2013 ASCO Annual Meeting

CHICAGO – A novel heat-shock protein inhibitor, ganetespib, showed glimmers of a survival benefit for lung cancer patients in a randomized phase II trial presented at the annual meeting of the American Society of Clinical Oncology.

Tested in combination with docetaxel, the experimental drug appeared to improve overall and progression-free survival, compared with docetaxel alone, as second-line therapy for patients with advanced non–small cell adenocarcinoma of the lung, Dr. Suresh Ramalingam reported.

Neither measure, however, was a primary end point of the study. Heat-shock protein 90 is a chaperone protein that activates other proteins binding to it so that they can perform their normal cellular function. Ganetespib binds to and inhibits Hsp90, causing oncoproteins to become inactivated and to degrade before they have had a chance to unfold into their functional configuration.

In the randomized phase II GALAXY-1 study, median progression-free survival reached 4.5 months among 125 patients assigned to ganetespib and docetaxel, compared with 3.2 months for 127 patients assigned to docetaxel and placebo (hazard ratio, 0.84; P = .038) in an unadjusted analysis.

However, after adjusting for sex, smoking status, lactate dehydrogenase (LDH), performance status, interval since diagnosis, and other common factors, the difference was no longer significant, said Dr. Ramalingam, chief of thoracic oncology and director of medical oncology, at Emory University in Atlanta.

Overall survival, in contrast, was not significantly different in an unadjusted analysis, at a median of 9.8 months for the combination and 7.4 months for docetaxel alone (HR, 0.82), but became significant after adjustment for potential confounders (adjusted HR, 0.73; P = .041).

"This is a first-in-class study showing the potential efficacy of this compound, and I think it presents a potential advance in an area of lung cancer where we haven’t had advances in a long time, and we’re all eagerly awaiting the outcome of the phase III trial," said Dr. Marjorie Zauderer, a medical oncologist and lung cancer specialist at Memorial Sloan-Kettering Cancer Center, New York.

Dr. Zauderer was not involved in the study, but commented on it in a briefing held prior to the presentation of data later in the day.

Overall survival and progression-free survival were secondary end points in the trial. The co-primary end points were progression-free survival in patients with elevated LDH levels or tumors with mutations in KRAS, but these data were not reported. According to Synta Pharmaceuticals, maker of ganetespib, neither KRAS nor epidermal growth factor receptor (EGFR) mutations correlated with an overall survival benefit for the experimental arm of the trial.

When the investigators looked at only those patients who had been diagnosed more than 6 months before being enrolled in the trial (the "6-month population") they found that, in both unadjusted and adjusted analyses, the ganetespib and docetaxel combination was superior to docetaxel and placebo, with median overall survival of 10.7 vs. 6.4 months (unadjusted HR, 0.61; P = .0093; adjusted HR, 0.55; P = .0036), and median progression-free survival of 5.4 vs. 3.4 months (unadjusted HR, 0.61, P = .0041; adjusted HR, 0.62, P = .0075).

About 70% of the patients in the trial were included in the 6-month population. The follow-on GALAXY-2 phase III trial will enroll only those patients who have lived with an adenocarcinoma diagnosis for at least 6 months, the population that derived the greatest benefit in the current study.

The ganetespib and docetaxel combination was generally well tolerated, with manageable mild-to-moderate diarrhea being the most common adverse event.

The study was sponsored by Synta Pharmaceuticals. Dr. Ramalingam said that his institution receives research support from the company but that he had no personal financial disclosures. Dr. Zauderer reported having no conflicts of interest.

CHICAGO – A novel heat-shock protein inhibitor, ganetespib, showed glimmers of a survival benefit for lung cancer patients in a randomized phase II trial presented at the annual meeting of the American Society of Clinical Oncology.

Tested in combination with docetaxel, the experimental drug appeared to improve overall and progression-free survival, compared with docetaxel alone, as second-line therapy for patients with advanced non–small cell adenocarcinoma of the lung, Dr. Suresh Ramalingam reported.

Neither measure, however, was a primary end point of the study. Heat-shock protein 90 is a chaperone protein that activates other proteins binding to it so that they can perform their normal cellular function. Ganetespib binds to and inhibits Hsp90, causing oncoproteins to become inactivated and to degrade before they have had a chance to unfold into their functional configuration.

In the randomized phase II GALAXY-1 study, median progression-free survival reached 4.5 months among 125 patients assigned to ganetespib and docetaxel, compared with 3.2 months for 127 patients assigned to docetaxel and placebo (hazard ratio, 0.84; P = .038) in an unadjusted analysis.

However, after adjusting for sex, smoking status, lactate dehydrogenase (LDH), performance status, interval since diagnosis, and other common factors, the difference was no longer significant, said Dr. Ramalingam, chief of thoracic oncology and director of medical oncology, at Emory University in Atlanta.

Overall survival, in contrast, was not significantly different in an unadjusted analysis, at a median of 9.8 months for the combination and 7.4 months for docetaxel alone (HR, 0.82), but became significant after adjustment for potential confounders (adjusted HR, 0.73; P = .041).

"This is a first-in-class study showing the potential efficacy of this compound, and I think it presents a potential advance in an area of lung cancer where we haven’t had advances in a long time, and we’re all eagerly awaiting the outcome of the phase III trial," said Dr. Marjorie Zauderer, a medical oncologist and lung cancer specialist at Memorial Sloan-Kettering Cancer Center, New York.

Dr. Zauderer was not involved in the study, but commented on it in a briefing held prior to the presentation of data later in the day.

Overall survival and progression-free survival were secondary end points in the trial. The co-primary end points were progression-free survival in patients with elevated LDH levels or tumors with mutations in KRAS, but these data were not reported. According to Synta Pharmaceuticals, maker of ganetespib, neither KRAS nor epidermal growth factor receptor (EGFR) mutations correlated with an overall survival benefit for the experimental arm of the trial.

When the investigators looked at only those patients who had been diagnosed more than 6 months before being enrolled in the trial (the "6-month population") they found that, in both unadjusted and adjusted analyses, the ganetespib and docetaxel combination was superior to docetaxel and placebo, with median overall survival of 10.7 vs. 6.4 months (unadjusted HR, 0.61; P = .0093; adjusted HR, 0.55; P = .0036), and median progression-free survival of 5.4 vs. 3.4 months (unadjusted HR, 0.61, P = .0041; adjusted HR, 0.62, P = .0075).

About 70% of the patients in the trial were included in the 6-month population. The follow-on GALAXY-2 phase III trial will enroll only those patients who have lived with an adenocarcinoma diagnosis for at least 6 months, the population that derived the greatest benefit in the current study.

The ganetespib and docetaxel combination was generally well tolerated, with manageable mild-to-moderate diarrhea being the most common adverse event.

The study was sponsored by Synta Pharmaceuticals. Dr. Ramalingam said that his institution receives research support from the company but that he had no personal financial disclosures. Dr. Zauderer reported having no conflicts of interest.

CHICAGO – A novel heat-shock protein inhibitor, ganetespib, showed glimmers of a survival benefit for lung cancer patients in a randomized phase II trial presented at the annual meeting of the American Society of Clinical Oncology.

Tested in combination with docetaxel, the experimental drug appeared to improve overall and progression-free survival, compared with docetaxel alone, as second-line therapy for patients with advanced non–small cell adenocarcinoma of the lung, Dr. Suresh Ramalingam reported.

Neither measure, however, was a primary end point of the study. Heat-shock protein 90 is a chaperone protein that activates other proteins binding to it so that they can perform their normal cellular function. Ganetespib binds to and inhibits Hsp90, causing oncoproteins to become inactivated and to degrade before they have had a chance to unfold into their functional configuration.

In the randomized phase II GALAXY-1 study, median progression-free survival reached 4.5 months among 125 patients assigned to ganetespib and docetaxel, compared with 3.2 months for 127 patients assigned to docetaxel and placebo (hazard ratio, 0.84; P = .038) in an unadjusted analysis.

However, after adjusting for sex, smoking status, lactate dehydrogenase (LDH), performance status, interval since diagnosis, and other common factors, the difference was no longer significant, said Dr. Ramalingam, chief of thoracic oncology and director of medical oncology, at Emory University in Atlanta.

Overall survival, in contrast, was not significantly different in an unadjusted analysis, at a median of 9.8 months for the combination and 7.4 months for docetaxel alone (HR, 0.82), but became significant after adjustment for potential confounders (adjusted HR, 0.73; P = .041).

"This is a first-in-class study showing the potential efficacy of this compound, and I think it presents a potential advance in an area of lung cancer where we haven’t had advances in a long time, and we’re all eagerly awaiting the outcome of the phase III trial," said Dr. Marjorie Zauderer, a medical oncologist and lung cancer specialist at Memorial Sloan-Kettering Cancer Center, New York.

Dr. Zauderer was not involved in the study, but commented on it in a briefing held prior to the presentation of data later in the day.

Overall survival and progression-free survival were secondary end points in the trial. The co-primary end points were progression-free survival in patients with elevated LDH levels or tumors with mutations in KRAS, but these data were not reported. According to Synta Pharmaceuticals, maker of ganetespib, neither KRAS nor epidermal growth factor receptor (EGFR) mutations correlated with an overall survival benefit for the experimental arm of the trial.

When the investigators looked at only those patients who had been diagnosed more than 6 months before being enrolled in the trial (the "6-month population") they found that, in both unadjusted and adjusted analyses, the ganetespib and docetaxel combination was superior to docetaxel and placebo, with median overall survival of 10.7 vs. 6.4 months (unadjusted HR, 0.61; P = .0093; adjusted HR, 0.55; P = .0036), and median progression-free survival of 5.4 vs. 3.4 months (unadjusted HR, 0.61, P = .0041; adjusted HR, 0.62, P = .0075).

About 70% of the patients in the trial were included in the 6-month population. The follow-on GALAXY-2 phase III trial will enroll only those patients who have lived with an adenocarcinoma diagnosis for at least 6 months, the population that derived the greatest benefit in the current study.

The ganetespib and docetaxel combination was generally well tolerated, with manageable mild-to-moderate diarrhea being the most common adverse event.

The study was sponsored by Synta Pharmaceuticals. Dr. Ramalingam said that his institution receives research support from the company but that he had no personal financial disclosures. Dr. Zauderer reported having no conflicts of interest.

CHICAGO – Selumetinib, an investigational MEK 1/2 inhibitor, shrank uveal melanomas in half of all treated patients, with a duration of disease control that was more than twice that achieved with the comparator therapy temozolomide, based on the final analysis of data from 98 patients in a phase II crossover study.

This is the first clinical trial to identify a drug that improves clinical outcome in patients with advanced melanoma of the eye, said Dr. Richard D. Carvajal, who presented the data at the annual meeting of the American Society of Clinical Oncology.

"Selumetinib is a new standard of therapy for uveal metastatic melanoma," he said at a press conference announcing the results. Before this study, there was no evidence that any systemic therapy was truly effective in this disease. In eight different clinical trials conducted in the last decade, 2 of 157 patients have responded to potential new therapies, including chemotherapy, targeted therapy, and immunotherapy.

