defined as visceral metastases and/or four or more metastatic bone lesions; antiandrogen therapy use beyond 30 days, age, ECOG (Eastern Cooperative Oncology Group) performance status, prior adjuvant ADT for less than or more than 1 year, and whether they had used a Food and Drug Administration–approved drug for preventing skeletal events, such as a bisphosphonate.

Of the patients assigned to ADT only, 124 received docetaxel at the time of disease progression. Of those in the combination group, 45 who had disease progression received additional docetaxel.

Data released early

Neil Osterweil/Frontline Medical News

At the fourth planned interim analysis in September 2013, when 53% of planned information had been accrued, the data-monitoring committee determined that the ADT-docetaxel combination had crossed the O’Brien-Fleming upper boundary, signaling statistically significant efficacy, and decided to release all available data.

As of Jan. 16, 2014, with a median follow-up of 29 months, there had been 137 deaths among patients treated with ADT alone, compared with 104 treated with ADT-docetaxel.

As noted before, median overall survival was 44 months for those on ADT alone, compared with 57.6 months for those on the combination (P = .0006). This translated into a hazard ratio for death of 0.61 (P = .0003).

The hazard ratio was similar for the subset of men with high-volume disease, at 0.60 (P = .0006), who received both ADT and docetaxel. The hazard ratio for men with low-volume disease was not significant, but as noted before, median overall survival in this group has not yet been reached, likely because men with low-volume disease tend to derive greater benefit from ADT, suggesting that it may take longer follow-up for an added effect of docetaxel to be seen.

In addition to the survival advantage, the combination was better than ADT alone at driving down prostate-specific antigen (PSA) levels, with 27.5% of patients on the ADT-docetaxel arm having a PSA below 0.2 ng/mL at 6 months, compared with 14% of patients treated with ADT alone (P less than .0001). At 12 months, the respective percentages were 22.7% and 11.7% (P less than .0001)

The combination was also better at delaying the median time to development of castration-resistant prostate cancer (20.7 vs. 14.7 months; P less than .0001), and the median time to clinical progression (32.7 vs. 19.8 months).

The most serious adverse events were febrile neutropenia and neuropathy. Of the 101 patients in the combination group who died, 84 of the deaths (83.2%) were from prostate cancer, 8 were from unknown causes, and 1 was attributed to the study protocol. Of the 136 in the ADT-alone arm who died, 112 deaths (83.6%) were from prostate cancers, and 22 were from other or unknown causes; data on the causes of death in 2 patients were missing.

"The clinical interpretation of the data is that six cycles of docetaxel in addition to ADT represents an appropriate option for men with metastatic prostate cancer commencing ADT who are suitable for docetaxel therapy," Dr. Sweeney said in the plenary session.

Dr. Michael J, Morris, the invited discussant, pointed out that the superior overall survival seen with the combination in this study far outstrips that of other drugs tried in this population, with median overall survival benefits ranging from 2.2 to 5.2 months.

"The investigators have adequately shown that high-volume patients with castration-sensitive metastatic disease can benefit from upfront docetaxel," he said. "But there is insufficient data at this after 29 months of median follow-up to recommend that low-volume patients with castration-sensitive disease undergo chemotherapy. We need to optimize the distinction between those who benefit from chemotherapy and those who don’t."

Dr. Morris of Memorial Sloan–Kettering Cancer Center and of Weill Cornell Medical College in New York was not involved in the study.

The study was funded by the National Cancer Institute. Dr. Sweeney disclosed serving in a consulting or advisory role to Astellas Pharma, BIND Biosciences; Bionomics, Exelixis, Genentech, Janssen Pharmaceuticals, Roche and Sanofi. Dr. Morris disclosed consulting/advising Astellas, Bayer, Janssen, Millennium, and Progenics, stock ownership in Biogen Idec, Procter & Gamble, and Teva, and research funding from Agensys, Algeta, Bayer, Medivation, and Sanofi. Dr. Hudis served as a DSMB Chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck & Co.