“Right now, there are no plans for an official compassionate use program; however, we are reopening up our trial without the randomization such that additional patients can receive selumetinib through this mechanism,” he said in an interview after the meeting.

With about 2,000 cases diagnosed each year in the United States, uveal melanoma is an orphan disease that is biologically distinct from cutaneous melanoma. Treatment consists of surgery to remove the tumor or eye, as well as radiation therapy or chemotherapy. About half of cases metastasize, and survival for these patients is 9-12 months.

In this study, 98 patients with metastatic melanoma of the eye were randomly assigned to receive selumetinib or temozolomide (Temodar), with 48 receiving selumetinib and 50 receiving temozolomide. Based on imaging studies using RECIST (Response Evaluation Criteria in Solid Tumors), patients whose disease worsened on temozolomide were permitted to cross over to selumetinib.

Looking at the response patterns, tumors regressed in 11% (RECIST response, 0%) of 46 evaluable patients in the temozolomide arm and in 50% (RECIST response, 15%) of 46 evaluable patients in the selumetinib arm, for a highly significant hazard ratio of 0.46, reported Dr. Carvajal of Memorial Sloan-Kettering Cancer Center in New York.

Progression-free survival was improved to nearly 16 weeks for selumetinib as compared with 7 weeks for temozolomide. Overall survival was 10.8 months for selumetinib and 9.4 months with temozolomide.

More than 90% of patients in both arms of the study had metastatic liver disease and more than 50% had an elevated lactate dehydrogenase, Dr. Carvajal noted. Further, the study allowed for crossover to selumetinib by temozolomide-treated patients with no evidence of response at 4 weeks; 80% of patients in the temozolomide arm crossed over to selumetinib.

Selumetinib blocks the MEK protein, a key component of the MAPK pathway, which is activated by Gnaq and Gna11 gene mutations, found in 84% of the uveal melanoma patients in the study. Selumetinib also is being investigated for the treatment of cancers of the thyroid and lung, and trials are underway with selumetinib in combination with other drugs.

Dr. Carvajal noted that another MEK inhibitor, trametinib (Mekinist, GlaxoSmithKline), recently became the first MEK inhibitor to be approved by the Food and Drug Administration. Trametinib was approved in May 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations.

AstraZeneca is developing selumetinib under a licensing agreement with Array Biopharma.

The selumetinib study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge. Dr. Carvajal had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – Selumetinib, an investigational MEK 1/2 inhibitor, shrank uveal melanomas in half of all treated patients, with a duration of disease control that was more than twice that achieved with the comparator therapy temozolomide, based on the final analysis of data from 98 patients in a phase II crossover study.

This is the first clinical trial to identify a drug that improves clinical outcome in patients with advanced melanoma of the eye, said Dr. Richard D. Carvajal, who presented the data at the annual meeting of the American Society of Clinical Oncology.

"Selumetinib is a new standard of therapy for uveal metastatic melanoma," he said at a press conference announcing the results. Before this study, there was no evidence that any systemic therapy was truly effective in this disease. In eight different clinical trials conducted in the last decade, 2 of 157 patients have responded to potential new therapies, including chemotherapy, targeted therapy, and immunotherapy.

“Right now, there are no plans for an official compassionate use program; however, we are reopening up our trial without the randomization such that additional patients can receive selumetinib through this mechanism,” he said in an interview after the meeting.

With about 2,000 cases diagnosed each year in the United States, uveal melanoma is an orphan disease that is biologically distinct from cutaneous melanoma. Treatment consists of surgery to remove the tumor or eye, as well as radiation therapy or chemotherapy. About half of cases metastasize, and survival for these patients is 9-12 months.

In this study, 98 patients with metastatic melanoma of the eye were randomly assigned to receive selumetinib or temozolomide (Temodar), with 48 receiving selumetinib and 50 receiving temozolomide. Based on imaging studies using RECIST (Response Evaluation Criteria in Solid Tumors), patients whose disease worsened on temozolomide were permitted to cross over to selumetinib.

Looking at the response patterns, tumors regressed in 11% (RECIST response, 0%) of 46 evaluable patients in the temozolomide arm and in 50% (RECIST response, 15%) of 46 evaluable patients in the selumetinib arm, for a highly significant hazard ratio of 0.46, reported Dr. Carvajal of Memorial Sloan-Kettering Cancer Center in New York.

Progression-free survival was improved to nearly 16 weeks for selumetinib as compared with 7 weeks for temozolomide. Overall survival was 10.8 months for selumetinib and 9.4 months with temozolomide.

More than 90% of patients in both arms of the study had metastatic liver disease and more than 50% had an elevated lactate dehydrogenase, Dr. Carvajal noted. Further, the study allowed for crossover to selumetinib by temozolomide-treated patients with no evidence of response at 4 weeks; 80% of patients in the temozolomide arm crossed over to selumetinib.

Selumetinib blocks the MEK protein, a key component of the MAPK pathway, which is activated by Gnaq and Gna11 gene mutations, found in 84% of the uveal melanoma patients in the study. Selumetinib also is being investigated for the treatment of cancers of the thyroid and lung, and trials are underway with selumetinib in combination with other drugs.

Dr. Carvajal noted that another MEK inhibitor, trametinib (Mekinist, GlaxoSmithKline), recently became the first MEK inhibitor to be approved by the Food and Drug Administration. Trametinib was approved in May 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations.

AstraZeneca is developing selumetinib under a licensing agreement with Array Biopharma.

The selumetinib study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge. Dr. Carvajal had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – Selumetinib, an investigational MEK 1/2 inhibitor, shrank uveal melanomas in half of all treated patients, with a duration of disease control that was more than twice that achieved with the comparator therapy temozolomide, based on the final analysis of data from 98 patients in a phase II crossover study.

This is the first clinical trial to identify a drug that improves clinical outcome in patients with advanced melanoma of the eye, said Dr. Richard D. Carvajal, who presented the data at the annual meeting of the American Society of Clinical Oncology.

"Selumetinib is a new standard of therapy for uveal metastatic melanoma," he said at a press conference announcing the results. Before this study, there was no evidence that any systemic therapy was truly effective in this disease. In eight different clinical trials conducted in the last decade, 2 of 157 patients have responded to potential new therapies, including chemotherapy, targeted therapy, and immunotherapy.

“Right now, there are no plans for an official compassionate use program; however, we are reopening up our trial without the randomization such that additional patients can receive selumetinib through this mechanism,” he said in an interview after the meeting.

With about 2,000 cases diagnosed each year in the United States, uveal melanoma is an orphan disease that is biologically distinct from cutaneous melanoma. Treatment consists of surgery to remove the tumor or eye, as well as radiation therapy or chemotherapy. About half of cases metastasize, and survival for these patients is 9-12 months.

In this study, 98 patients with metastatic melanoma of the eye were randomly assigned to receive selumetinib or temozolomide (Temodar), with 48 receiving selumetinib and 50 receiving temozolomide. Based on imaging studies using RECIST (Response Evaluation Criteria in Solid Tumors), patients whose disease worsened on temozolomide were permitted to cross over to selumetinib.

Looking at the response patterns, tumors regressed in 11% (RECIST response, 0%) of 46 evaluable patients in the temozolomide arm and in 50% (RECIST response, 15%) of 46 evaluable patients in the selumetinib arm, for a highly significant hazard ratio of 0.46, reported Dr. Carvajal of Memorial Sloan-Kettering Cancer Center in New York.

Progression-free survival was improved to nearly 16 weeks for selumetinib as compared with 7 weeks for temozolomide. Overall survival was 10.8 months for selumetinib and 9.4 months with temozolomide.

More than 90% of patients in both arms of the study had metastatic liver disease and more than 50% had an elevated lactate dehydrogenase, Dr. Carvajal noted. Further, the study allowed for crossover to selumetinib by temozolomide-treated patients with no evidence of response at 4 weeks; 80% of patients in the temozolomide arm crossed over to selumetinib.

Selumetinib blocks the MEK protein, a key component of the MAPK pathway, which is activated by Gnaq and Gna11 gene mutations, found in 84% of the uveal melanoma patients in the study. Selumetinib also is being investigated for the treatment of cancers of the thyroid and lung, and trials are underway with selumetinib in combination with other drugs.

Dr. Carvajal noted that another MEK inhibitor, trametinib (Mekinist, GlaxoSmithKline), recently became the first MEK inhibitor to be approved by the Food and Drug Administration. Trametinib was approved in May 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations.

AstraZeneca is developing selumetinib under a licensing agreement with Array Biopharma.

The selumetinib study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge. Dr. Carvajal had no relevant financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

[email protected]

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

[email protected]

CHICAGO – The long wait for a new medical therapy for advanced radioactive-refractory thyroid cancer is drawing to a close.

Twice-daily oral sorafenib (Nexavar) nearly doubled the median time to disease progression from 5.8 months with placebo to 10.8 months (hazard ratio, 0.587; P less than .0001) among 417 patients in the double-blind, international phase III DECISION study.

The benefit of sorafenib on this primary endpoint was seen across all patient characteristics, including age, histology, and geographic region, principal investigator Dr. Marcia S. Brose said during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Median overall survival has not been reached for either arm, and will be strongly affected by the 71% of controls who crossed over to open-label treatment with the multikinase inhibitor.

No standard therapy exists for the 5%-15% of patients with thyroid cancer who are refractory to standard treatment with surgery and radioactive iodine (RAI). Doxorubicin (Adriamycin) chemotherapy was approved some 30 years ago, but it is ineffective and toxic.

"Sorafenib is a potential new treatment option for patients with locally advanced or metastatic radioactive-refractory differentiated thyroid cancer," said Dr. Brose, director of thyroid cancer therapeutics and head and neck clinical trials at the University of Pennsylvania, Philadelphia.

Approval sought in U.S. and abroad

DECISION (Study of sorafenib in locally advanced or metastatic patients with radioactive iodine refractory thyroid cancer) is the first phase III study to demonstrate treatment efficacy in this setting. Based on its results, a supplemental New Drug Application will be submitted for sorafenib by midyear in the United States, with global submissions to follow, according to study sponsors Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals. The drug is already approved in the United States for advanced renal and liver cancer.

DECISION involved 417 patients in the United States, Europe, or Asia who had locally advanced or metastatic RAI-refractory differentiated thyroid cancer that had progressed within the previous 14 months and had received no prior chemotherapy, targeted therapy, or thalidomide. Patients received twice-daily sorafenib 400 mg or placebo. The majority had distant metastases (96%), 66% had papillary histology, and 61% had an ECOG performance status of 0. Their median age was 63 years.

Sorafenib did not induce any complete responses. Partial responses, defined by at least a 30% reduction in tumor size, occurred in 12.2% of sorafenib patients vs. 0.5% of controls, and lasted for a median of 10.2 months, Dr. Brose said. An additional 42% of patients experienced stable disease for more than 6 months, resulting in a disease control rate of 54% in the sorafenib arm vs. 34% in the placebo arm.

In all, 73% of sorafenib-treated patients had some tumor shrinkage, compared with 27% of placebo-treated patients, and this was often sufficient to relieve symptoms, she said.

It would have been nice to see more partial responses, but all responses were clinically meaningful, Dr. Brose said in an interview.

"Unlike other cancers, what’s interesting is that these patients can have 100 nodules in their chest and actually experience very few symptoms, but what will kill them is when those grow," she said. "So the more clinically important number that is going to prevent the hospitalizations and other complications is not so much the issue of response, but how long it lasts."

Whom and when to treat

Invited discussant Dr. Ezra Cohen, codirector of the head and neck cancer program at the University of Chicago Comprehensive Cancer Center, said not all iodine-refractory patients need treatment, noting that at 400 days, 25% of placebo-treated patients did not progress in DECISION.

The real question going forward is not whether all refractory differentiated thyroid cancer patients should receive sorafenib, but whom and when to treat, he said. Factors that will come into play are whether the patient is symptomatic, the location of the disease and whether that location will portend the onset of symptoms in the near future, and the growth rate of their anatomic disease.

"What you don’t see on this list is the change in chemical factors, and that is specifically thyroid globulin," Dr. Cohen said. "The rise in thyroid globulin, while often important to patients, in my opinion should not be used as a criterion to initiate therapy."

He pointed out that other vascular endothelial growth factor (VEGF) receptor inhibitors are currently being evaluated in iodine-refractory differentiated thyroid cancer, including the ongoing phase III trial of lenvatinib (NCT01321554). "If I had to guess, it will reinforce the data we just saw with sorafenib," he added.

Finally, Dr. Cohen said clinicians are already seeing a wave of patients in the clinic who are refractory to VEGF inhibitors, and that this emerging entity needs to be addressed and patients encouraged to enter clinical trials.

During a press briefing at the meeting, Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center in Newark, Del., told reporters that apart from entering patients in clinical trials, there are no good options for patients who progress.

"Now we have an option where we know that we can prolong progression-free survival, and I think using this for our patients will become a very attractive option and I think, yes, it will become the standard of care," he said.

DECISION was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Dr. Brose reported consulting fees, honoraria, and research funding from these companies. Dr. Cohen disclosed relationships with other companies.

[email protected]

CHICAGO – Combining two approved therapies – GM-CSF and ipilimumab – extended overall survival rates by 35% and resulted in fewer grade 3-5 adverse events when compared with ipilimumab alone in a randomized study of 245 patients with metastatic melanoma.

At 1 year, the overall survival rate in the combination therapy group was 69%, with a median follow-up of nearly 18 months. At 1 year, survival in the ipilimumab-only group was 53% with a median follow-up of nearly 13 months, Dr. F. Stephen Hodi, Jr. reported at the annual meeting of the American Society of Clinical Oncology.

This is the first phase II trial to look at ipilimumab (Yervoy, Bristol-Myers Squibb) and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim (Leukine, Sanofi) in combination in any cancer, said Dr. Hodi, the principal investigator for the trial, which was conducted by the ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group) trial. In this study, ipilimumab was used at a dose of 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg.

"We are waiting for the data to mature in ongoing studies examining the relative efficacy of 3 mg/kg and 10 mg/kg dosing," said Dr. Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston.

The results in the current trial are another indication of the impact that immunotherapy can have for patients with advanced melanoma. Since both GM-CSF and ipilimumab are commercially available, oncologists need to determine the best way to apply these findings in everyday practice. The next step will then be to define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as therapies that target the PD-1 and PD-L1 pathway, he said.

"We have been using GM-CSF in melanoma as a stand-alone therapy," Dr. Lynn M. Schuchter, the C. Willard Robinson Professor of Hematology-Oncology at the University of Pennsylvania, Philadelphia, and an expert on melanoma, said at a press conference where the study results were announced. "It will be interesting to see if payers will cover this (combination treatment)."

Ipilimumab targets CTLA-4, a protein that keeps immune T-cells in an inactive state. GM-CSF is a growth factor commonly used to boost white blood cell counts after chemotherapy or stem cell transplantation.

For this study, 245 patients were randomized to receive ipilimumab plus GM-CSF or ipilimumab alone. All study participants were in otherwise good health, with an ECOG performance status of 0-1 and adequate end-organ function, no autoimmune disease, and no prior use of CTLA-4 blockade or CD137 agonists. All had radiographically measurable metastatic melanoma, but with no CNS metastases, and had received up to one prior treatment over 4 weeks before starting in the trial.

The 123 patients randomized to the combination therapy were given sargramostim at 250 micrograms injected subcutaneously on day 1-14 of a 21 day cycle. For induction therapy, ipilimumab was given at a dose of 10 mg/kg intravenously once every 3 weeks for four cycles as induction therapy and once every 12 weeks as maintenance therapy. The 122 patients randomized to ipilimumab alone received the drug on the same schedule.

In both study arms, tumor shrinkage rates were comparable at 11% and 14%, and progression-free survival was similar at about 3 months. But the overall survival rate was longer in the combination treatment arm. One year after the start of therapy and with a median follow-up of 13.3 months, 69% of patients given the combination therapy and 53% of those who got ipilimumab alone were still alive, for a 35% lower risk of death with the combination therapy (hazard ratio, 0.64; P = .014).

Additionally, the combination treatment was associated with fewer serious side effects, compared with ipilimumab alone. The most significant differences were in lung and gastrointestinal toxicities.

Grade 3-5 adverse events occurred in 45% of patients given the combination therapy and in 57% given ipilimumab alone (p2 = 0.078). There were two possible treatment-related deaths in the combination arm (one colonic perforation and one cardiac arrest) and 7 possible treatment-related deaths in the ipilimumab-only arm: (two cases of multi-organ failure, two colonic perforations, one case of liver failure, and two cases of respiratory failure).

The research was supported in part by the National Cancer Institute (Cancer Therapy Evaluation Program), Sanofi, and Bristol-Myers Squibb. Dr. Hodi disclosed receiving research funding and a being a consultant or in an advisory role with Bristol-Myers Squibb.

CHICAGO – Combining two approved therapies – GM-CSF and ipilimumab – extended overall survival rates by 35% and resulted in fewer grade 3-5 adverse events when compared with ipilimumab alone in a randomized study of 245 patients with metastatic melanoma.

At 1 year, the overall survival rate in the combination therapy group was 69%, with a median follow-up of nearly 18 months. At 1 year, survival in the ipilimumab-only group was 53% with a median follow-up of nearly 13 months, Dr. F. Stephen Hodi, Jr. reported at the annual meeting of the American Society of Clinical Oncology.

This is the first phase II trial to look at ipilimumab (Yervoy, Bristol-Myers Squibb) and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim (Leukine, Sanofi) in combination in any cancer, said Dr. Hodi, the principal investigator for the trial, which was conducted by the ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group) trial. In this study, ipilimumab was used at a dose of 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg.

"We are waiting for the data to mature in ongoing studies examining the relative efficacy of 3 mg/kg and 10 mg/kg dosing," said Dr. Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston.

The results in the current trial are another indication of the impact that immunotherapy can have for patients with advanced melanoma. Since both GM-CSF and ipilimumab are commercially available, oncologists need to determine the best way to apply these findings in everyday practice. The next step will then be to define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as therapies that target the PD-1 and PD-L1 pathway, he said.

"We have been using GM-CSF in melanoma as a stand-alone therapy," Dr. Lynn M. Schuchter, the C. Willard Robinson Professor of Hematology-Oncology at the University of Pennsylvania, Philadelphia, and an expert on melanoma, said at a press conference where the study results were announced. "It will be interesting to see if payers will cover this (combination treatment)."

Ipilimumab targets CTLA-4, a protein that keeps immune T-cells in an inactive state. GM-CSF is a growth factor commonly used to boost white blood cell counts after chemotherapy or stem cell transplantation.

For this study, 245 patients were randomized to receive ipilimumab plus GM-CSF or ipilimumab alone. All study participants were in otherwise good health, with an ECOG performance status of 0-1 and adequate end-organ function, no autoimmune disease, and no prior use of CTLA-4 blockade or CD137 agonists. All had radiographically measurable metastatic melanoma, but with no CNS metastases, and had received up to one prior treatment over 4 weeks before starting in the trial.

The 123 patients randomized to the combination therapy were given sargramostim at 250 micrograms injected subcutaneously on day 1-14 of a 21 day cycle. For induction therapy, ipilimumab was given at a dose of 10 mg/kg intravenously once every 3 weeks for four cycles as induction therapy and once every 12 weeks as maintenance therapy. The 122 patients randomized to ipilimumab alone received the drug on the same schedule.

In both study arms, tumor shrinkage rates were comparable at 11% and 14%, and progression-free survival was similar at about 3 months. But the overall survival rate was longer in the combination treatment arm. One year after the start of therapy and with a median follow-up of 13.3 months, 69% of patients given the combination therapy and 53% of those who got ipilimumab alone were still alive, for a 35% lower risk of death with the combination therapy (hazard ratio, 0.64; P = .014).

Additionally, the combination treatment was associated with fewer serious side effects, compared with ipilimumab alone. The most significant differences were in lung and gastrointestinal toxicities.

Grade 3-5 adverse events occurred in 45% of patients given the combination therapy and in 57% given ipilimumab alone (p2 = 0.078). There were two possible treatment-related deaths in the combination arm (one colonic perforation and one cardiac arrest) and 7 possible treatment-related deaths in the ipilimumab-only arm: (two cases of multi-organ failure, two colonic perforations, one case of liver failure, and two cases of respiratory failure).

The research was supported in part by the National Cancer Institute (Cancer Therapy Evaluation Program), Sanofi, and Bristol-Myers Squibb. Dr. Hodi disclosed receiving research funding and a being a consultant or in an advisory role with Bristol-Myers Squibb.

CHICAGO – Combining two approved therapies – GM-CSF and ipilimumab – extended overall survival rates by 35% and resulted in fewer grade 3-5 adverse events when compared with ipilimumab alone in a randomized study of 245 patients with metastatic melanoma.

At 1 year, the overall survival rate in the combination therapy group was 69%, with a median follow-up of nearly 18 months. At 1 year, survival in the ipilimumab-only group was 53% with a median follow-up of nearly 13 months, Dr. F. Stephen Hodi, Jr. reported at the annual meeting of the American Society of Clinical Oncology.

This is the first phase II trial to look at ipilimumab (Yervoy, Bristol-Myers Squibb) and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim (Leukine, Sanofi) in combination in any cancer, said Dr. Hodi, the principal investigator for the trial, which was conducted by the ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group) trial. In this study, ipilimumab was used at a dose of 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg.

"We are waiting for the data to mature in ongoing studies examining the relative efficacy of 3 mg/kg and 10 mg/kg dosing," said Dr. Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston.

The results in the current trial are another indication of the impact that immunotherapy can have for patients with advanced melanoma. Since both GM-CSF and ipilimumab are commercially available, oncologists need to determine the best way to apply these findings in everyday practice. The next step will then be to define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as therapies that target the PD-1 and PD-L1 pathway, he said.

"We have been using GM-CSF in melanoma as a stand-alone therapy," Dr. Lynn M. Schuchter, the C. Willard Robinson Professor of Hematology-Oncology at the University of Pennsylvania, Philadelphia, and an expert on melanoma, said at a press conference where the study results were announced. "It will be interesting to see if payers will cover this (combination treatment)."