1. A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia.

Herbert Aaron Eradat, et al., Abstract TPS7127

2. Independent evaluation of ibrutinib efficacy 3 years postinitiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.

Susan Mary O’Brien, et al., Abstract 7014

3. Randomized comparison of ibrutinib vs. ofatumumab in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.

John C. Byrd, Abstract LBA7008

4. Efficacy and safety of imatinib in chronic myeloid leukemia over 10 years.

Rüdiger Hehlmann, Abstract 7021

5. Chronic myelomonocytic leukemia: Next-generation sequencing in 30 treatment-naive cases.

Priyanka Priyanka, et al., Abstract 7051

Dr. Henry is with the department of medicine at the University of Pennsylvania, Philadelphia. He is a member of the medical staff at Pennsylvania Hospital in the division of hematology/oncology and is vice chairman of its department of medicine, and editor in chief of the Journal of Community and Supportive Oncology.

1. A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia.

Herbert Aaron Eradat, et al., Abstract TPS7127

2. Independent evaluation of ibrutinib efficacy 3 years postinitiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.

Susan Mary O’Brien, et al., Abstract 7014

3. Randomized comparison of ibrutinib vs. ofatumumab in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.

John C. Byrd, Abstract LBA7008

4. Efficacy and safety of imatinib in chronic myeloid leukemia over 10 years.

Rüdiger Hehlmann, Abstract 7021

5. Chronic myelomonocytic leukemia: Next-generation sequencing in 30 treatment-naive cases.

Priyanka Priyanka, et al., Abstract 7051

Dr. Henry is with the department of medicine at the University of Pennsylvania, Philadelphia. He is a member of the medical staff at Pennsylvania Hospital in the division of hematology/oncology and is vice chairman of its department of medicine, and editor in chief of the Journal of Community and Supportive Oncology.

1. A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia.

Herbert Aaron Eradat, et al., Abstract TPS7127

2. Independent evaluation of ibrutinib efficacy 3 years postinitiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.

Susan Mary O’Brien, et al., Abstract 7014

3. Randomized comparison of ibrutinib vs. ofatumumab in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.

John C. Byrd, Abstract LBA7008

4. Efficacy and safety of imatinib in chronic myeloid leukemia over 10 years.

Rüdiger Hehlmann, Abstract 7021

5. Chronic myelomonocytic leukemia: Next-generation sequencing in 30 treatment-naive cases.

Priyanka Priyanka, et al., Abstract 7051

Dr. Henry is with the department of medicine at the University of Pennsylvania, Philadelphia. He is a member of the medical staff at Pennsylvania Hospital in the division of hematology/oncology and is vice chairman of its department of medicine, and editor in chief of the Journal of Community and Supportive Oncology.

CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Laura Nikolaides/Frontline Medical News

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.

"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.

The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.

[email protected]

On Twitter @nikolaideslaura

CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Laura Nikolaides/Frontline Medical News

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.

"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.

The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.

[email protected]

On Twitter @nikolaideslaura

CHICAGO – Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Laura Nikolaides/Frontline Medical News

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. "I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial," he said. "This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities," he added.

"We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors," commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. "Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer," he added.

The research was supported by the National Institutes of Health. Dr. Cmelak reported a consultancy role and honoraria from Bristol-Myers Squibb. Dr. Masters reported no disclosures.

[email protected]

On Twitter @nikolaideslaura

CHICAGO – Lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with relapsed iodine-refractory differentiated thyroid cancer. We catch up with study coauthor Dr. Lori C. Wirth, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, Boston, to discuss the promising results at the annual meeting of the American Society of Clinical Oncology.

The study was funded by Eisai. Dr. Wirth reported no financial disclosures.

CHICAGO – Lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with relapsed iodine-refractory differentiated thyroid cancer. We catch up with study coauthor Dr. Lori C. Wirth, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, Boston, to discuss the promising results at the annual meeting of the American Society of Clinical Oncology.

The study was funded by Eisai. Dr. Wirth reported no financial disclosures.

CHICAGO – Lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with relapsed iodine-refractory differentiated thyroid cancer. We catch up with study coauthor Dr. Lori C. Wirth, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, Boston, to discuss the promising results at the annual meeting of the American Society of Clinical Oncology.

The study was funded by Eisai. Dr. Wirth reported no financial disclosures.

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

[email protected]

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

[email protected]

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

[email protected]