Ipilimumab targets CTLA-4, a protein that keeps immune T-cells in an inactive state. GM-CSF is a growth factor commonly used to boost white blood cell counts after chemotherapy or stem cell transplantation.

For this study, 245 patients were randomized to receive ipilimumab plus GM-CSF or ipilimumab alone. All study participants were in otherwise good health, with an ECOG performance status of 0-1 and adequate end-organ function, no autoimmune disease, and no prior use of CTLA-4 blockade or CD137 agonists. All had radiographically measurable metastatic melanoma, but with no CNS metastases, and had received up to one prior treatment over 4 weeks before starting in the trial.

The 123 patients randomized to the combination therapy were given sargramostim at 250 micrograms injected subcutaneously on day 1-14 of a 21 day cycle. For induction therapy, ipilimumab was given at a dose of 10 mg/kg intravenously once every 3 weeks for four cycles as induction therapy and once every 12 weeks as maintenance therapy. The 122 patients randomized to ipilimumab alone received the drug on the same schedule.

In both study arms, tumor shrinkage rates were comparable at 11% and 14%, and progression-free survival was similar at about 3 months. But the overall survival rate was longer in the combination treatment arm. One year after the start of therapy and with a median follow-up of 13.3 months, 69% of patients given the combination therapy and 53% of those who got ipilimumab alone were still alive, for a 35% lower risk of death with the combination therapy (hazard ratio, 0.64; P = .014).

Additionally, the combination treatment was associated with fewer serious side effects, compared with ipilimumab alone. The most significant differences were in lung and gastrointestinal toxicities.

Grade 3-5 adverse events occurred in 45% of patients given the combination therapy and in 57% given ipilimumab alone (p2 = 0.078). There were two possible treatment-related deaths in the combination arm (one colonic perforation and one cardiac arrest) and 7 possible treatment-related deaths in the ipilimumab-only arm: (two cases of multi-organ failure, two colonic perforations, one case of liver failure, and two cases of respiratory failure).

The research was supported in part by the National Cancer Institute (Cancer Therapy Evaluation Program), Sanofi, and Bristol-Myers Squibb. Dr. Hodi disclosed receiving research funding and a being a consultant or in an advisory role with Bristol-Myers Squibb.

CHICAGO – The oral tyrosine kinase inhibitor pazopanib is likely to become a new option in maintenance therapy for advanced ovarian cancer, based on phase III trial results presented at the annual meeting of the American Society of Clinical Oncology.

Among the 940 patients studied, none of whom had disease progression after completing first-line chemotherapy, pazopanib (Votrient) prolonged median progression-free survival by 5.6 months as compared with placebo, reported lead author Dr. Andreas Du Bois, a professor of gynecologic oncology at Kliniken Essen Mitte in Essen, Germany.

IMNG Medical Media

Pazopanib’s safety and tolerability profiles were as expected from previous experience with the drug and its known antiangiogenic activity, consisting mainly of adverse effects such as hypertension, diarrhea, and fatigue.

"Pazopanib maintenance therapy significantly extends time without recurrence and thus increases progression-free survival and delays need for further chemotherapy in ovarian cancer. So it prolongs the time the patient has control over the disease instead of disease having control over the patient," Dr. Du Bois commented in a press briefing.

"This is the first phase III maintenance study demonstrating superior outcome for a targeted therapy in ovarian cancer. Therefore, pazopanib may be a valuable option in the future" for this patient population, he added. "This study will be used for registration purposes, and hopefully we will have this drug available soon."

Dr. Du Bois acknowledged that previous trials have assessed use of bevacizumab (Avastin), another agent having antiangiogenic activity, for maintenance therapy. But bevacizumab was started together with chemotherapy and then continued. "It was not a pure maintenance setting," he said, so it is unclear which component was responsible for benefit.

Additionally, the trial populations differed in residual tumor burden, with 85% of the patients in the pazopanib trial having no evidence of residual disease at the time of enrollment.

Commenting during the press briefing, Dr. Carol Aghajanian, chief of the Gynecologic Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York and an ASCO spokesperson, said that the jury is still out on the optimal targeted agent and the optimal timing of its use in ovarian cancer.

"There has been a lot of discussion in ovarian cancer as to whether the patient should receive these agents as part of their initial treatment, or should you save this benefit for a later time in the course of their disease, at the time of treatment for recurrence or even at the time of treatment for platinum-resistant disease," she said. "But what we do have from the trial presented here by Dr. Du Bois is confirmation that targeting angiogenesis in ovarian cancer is important and effective."

Patients were eligible for the trail, the international intergroup trial AGO-OVAR16 sponsored by GlaxoSmithKline, if they had FIGO stage II to IV ovarian, fallopian tube, or primary peritoneal cancer, had not had progression after resection and completion of at least five cycles of first-line platinum-taxane chemotherapy, and had residual tumors measuring less than 2 cm.

They were randomized evenly to receive 800 mg pazopanib or placebo daily for 24 months.

Pazopanib is a multitargeted tyrosine kinase inhibitor that acts mainly on vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit signaling. It is approved by the Food and Drug Administration for treatment of kidney cancer and soft tissue sarcoma.

Main trial results showed that after a median follow-up of 24.3 months, median progression-free survival was 17.9 months with pazopanib and 12.3 months with placebo (hazard ratio, 0.77, P = .002). The findings were similar in subgroup analyses, according to Dr. Du Bois, who disclosed that he receives honoraria and research funding from GlaxoSmithKline.

An interim analysis of overall survival showed no significant difference between groups, but only a fifth of the patients had died as of the analysis.

Relative to placebo, pazopanib was associated with a higher incidence of serious adverse events (26% vs. 11%), according to the abstract. Three patients in the pazopanib group and one patient in the placebo group had a fatal serious adverse event.

"Predicting tolerability will be subject to further research," Dr. Du Bois noted.

CHICAGO – The oral tyrosine kinase inhibitor pazopanib is likely to become a new option in maintenance therapy for advanced ovarian cancer, based on phase III trial results presented at the annual meeting of the American Society of Clinical Oncology.

Among the 940 patients studied, none of whom had disease progression after completing first-line chemotherapy, pazopanib (Votrient) prolonged median progression-free survival by 5.6 months as compared with placebo, reported lead author Dr. Andreas Du Bois, a professor of gynecologic oncology at Kliniken Essen Mitte in Essen, Germany.

IMNG Medical Media

Pazopanib’s safety and tolerability profiles were as expected from previous experience with the drug and its known antiangiogenic activity, consisting mainly of adverse effects such as hypertension, diarrhea, and fatigue.

"Pazopanib maintenance therapy significantly extends time without recurrence and thus increases progression-free survival and delays need for further chemotherapy in ovarian cancer. So it prolongs the time the patient has control over the disease instead of disease having control over the patient," Dr. Du Bois commented in a press briefing.

"This is the first phase III maintenance study demonstrating superior outcome for a targeted therapy in ovarian cancer. Therefore, pazopanib may be a valuable option in the future" for this patient population, he added. "This study will be used for registration purposes, and hopefully we will have this drug available soon."

Dr. Du Bois acknowledged that previous trials have assessed use of bevacizumab (Avastin), another agent having antiangiogenic activity, for maintenance therapy. But bevacizumab was started together with chemotherapy and then continued. "It was not a pure maintenance setting," he said, so it is unclear which component was responsible for benefit.

Additionally, the trial populations differed in residual tumor burden, with 85% of the patients in the pazopanib trial having no evidence of residual disease at the time of enrollment.

Commenting during the press briefing, Dr. Carol Aghajanian, chief of the Gynecologic Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York and an ASCO spokesperson, said that the jury is still out on the optimal targeted agent and the optimal timing of its use in ovarian cancer.

"There has been a lot of discussion in ovarian cancer as to whether the patient should receive these agents as part of their initial treatment, or should you save this benefit for a later time in the course of their disease, at the time of treatment for recurrence or even at the time of treatment for platinum-resistant disease," she said. "But what we do have from the trial presented here by Dr. Du Bois is confirmation that targeting angiogenesis in ovarian cancer is important and effective."

Patients were eligible for the trail, the international intergroup trial AGO-OVAR16 sponsored by GlaxoSmithKline, if they had FIGO stage II to IV ovarian, fallopian tube, or primary peritoneal cancer, had not had progression after resection and completion of at least five cycles of first-line platinum-taxane chemotherapy, and had residual tumors measuring less than 2 cm.

They were randomized evenly to receive 800 mg pazopanib or placebo daily for 24 months.

Pazopanib is a multitargeted tyrosine kinase inhibitor that acts mainly on vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit signaling. It is approved by the Food and Drug Administration for treatment of kidney cancer and soft tissue sarcoma.

Main trial results showed that after a median follow-up of 24.3 months, median progression-free survival was 17.9 months with pazopanib and 12.3 months with placebo (hazard ratio, 0.77, P = .002). The findings were similar in subgroup analyses, according to Dr. Du Bois, who disclosed that he receives honoraria and research funding from GlaxoSmithKline.

An interim analysis of overall survival showed no significant difference between groups, but only a fifth of the patients had died as of the analysis.

Relative to placebo, pazopanib was associated with a higher incidence of serious adverse events (26% vs. 11%), according to the abstract. Three patients in the pazopanib group and one patient in the placebo group had a fatal serious adverse event.

"Predicting tolerability will be subject to further research," Dr. Du Bois noted.

CHICAGO – The oral tyrosine kinase inhibitor pazopanib is likely to become a new option in maintenance therapy for advanced ovarian cancer, based on phase III trial results presented at the annual meeting of the American Society of Clinical Oncology.

Among the 940 patients studied, none of whom had disease progression after completing first-line chemotherapy, pazopanib (Votrient) prolonged median progression-free survival by 5.6 months as compared with placebo, reported lead author Dr. Andreas Du Bois, a professor of gynecologic oncology at Kliniken Essen Mitte in Essen, Germany.

IMNG Medical Media

Pazopanib’s safety and tolerability profiles were as expected from previous experience with the drug and its known antiangiogenic activity, consisting mainly of adverse effects such as hypertension, diarrhea, and fatigue.

"Pazopanib maintenance therapy significantly extends time without recurrence and thus increases progression-free survival and delays need for further chemotherapy in ovarian cancer. So it prolongs the time the patient has control over the disease instead of disease having control over the patient," Dr. Du Bois commented in a press briefing.

"This is the first phase III maintenance study demonstrating superior outcome for a targeted therapy in ovarian cancer. Therefore, pazopanib may be a valuable option in the future" for this patient population, he added. "This study will be used for registration purposes, and hopefully we will have this drug available soon."

Dr. Du Bois acknowledged that previous trials have assessed use of bevacizumab (Avastin), another agent having antiangiogenic activity, for maintenance therapy. But bevacizumab was started together with chemotherapy and then continued. "It was not a pure maintenance setting," he said, so it is unclear which component was responsible for benefit.

Additionally, the trial populations differed in residual tumor burden, with 85% of the patients in the pazopanib trial having no evidence of residual disease at the time of enrollment.

Commenting during the press briefing, Dr. Carol Aghajanian, chief of the Gynecologic Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York and an ASCO spokesperson, said that the jury is still out on the optimal targeted agent and the optimal timing of its use in ovarian cancer.

"There has been a lot of discussion in ovarian cancer as to whether the patient should receive these agents as part of their initial treatment, or should you save this benefit for a later time in the course of their disease, at the time of treatment for recurrence or even at the time of treatment for platinum-resistant disease," she said. "But what we do have from the trial presented here by Dr. Du Bois is confirmation that targeting angiogenesis in ovarian cancer is important and effective."

Patients were eligible for the trail, the international intergroup trial AGO-OVAR16 sponsored by GlaxoSmithKline, if they had FIGO stage II to IV ovarian, fallopian tube, or primary peritoneal cancer, had not had progression after resection and completion of at least five cycles of first-line platinum-taxane chemotherapy, and had residual tumors measuring less than 2 cm.

They were randomized evenly to receive 800 mg pazopanib or placebo daily for 24 months.

Pazopanib is a multitargeted tyrosine kinase inhibitor that acts mainly on vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit signaling. It is approved by the Food and Drug Administration for treatment of kidney cancer and soft tissue sarcoma.

Main trial results showed that after a median follow-up of 24.3 months, median progression-free survival was 17.9 months with pazopanib and 12.3 months with placebo (hazard ratio, 0.77, P = .002). The findings were similar in subgroup analyses, according to Dr. Du Bois, who disclosed that he receives honoraria and research funding from GlaxoSmithKline.

An interim analysis of overall survival showed no significant difference between groups, but only a fifth of the patients had died as of the analysis.

Relative to placebo, pazopanib was associated with a higher incidence of serious adverse events (26% vs. 11%), according to the abstract. Three patients in the pazopanib group and one patient in the placebo group had a fatal serious adverse event.

"Predicting tolerability will be subject to further research," Dr. Du Bois noted.

CHICAGO – Partners of patients with human papillomavirus-positive oropharyngeal cancer do not appear to be at an increased risk for HPV-related cancers, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Of 88 female partners of persons with HPV-positive oropharyngeal cancers, 4 were found to be positive for HPV infection, and 2 of the 4 were positive for the oncogenic HPV-16 subtype. The prevalence of HPV infection in this sample was 5%, similar to that of women in the general population (3.6%), reported Gypsyamber D’Souza, Ph.D., an epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Md.

None of the male partners in this small pilot study tested positive for oral HPV 16, but the male sample size was too small to draw significant conclusions about the risks of HPV transmission in men, Dr. D’Souza said.

"This is the first study to examine oral HPV prevalence among spouses of HPV-related oropharyngeal cancer patients, and it’s very reassuring that the oral HPV prevalence was similar to that observed in the general population. This suggests that risk of HPV-related cancer remains low among these spouses," she said in a media briefing prior to her presentation.

The study also supports epidemiologic data showing that although HPV infections are common in the general population, the overwhelming majority of people who are infected will spontaneously clear the virus and not get cancer.

"We certainly will need longer follow-up on how HPV infection and co-infection in the partners will affect patients and the development of cancer, but we recognize this as an important breakthrough in the understanding of the biology of oropharyngeal cancer," commented Dr. Gregory Masters, a medical oncologist at the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing.

Dr. Marcia S. Brose, a head and neck surgeon at the Hospital of the University of Pennsylvania in Philadelphia, said that despite the handful of male partners, the study sends an important message to patients and their partners.

"As oncologists, we’re not just in the business of the disease itself; we also have to treat the family members and their concerns. If you’re the spouse of someone who has a communicable disease-related cancer, you’re going to have to make decisions that affect your private life, and it means a lot that someone is doing the research that says you don’t have to worry," she said in an interview.

The study was prompted by concerns frequently expressed by patients with oropharyngeal cancer and their spouses/sexual partners about oral transmission of HPV and increased cancer risk, Dr. D’Souza said.

The investigators enrolled 147 men and 19 women (median age 56) with oropharyngeal cancers, and 94 of their spouses or long-term partners.

Oral rinse and gargle samples were collected from all cases and partners in the study at baseline and 1 year later. The samples were tested for the presence of HPV DNA. Imperfect as it is in sensitivity and specificity for HPV, the test is nonetheless the gold standard for detecting HPV in oral cancers, Dr. D’Souza said.

At the time of diagnosis, 65% of patients tested positive for HPV, and 54% of all patients had HPV 16.

At 1 year, however, following completion of therapy, only 5.6% of patients still tested positive for HPV 16.

Overall, the prevalence of oral HPV among partners was 6.5%, comparable to HPV prevalence among the general population in National Health and Nutrition Examination Survery (NHANES) data from 2009-2010. Among male partners, the prevalence of HPV also was similar to that seen among men in the general population (10.1%), but the small number made it difficult if not impossible to draw meaningful conclusions.

No oral or oropharyngeal cancers were detected in partners in an oral cancer screen, but three patients reported having previous partners with oropharyngeal cancer. In addition, five male patients reported having a partner who developed cervical cancer or a precancerous condition (one current partner and two previous partners had cervical cancers, and two current partners had cervical dysplasia).

The study was supported by the Johns Hopkins Innovation Fund. Dr. D’Souza reported receiving research support from Merck, maker of Gardasil.

CHICAGO – Partners of patients with human papillomavirus-positive oropharyngeal cancer do not appear to be at an increased risk for HPV-related cancers, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Of 88 female partners of persons with HPV-positive oropharyngeal cancers, 4 were found to be positive for HPV infection, and 2 of the 4 were positive for the oncogenic HPV-16 subtype. The prevalence of HPV infection in this sample was 5%, similar to that of women in the general population (3.6%), reported Gypsyamber D’Souza, Ph.D., an epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Md.

None of the male partners in this small pilot study tested positive for oral HPV 16, but the male sample size was too small to draw significant conclusions about the risks of HPV transmission in men, Dr. D’Souza said.

"This is the first study to examine oral HPV prevalence among spouses of HPV-related oropharyngeal cancer patients, and it’s very reassuring that the oral HPV prevalence was similar to that observed in the general population. This suggests that risk of HPV-related cancer remains low among these spouses," she said in a media briefing prior to her presentation.

The study also supports epidemiologic data showing that although HPV infections are common in the general population, the overwhelming majority of people who are infected will spontaneously clear the virus and not get cancer.

"We certainly will need longer follow-up on how HPV infection and co-infection in the partners will affect patients and the development of cancer, but we recognize this as an important breakthrough in the understanding of the biology of oropharyngeal cancer," commented Dr. Gregory Masters, a medical oncologist at the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing.

Dr. Marcia S. Brose, a head and neck surgeon at the Hospital of the University of Pennsylvania in Philadelphia, said that despite the handful of male partners, the study sends an important message to patients and their partners.

"As oncologists, we’re not just in the business of the disease itself; we also have to treat the family members and their concerns. If you’re the spouse of someone who has a communicable disease-related cancer, you’re going to have to make decisions that affect your private life, and it means a lot that someone is doing the research that says you don’t have to worry," she said in an interview.

The study was prompted by concerns frequently expressed by patients with oropharyngeal cancer and their spouses/sexual partners about oral transmission of HPV and increased cancer risk, Dr. D’Souza said.

The investigators enrolled 147 men and 19 women (median age 56) with oropharyngeal cancers, and 94 of their spouses or long-term partners.

Oral rinse and gargle samples were collected from all cases and partners in the study at baseline and 1 year later. The samples were tested for the presence of HPV DNA. Imperfect as it is in sensitivity and specificity for HPV, the test is nonetheless the gold standard for detecting HPV in oral cancers, Dr. D’Souza said.

At the time of diagnosis, 65% of patients tested positive for HPV, and 54% of all patients had HPV 16.

At 1 year, however, following completion of therapy, only 5.6% of patients still tested positive for HPV 16.

Overall, the prevalence of oral HPV among partners was 6.5%, comparable to HPV prevalence among the general population in National Health and Nutrition Examination Survery (NHANES) data from 2009-2010. Among male partners, the prevalence of HPV also was similar to that seen among men in the general population (10.1%), but the small number made it difficult if not impossible to draw meaningful conclusions.

No oral or oropharyngeal cancers were detected in partners in an oral cancer screen, but three patients reported having previous partners with oropharyngeal cancer. In addition, five male patients reported having a partner who developed cervical cancer or a precancerous condition (one current partner and two previous partners had cervical cancers, and two current partners had cervical dysplasia).

The study was supported by the Johns Hopkins Innovation Fund. Dr. D’Souza reported receiving research support from Merck, maker of Gardasil.

CHICAGO – Partners of patients with human papillomavirus-positive oropharyngeal cancer do not appear to be at an increased risk for HPV-related cancers, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Of 88 female partners of persons with HPV-positive oropharyngeal cancers, 4 were found to be positive for HPV infection, and 2 of the 4 were positive for the oncogenic HPV-16 subtype. The prevalence of HPV infection in this sample was 5%, similar to that of women in the general population (3.6%), reported Gypsyamber D’Souza, Ph.D., an epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Md.

None of the male partners in this small pilot study tested positive for oral HPV 16, but the male sample size was too small to draw significant conclusions about the risks of HPV transmission in men, Dr. D’Souza said.

"This is the first study to examine oral HPV prevalence among spouses of HPV-related oropharyngeal cancer patients, and it’s very reassuring that the oral HPV prevalence was similar to that observed in the general population. This suggests that risk of HPV-related cancer remains low among these spouses," she said in a media briefing prior to her presentation.

The study also supports epidemiologic data showing that although HPV infections are common in the general population, the overwhelming majority of people who are infected will spontaneously clear the virus and not get cancer.

"We certainly will need longer follow-up on how HPV infection and co-infection in the partners will affect patients and the development of cancer, but we recognize this as an important breakthrough in the understanding of the biology of oropharyngeal cancer," commented Dr. Gregory Masters, a medical oncologist at the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing.

Dr. Marcia S. Brose, a head and neck surgeon at the Hospital of the University of Pennsylvania in Philadelphia, said that despite the handful of male partners, the study sends an important message to patients and their partners.

"As oncologists, we’re not just in the business of the disease itself; we also have to treat the family members and their concerns. If you’re the spouse of someone who has a communicable disease-related cancer, you’re going to have to make decisions that affect your private life, and it means a lot that someone is doing the research that says you don’t have to worry," she said in an interview.

The study was prompted by concerns frequently expressed by patients with oropharyngeal cancer and their spouses/sexual partners about oral transmission of HPV and increased cancer risk, Dr. D’Souza said.

The investigators enrolled 147 men and 19 women (median age 56) with oropharyngeal cancers, and 94 of their spouses or long-term partners.

Oral rinse and gargle samples were collected from all cases and partners in the study at baseline and 1 year later. The samples were tested for the presence of HPV DNA. Imperfect as it is in sensitivity and specificity for HPV, the test is nonetheless the gold standard for detecting HPV in oral cancers, Dr. D’Souza said.

At the time of diagnosis, 65% of patients tested positive for HPV, and 54% of all patients had HPV 16.

At 1 year, however, following completion of therapy, only 5.6% of patients still tested positive for HPV 16.

Overall, the prevalence of oral HPV among partners was 6.5%, comparable to HPV prevalence among the general population in National Health and Nutrition Examination Survery (NHANES) data from 2009-2010. Among male partners, the prevalence of HPV also was similar to that seen among men in the general population (10.1%), but the small number made it difficult if not impossible to draw meaningful conclusions.

No oral or oropharyngeal cancers were detected in partners in an oral cancer screen, but three patients reported having previous partners with oropharyngeal cancer. In addition, five male patients reported having a partner who developed cervical cancer or a precancerous condition (one current partner and two previous partners had cervical cancers, and two current partners had cervical dysplasia).

The study was supported by the Johns Hopkins Innovation Fund. Dr. D’Souza reported receiving research support from Merck, maker of Gardasil.

CHICAGO – Pairing cetuximab with first-line FOLFIRI chemotherapy significantly extended overall survival by roughly 4 months over bevacizumab plus FOLFIRI among patients with KRAS wild-type metastatic colorectal cancer in the phase III FIRE-3 trial.

Patients in the cetuximab (Erbitux) and bevacizumab (Avastin) arms had similar times to disease progression of 10 and 10.3 months, respectively (Hazard ratio, 1.06; P = .54), but those given cetuximab lived for 28.7 months vs. 25 months with bevacizumab (HR, 0.77; P = .017).

The German AIO (Arbeitsgemeinschaft In-ternistische Onkologie) study group trial is the first to directly compare the two approved targeted agents with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.

"Based on our findings, we believe that a substantial gain in survival can be achieved when doctors offer cetuximab-based treatment as first-line to their patients with KRAS wild-type metastatic colorectal cancer," lead author Dr. Volker Heinemann said in a press briefing at the annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented.

FIRE-3 was a negative trial, however, as the primary end point of objective response rate was statistically similar between the cetuximab and bevacizumab arms at 62% and 57% in an intent-to-treat analysis of all 592 patients (odds ratio, 1.18; P = .18). Response was significantly greater with cetuximab though among the 526 patients assessable for efficacy (72.2% vs. 63.1%; OR, 1.52; P = .17), said Dr. Heinemann, professor of medical oncology at the University of Munich.

The take-home message is that patients with metastatic colorectal cancer have options, but the mixed results also raise questions about the influence of subsequent therapies on overall survival, Dr. Richard Goldberg, physician-in-chief at The Ohio State University’s Comprehensive Cancer Center and an ASCO spokesperson, said at the briefing.

"Really all of the different lines of therapy contributed to this outcome and I would challenge the investigators from the AIO to go back and study their data -- study the second, third and fourth-line treatments that their patients had and help explain this finding, which does seem a bit anomalous," he said.

Dr. Heinemann responded that these data will be presented at a forthcoming meeting in Barcelona, and that data suggest cetuximab-based therapy causes deeper tumor shrinkage than bevacizumab. About 60% of all patients received second-line therapy and about 40% crossed over to the other study arm, he added.

The survival benefit is impressive and will reinforce cetuximab and FOLFIRI in those already using the combination, but is unlikely to result in a profound shift in prescribing habits away from bevacizumab and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy, the dominant combination in the United States, Dr. Al B. Benson III, said in an interview. Instead, many clinicians are awaiting results from the North American intergroup phase III C80405 trial comparing cetuximab with bevacizumab in some patients on FOLFIRI, but the majority on FOLFOX.

"One of the problems in the U.S. with cetuximab is that many patients really do not want to be exposed to the risk of rash; so, what we’ve found, is that people would rather postpone that decision to receive cetuximab if they’re wild-type," said Dr. Benson, professor of hematology/oncology and associate director for clinical investigations at the Robert Lurie Comprehensive Cancer Center of Northwestern University in Chicago.

Dr. Goldberg agreed that it’s doubtful FIRE-3 will change U.S. practice, and said the 80405 trial investigators have petitioned to have the data released ahead of its expected timeline of next year.

"We’re hoping that the data monitoring committee will respond to the uncertainty that this presentation raises and if there is no compelling reason to keep the data blinded, release the data for public scrutiny sometime this year," he said in an interview.

FOLFOX and FOLFIRI are each recommended first-line treatments in the recently updated 2013 National Comprehensive Cancer Network (NCCN) guidelines for metastatic colon cancer, with the addition of a biologic agent optional. If patients receive a bevacizumab-containing regimen first line, the guidelines now recommend that bevacizumab continuation with a different chemotherapy backbone after progression.

Dr. Benson, who helped pen the 2013 NCCN update and is an 80405 trial investigator, said that subsequent therapies, as well as dose reductions and treatment duration, will influence interpretation of the FIRE-3 survival data.

FIRE-3 randomized 592 patients with wild-type tumors to FOLFIRI every 2 weeks plus cetuximab 400 mg/m2 on day 1, followed by 250 mg/m2 weekly, or bevacizumab 5 mg/kg every 2 weeks. An ECOG performance status of 0-1 was present in 98% of patients, 66% were male, and their median age was 64 years.

The trial initially recruited 735 patients independent of KRAS status, but was amended to include only KRAS wild-type tumors after it became known that cetuximab was not active in these patients. At the ASCO 2011 meeting, Dr. Heinemann reported no difference in efficacy or survival between the two strategies in the subgroup of patients with KRAS-mutated tumors.

Among patients with wild-type tumors, the median treatment duration was shorter with cetuximab at 4.7 months vs. 5.3 months with bevacizumab. This is not surprising given the potential for skin issues with cetuximab, but that the toxicity profiles were manageable for both combinations, he said in an interview.

Dr. Heinemann reported honoraria, other remuneration and research funding from the study sponsor, Merck, and honoraria and other remuneration from Roche. Several of his coauthors reported honoraria, other remuneration, and research funding from Merck. Merck distributes cetuximab outside of the United States.

Heinemann, V., et al. "Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRIE plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0303 (FIRE-3)." LBA3506.

[email protected]

CHICAGO – Pairing cetuximab with first-line FOLFIRI chemotherapy significantly extended overall survival by roughly 4 months over bevacizumab plus FOLFIRI among patients with KRAS wild-type metastatic colorectal cancer in the phase III FIRE-3 trial.

Patients in the cetuximab (Erbitux) and bevacizumab (Avastin) arms had similar times to disease progression of 10 and 10.3 months, respectively (Hazard ratio, 1.06; P = .54), but those given cetuximab lived for 28.7 months vs. 25 months with bevacizumab (HR, 0.77; P = .017).

The German AIO (Arbeitsgemeinschaft In-ternistische Onkologie) study group trial is the first to directly compare the two approved targeted agents with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.

"Based on our findings, we believe that a substantial gain in survival can be achieved when doctors offer cetuximab-based treatment as first-line to their patients with KRAS wild-type metastatic colorectal cancer," lead author Dr. Volker Heinemann said in a press briefing at the annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented.

FIRE-3 was a negative trial, however, as the primary end point of objective response rate was statistically similar between the cetuximab and bevacizumab arms at 62% and 57% in an intent-to-treat analysis of all 592 patients (odds ratio, 1.18; P = .18). Response was significantly greater with cetuximab though among the 526 patients assessable for efficacy (72.2% vs. 63.1%; OR, 1.52; P = .17), said Dr. Heinemann, professor of medical oncology at the University of Munich.

The take-home message is that patients with metastatic colorectal cancer have options, but the mixed results also raise questions about the influence of subsequent therapies on overall survival, Dr. Richard Goldberg, physician-in-chief at The Ohio State University’s Comprehensive Cancer Center and an ASCO spokesperson, said at the briefing.

"Really all of the different lines of therapy contributed to this outcome and I would challenge the investigators from the AIO to go back and study their data -- study the second, third and fourth-line treatments that their patients had and help explain this finding, which does seem a bit anomalous," he said.

Dr. Heinemann responded that these data will be presented at a forthcoming meeting in Barcelona, and that data suggest cetuximab-based therapy causes deeper tumor shrinkage than bevacizumab. About 60% of all patients received second-line therapy and about 40% crossed over to the other study arm, he added.

The survival benefit is impressive and will reinforce cetuximab and FOLFIRI in those already using the combination, but is unlikely to result in a profound shift in prescribing habits away from bevacizumab and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy, the dominant combination in the United States, Dr. Al B. Benson III, said in an interview. Instead, many clinicians are awaiting results from the North American intergroup phase III C80405 trial comparing cetuximab with bevacizumab in some patients on FOLFIRI, but the majority on FOLFOX.

"One of the problems in the U.S. with cetuximab is that many patients really do not want to be exposed to the risk of rash; so, what we’ve found, is that people would rather postpone that decision to receive cetuximab if they’re wild-type," said Dr. Benson, professor of hematology/oncology and associate director for clinical investigations at the Robert Lurie Comprehensive Cancer Center of Northwestern University in Chicago.

Dr. Goldberg agreed that it’s doubtful FIRE-3 will change U.S. practice, and said the 80405 trial investigators have petitioned to have the data released ahead of its expected timeline of next year.

"We’re hoping that the data monitoring committee will respond to the uncertainty that this presentation raises and if there is no compelling reason to keep the data blinded, release the data for public scrutiny sometime this year," he said in an interview.

FOLFOX and FOLFIRI are each recommended first-line treatments in the recently updated 2013 National Comprehensive Cancer Network (NCCN) guidelines for metastatic colon cancer, with the addition of a biologic agent optional. If patients receive a bevacizumab-containing regimen first line, the guidelines now recommend that bevacizumab continuation with a different chemotherapy backbone after progression.

Dr. Benson, who helped pen the 2013 NCCN update and is an 80405 trial investigator, said that subsequent therapies, as well as dose reductions and treatment duration, will influence interpretation of the FIRE-3 survival data.

FIRE-3 randomized 592 patients with wild-type tumors to FOLFIRI every 2 weeks plus cetuximab 400 mg/m2 on day 1, followed by 250 mg/m2 weekly, or bevacizumab 5 mg/kg every 2 weeks. An ECOG performance status of 0-1 was present in 98% of patients, 66% were male, and their median age was 64 years.

The trial initially recruited 735 patients independent of KRAS status, but was amended to include only KRAS wild-type tumors after it became known that cetuximab was not active in these patients. At the ASCO 2011 meeting, Dr. Heinemann reported no difference in efficacy or survival between the two strategies in the subgroup of patients with KRAS-mutated tumors.

Among patients with wild-type tumors, the median treatment duration was shorter with cetuximab at 4.7 months vs. 5.3 months with bevacizumab. This is not surprising given the potential for skin issues with cetuximab, but that the toxicity profiles were manageable for both combinations, he said in an interview.

Dr. Heinemann reported honoraria, other remuneration and research funding from the study sponsor, Merck, and honoraria and other remuneration from Roche. Several of his coauthors reported honoraria, other remuneration, and research funding from Merck. Merck distributes cetuximab outside of the United States.

Heinemann, V., et al. "Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRIE plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0303 (FIRE-3)." LBA3506.

[email protected]

CHICAGO – Pairing cetuximab with first-line FOLFIRI chemotherapy significantly extended overall survival by roughly 4 months over bevacizumab plus FOLFIRI among patients with KRAS wild-type metastatic colorectal cancer in the phase III FIRE-3 trial.

Patients in the cetuximab (Erbitux) and bevacizumab (Avastin) arms had similar times to disease progression of 10 and 10.3 months, respectively (Hazard ratio, 1.06; P = .54), but those given cetuximab lived for 28.7 months vs. 25 months with bevacizumab (HR, 0.77; P = .017).

The German AIO (Arbeitsgemeinschaft In-ternistische Onkologie) study group trial is the first to directly compare the two approved targeted agents with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.

"Based on our findings, we believe that a substantial gain in survival can be achieved when doctors offer cetuximab-based treatment as first-line to their patients with KRAS wild-type metastatic colorectal cancer," lead author Dr. Volker Heinemann said in a press briefing at the annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented.

FIRE-3 was a negative trial, however, as the primary end point of objective response rate was statistically similar between the cetuximab and bevacizumab arms at 62% and 57% in an intent-to-treat analysis of all 592 patients (odds ratio, 1.18; P = .18). Response was significantly greater with cetuximab though among the 526 patients assessable for efficacy (72.2% vs. 63.1%; OR, 1.52; P = .17), said Dr. Heinemann, professor of medical oncology at the University of Munich.

The take-home message is that patients with metastatic colorectal cancer have options, but the mixed results also raise questions about the influence of subsequent therapies on overall survival, Dr. Richard Goldberg, physician-in-chief at The Ohio State University’s Comprehensive Cancer Center and an ASCO spokesperson, said at the briefing.

"Really all of the different lines of therapy contributed to this outcome and I would challenge the investigators from the AIO to go back and study their data -- study the second, third and fourth-line treatments that their patients had and help explain this finding, which does seem a bit anomalous," he said.

Dr. Heinemann responded that these data will be presented at a forthcoming meeting in Barcelona, and that data suggest cetuximab-based therapy causes deeper tumor shrinkage than bevacizumab. About 60% of all patients received second-line therapy and about 40% crossed over to the other study arm, he added.

The survival benefit is impressive and will reinforce cetuximab and FOLFIRI in those already using the combination, but is unlikely to result in a profound shift in prescribing habits away from bevacizumab and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy, the dominant combination in the United States, Dr. Al B. Benson III, said in an interview. Instead, many clinicians are awaiting results from the North American intergroup phase III C80405 trial comparing cetuximab with bevacizumab in some patients on FOLFIRI, but the majority on FOLFOX.

"One of the problems in the U.S. with cetuximab is that many patients really do not want to be exposed to the risk of rash; so, what we’ve found, is that people would rather postpone that decision to receive cetuximab if they’re wild-type," said Dr. Benson, professor of hematology/oncology and associate director for clinical investigations at the Robert Lurie Comprehensive Cancer Center of Northwestern University in Chicago.

Dr. Goldberg agreed that it’s doubtful FIRE-3 will change U.S. practice, and said the 80405 trial investigators have petitioned to have the data released ahead of its expected timeline of next year.

"We’re hoping that the data monitoring committee will respond to the uncertainty that this presentation raises and if there is no compelling reason to keep the data blinded, release the data for public scrutiny sometime this year," he said in an interview.

FOLFOX and FOLFIRI are each recommended first-line treatments in the recently updated 2013 National Comprehensive Cancer Network (NCCN) guidelines for metastatic colon cancer, with the addition of a biologic agent optional. If patients receive a bevacizumab-containing regimen first line, the guidelines now recommend that bevacizumab continuation with a different chemotherapy backbone after progression.

Dr. Benson, who helped pen the 2013 NCCN update and is an 80405 trial investigator, said that subsequent therapies, as well as dose reductions and treatment duration, will influence interpretation of the FIRE-3 survival data.

FIRE-3 randomized 592 patients with wild-type tumors to FOLFIRI every 2 weeks plus cetuximab 400 mg/m2 on day 1, followed by 250 mg/m2 weekly, or bevacizumab 5 mg/kg every 2 weeks. An ECOG performance status of 0-1 was present in 98% of patients, 66% were male, and their median age was 64 years.

The trial initially recruited 735 patients independent of KRAS status, but was amended to include only KRAS wild-type tumors after it became known that cetuximab was not active in these patients. At the ASCO 2011 meeting, Dr. Heinemann reported no difference in efficacy or survival between the two strategies in the subgroup of patients with KRAS-mutated tumors.

Among patients with wild-type tumors, the median treatment duration was shorter with cetuximab at 4.7 months vs. 5.3 months with bevacizumab. This is not surprising given the potential for skin issues with cetuximab, but that the toxicity profiles were manageable for both combinations, he said in an interview.

Dr. Heinemann reported honoraria, other remuneration and research funding from the study sponsor, Merck, and honoraria and other remuneration from Roche. Several of his coauthors reported honoraria, other remuneration, and research funding from Merck. Merck distributes cetuximab outside of the United States.

Heinemann, V., et al. "Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRIE plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0303 (FIRE-3)." LBA3506.

[email protected]

A first-in-class investigative drug targeted to the P13K pathway was active in a phase-I study of 54 heavily pretreated patients with chronic lymphocytic leukemia.

The new oral drug, called idelalisib (GS-1101), selectively blocks PI3K-delta and produced "rapid and long-lasting tumor shrinkage in half (2 complete responses and 28 partial responses) of the patients treated with single-agent therapy, stalling disease progression for 17 months, on average. The activity of the drug is noteworthy, given that the patients had already undergone an average of five prior therapies," Dr. Jennifer R. Brown reported during a press conference sponsored by the American Society of Clinical Oncology that featured key research to be presented at its upcoming annual meeting.

Most symptomatic patients with chronic lymphocytic leukemia (CLL) experience a relapse at some point after initial chemoimmunotherapy. About 20% of them relapse within 6 months or do not respond to initial treatment and need better treatments, noted Dr. Brown of the Dana-Farber Cancer Institute, Boston.

"While this research is still early and ongoing, we hope this drug, along with others like it, will lead to prolonged survival and eventually help turn CLL into a condition that is treated like high blood pressure, where a patient can take a couple of pills every day. In the shorter term, these drugs may also provide an alternative to chemotherapy in elderly patients who tend not to tolerate chemotherapy well," she said.

Phase-III trials of idelalisib are under way with a 150-mg, twice-daily dosing schedule, Dr. Brown said.

She reported that the current trial included 54 patients (9 women and 45 men, ranging from 37 to 82 years of age) with bulky lymphadenopathy (80%), refractory disease (70%), and a median of 5 prior treatments (range, 2-14). They were treated continuously with single-agent oral idelalisib at doses ranging from 50 to 350 mg/dose on either a once- or twice-daily schedule for an average duration of 9 months (range, 0-42).

The objective response rate was 56% (2 complete responses and 28 partial responses). At least a 50% reduction in the nodal SPD (sum of the products of the greatest perpendicular diameters) was seen in 44 (81%). Splenomegaly resolved in 14 of 20 affected patients (70%) and cytopenias normalized in 17 of 25 (68%) with anemia, 27 of 34 (79%) with thrombocytopenia, and all 15 patients with neutropenia (100%), Dr. Brown reported.

The most common adverse events of grade 3 or higher, independent of causality, included fatigue (2%), diarrhea (6%), pyrexia (4%), pneumonia (19%), and ALT/AST elevation (2%). Treatment was discontinued because of adverse events in 15% (7% potentially treatment related). There were no dose-limiting toxicities.

The research was supported by Gilead Sciences.

[email protected]

On Twitter @maryjodales

A first-in-class investigative drug targeted to the P13K pathway was active in a phase-I study of 54 heavily pretreated patients with chronic lymphocytic leukemia.

The new oral drug, called idelalisib (GS-1101), selectively blocks PI3K-delta and produced "rapid and long-lasting tumor shrinkage in half (2 complete responses and 28 partial responses) of the patients treated with single-agent therapy, stalling disease progression for 17 months, on average. The activity of the drug is noteworthy, given that the patients had already undergone an average of five prior therapies," Dr. Jennifer R. Brown reported during a press conference sponsored by the American Society of Clinical Oncology that featured key research to be presented at its upcoming annual meeting.

Most symptomatic patients with chronic lymphocytic leukemia (CLL) experience a relapse at some point after initial chemoimmunotherapy. About 20% of them relapse within 6 months or do not respond to initial treatment and need better treatments, noted Dr. Brown of the Dana-Farber Cancer Institute, Boston.

"While this research is still early and ongoing, we hope this drug, along with others like it, will lead to prolonged survival and eventually help turn CLL into a condition that is treated like high blood pressure, where a patient can take a couple of pills every day. In the shorter term, these drugs may also provide an alternative to chemotherapy in elderly patients who tend not to tolerate chemotherapy well," she said.

Phase-III trials of idelalisib are under way with a 150-mg, twice-daily dosing schedule, Dr. Brown said.

She reported that the current trial included 54 patients (9 women and 45 men, ranging from 37 to 82 years of age) with bulky lymphadenopathy (80%), refractory disease (70%), and a median of 5 prior treatments (range, 2-14). They were treated continuously with single-agent oral idelalisib at doses ranging from 50 to 350 mg/dose on either a once- or twice-daily schedule for an average duration of 9 months (range, 0-42).

The objective response rate was 56% (2 complete responses and 28 partial responses). At least a 50% reduction in the nodal SPD (sum of the products of the greatest perpendicular diameters) was seen in 44 (81%). Splenomegaly resolved in 14 of 20 affected patients (70%) and cytopenias normalized in 17 of 25 (68%) with anemia, 27 of 34 (79%) with thrombocytopenia, and all 15 patients with neutropenia (100%), Dr. Brown reported.

The most common adverse events of grade 3 or higher, independent of causality, included fatigue (2%), diarrhea (6%), pyrexia (4%), pneumonia (19%), and ALT/AST elevation (2%). Treatment was discontinued because of adverse events in 15% (7% potentially treatment related). There were no dose-limiting toxicities.

The research was supported by Gilead Sciences.

[email protected]

On Twitter @maryjodales

A first-in-class investigative drug targeted to the P13K pathway was active in a phase-I study of 54 heavily pretreated patients with chronic lymphocytic leukemia.

The new oral drug, called idelalisib (GS-1101), selectively blocks PI3K-delta and produced "rapid and long-lasting tumor shrinkage in half (2 complete responses and 28 partial responses) of the patients treated with single-agent therapy, stalling disease progression for 17 months, on average. The activity of the drug is noteworthy, given that the patients had already undergone an average of five prior therapies," Dr. Jennifer R. Brown reported during a press conference sponsored by the American Society of Clinical Oncology that featured key research to be presented at its upcoming annual meeting.

Most symptomatic patients with chronic lymphocytic leukemia (CLL) experience a relapse at some point after initial chemoimmunotherapy. About 20% of them relapse within 6 months or do not respond to initial treatment and need better treatments, noted Dr. Brown of the Dana-Farber Cancer Institute, Boston.

"While this research is still early and ongoing, we hope this drug, along with others like it, will lead to prolonged survival and eventually help turn CLL into a condition that is treated like high blood pressure, where a patient can take a couple of pills every day. In the shorter term, these drugs may also provide an alternative to chemotherapy in elderly patients who tend not to tolerate chemotherapy well," she said.

Phase-III trials of idelalisib are under way with a 150-mg, twice-daily dosing schedule, Dr. Brown said.

She reported that the current trial included 54 patients (9 women and 45 men, ranging from 37 to 82 years of age) with bulky lymphadenopathy (80%), refractory disease (70%), and a median of 5 prior treatments (range, 2-14). They were treated continuously with single-agent oral idelalisib at doses ranging from 50 to 350 mg/dose on either a once- or twice-daily schedule for an average duration of 9 months (range, 0-42).

The objective response rate was 56% (2 complete responses and 28 partial responses). At least a 50% reduction in the nodal SPD (sum of the products of the greatest perpendicular diameters) was seen in 44 (81%). Splenomegaly resolved in 14 of 20 affected patients (70%) and cytopenias normalized in 17 of 25 (68%) with anemia, 27 of 34 (79%) with thrombocytopenia, and all 15 patients with neutropenia (100%), Dr. Brown reported.

The most common adverse events of grade 3 or higher, independent of causality, included fatigue (2%), diarrhea (6%), pyrexia (4%), pneumonia (19%), and ALT/AST elevation (2%). Treatment was discontinued because of adverse events in 15% (7% potentially treatment related). There were no dose-limiting toxicities.

The research was supported by Gilead Sciences.

[email protected]

On Twitter @maryjodales

Routine surveillance with computed tomography scans add little to the surveillance of patients in remission from diffuse large B-cell lymphoma, a large epidemiologic study shows.

Planned CT scans detected diffuse large B-cell lymphoma (DLBCL) relapse prior to clinical symptoms or signs in only 8 of the 537 (1.5%) patients who entered post-treatment surveillance.

The vast majority (62%) of relapses were detected by patients who contacted their provider because of symptoms before their planned visit, according to lead author Dr. Carrie A. Thompson, a hematologist at Mayo Clinic, Rochester, Minn.

"The take-home point is that the majority of relapses occur outside of planned follow-up visits and are accompanied by symptoms, exam or lab abnormalities," she said. "In this study, scheduled scans added little to patients who had none of the above."

She noted that DLBCL patients in remission in the United States undergo a median of 2.5 CT or positron emission tomography scans per year during surveillance, according to a recent study (Leuk. Lymphoma 2012;53:1113-6). Moreover, only 4.2% of patients in the series received no imaging.

DLBCL is the most common form of non-Hodgkin lymphoma, with about 20,000 new cases diagnosed each year in the United States. It is an aggressive lymphoma, but is potentially curable with chemotherapy. Post-treatment surveillance is necessary, but the optimal strategy is unclear, she explained at a press briefing highlighting studies at the upcoming American Society of Clinical Oncology (ASCO) meeting.

The National Comprehensive Cancer Network recommends that patients be evaluated every 3-6 months for 5 years, with a CT scan no more often than every 6 months for the first 2 years after treatment completion, and then as clinically indicated.

The investigators enrolled 644 patients with biopsy-proven DLBCL treated with anthracycline-based chemotherapy in the University of Iowa/Mayo Clinic SPORE (Specialized Programs of Research Excellence) Molecular Epidemiology Resource, a prospective cohort of newly diagnosed lymphoma patients. Their median age was 63 years (range 18-92), 54% were men, and median follow-up was 59 months (range 8-116). Overall disease management and follow-up was at the discretion of their hematologist/oncologist.

Of the 537 patients who entered surveillance, 109 (20%) relapsed. Medical records were available in 100 patients.

Of the 38 patients with relapse detected at a planned visit, 26 had an abnormal physical exam and/or labs, Dr. Thompson said. The remaining 12 patients were asymptomatic, and their relapses were detected solely by CT scan. "It is noteworthy that four of these relapses turned out to be another form of lymphoma, not diffuse B-cell lymphoma," she added.

Although the data show that scans detected relapses in a minority of patients, it is too early to say definitively how many scans are needed or how often they should be done, Dr. Thompson told reporters.

"I think it’s very interesting, it’s very provocative, but what I would like to see is a randomized study to determine just what the best surveillance strategy is in this disease," she said. "Is it scheduled scans, as we currently do, or clinically directed scans, where we only do a scan when a patient has new symptoms or abnormal findings on clinical exam or laboratory findings?"

Incoming ASCO president Clifford Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, observed that the low 1.5% rate of CT-detected relapse mirrors what has been observed in other common malignancies.

"These findings will help physicians develop guidelines for following patients who are in remission from DLBCL and will spare patients from the costs and excessive radiation exposure of unnecessary CT scans, not to mention the impact of false-positive findings on such scans," Dr. Hudis said.

Dr. Thomson reported having no financial disclosures.

[email protected]

Routine surveillance with computed tomography scans add little to the surveillance of patients in remission from diffuse large B-cell lymphoma, a large epidemiologic study shows.

Planned CT scans detected diffuse large B-cell lymphoma (DLBCL) relapse prior to clinical symptoms or signs in only 8 of the 537 (1.5%) patients who entered post-treatment surveillance.

The vast majority (62%) of relapses were detected by patients who contacted their provider because of symptoms before their planned visit, according to lead author Dr. Carrie A. Thompson, a hematologist at Mayo Clinic, Rochester, Minn.

"The take-home point is that the majority of relapses occur outside of planned follow-up visits and are accompanied by symptoms, exam or lab abnormalities," she said. "In this study, scheduled scans added little to patients who had none of the above."

She noted that DLBCL patients in remission in the United States undergo a median of 2.5 CT or positron emission tomography scans per year during surveillance, according to a recent study (Leuk. Lymphoma 2012;53:1113-6). Moreover, only 4.2% of patients in the series received no imaging.

DLBCL is the most common form of non-Hodgkin lymphoma, with about 20,000 new cases diagnosed each year in the United States. It is an aggressive lymphoma, but is potentially curable with chemotherapy. Post-treatment surveillance is necessary, but the optimal strategy is unclear, she explained at a press briefing highlighting studies at the upcoming American Society of Clinical Oncology (ASCO) meeting.

The National Comprehensive Cancer Network recommends that patients be evaluated every 3-6 months for 5 years, with a CT scan no more often than every 6 months for the first 2 years after treatment completion, and then as clinically indicated.

The investigators enrolled 644 patients with biopsy-proven DLBCL treated with anthracycline-based chemotherapy in the University of Iowa/Mayo Clinic SPORE (Specialized Programs of Research Excellence) Molecular Epidemiology Resource, a prospective cohort of newly diagnosed lymphoma patients. Their median age was 63 years (range 18-92), 54% were men, and median follow-up was 59 months (range 8-116). Overall disease management and follow-up was at the discretion of their hematologist/oncologist.

Of the 537 patients who entered surveillance, 109 (20%) relapsed. Medical records were available in 100 patients.

Of the 38 patients with relapse detected at a planned visit, 26 had an abnormal physical exam and/or labs, Dr. Thompson said. The remaining 12 patients were asymptomatic, and their relapses were detected solely by CT scan. "It is noteworthy that four of these relapses turned out to be another form of lymphoma, not diffuse B-cell lymphoma," she added.

Although the data show that scans detected relapses in a minority of patients, it is too early to say definitively how many scans are needed or how often they should be done, Dr. Thompson told reporters.

"I think it’s very interesting, it’s very provocative, but what I would like to see is a randomized study to determine just what the best surveillance strategy is in this disease," she said. "Is it scheduled scans, as we currently do, or clinically directed scans, where we only do a scan when a patient has new symptoms or abnormal findings on clinical exam or laboratory findings?"

Incoming ASCO president Clifford Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, observed that the low 1.5% rate of CT-detected relapse mirrors what has been observed in other common malignancies.

"These findings will help physicians develop guidelines for following patients who are in remission from DLBCL and will spare patients from the costs and excessive radiation exposure of unnecessary CT scans, not to mention the impact of false-positive findings on such scans," Dr. Hudis said.

Dr. Thomson reported having no financial disclosures.

[email protected]

Routine surveillance with computed tomography scans add little to the surveillance of patients in remission from diffuse large B-cell lymphoma, a large epidemiologic study shows.

Planned CT scans detected diffuse large B-cell lymphoma (DLBCL) relapse prior to clinical symptoms or signs in only 8 of the 537 (1.5%) patients who entered post-treatment surveillance.

The vast majority (62%) of relapses were detected by patients who contacted their provider because of symptoms before their planned visit, according to lead author Dr. Carrie A. Thompson, a hematologist at Mayo Clinic, Rochester, Minn.

"The take-home point is that the majority of relapses occur outside of planned follow-up visits and are accompanied by symptoms, exam or lab abnormalities," she said. "In this study, scheduled scans added little to patients who had none of the above."

She noted that DLBCL patients in remission in the United States undergo a median of 2.5 CT or positron emission tomography scans per year during surveillance, according to a recent study (Leuk. Lymphoma 2012;53:1113-6). Moreover, only 4.2% of patients in the series received no imaging.

DLBCL is the most common form of non-Hodgkin lymphoma, with about 20,000 new cases diagnosed each year in the United States. It is an aggressive lymphoma, but is potentially curable with chemotherapy. Post-treatment surveillance is necessary, but the optimal strategy is unclear, she explained at a press briefing highlighting studies at the upcoming American Society of Clinical Oncology (ASCO) meeting.

The National Comprehensive Cancer Network recommends that patients be evaluated every 3-6 months for 5 years, with a CT scan no more often than every 6 months for the first 2 years after treatment completion, and then as clinically indicated.

The investigators enrolled 644 patients with biopsy-proven DLBCL treated with anthracycline-based chemotherapy in the University of Iowa/Mayo Clinic SPORE (Specialized Programs of Research Excellence) Molecular Epidemiology Resource, a prospective cohort of newly diagnosed lymphoma patients. Their median age was 63 years (range 18-92), 54% were men, and median follow-up was 59 months (range 8-116). Overall disease management and follow-up was at the discretion of their hematologist/oncologist.

Of the 537 patients who entered surveillance, 109 (20%) relapsed. Medical records were available in 100 patients.

Of the 38 patients with relapse detected at a planned visit, 26 had an abnormal physical exam and/or labs, Dr. Thompson said. The remaining 12 patients were asymptomatic, and their relapses were detected solely by CT scan. "It is noteworthy that four of these relapses turned out to be another form of lymphoma, not diffuse B-cell lymphoma," she added.

Although the data show that scans detected relapses in a minority of patients, it is too early to say definitively how many scans are needed or how often they should be done, Dr. Thompson told reporters.

"I think it’s very interesting, it’s very provocative, but what I would like to see is a randomized study to determine just what the best surveillance strategy is in this disease," she said. "Is it scheduled scans, as we currently do, or clinically directed scans, where we only do a scan when a patient has new symptoms or abnormal findings on clinical exam or laboratory findings?"

Incoming ASCO president Clifford Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, observed that the low 1.5% rate of CT-detected relapse mirrors what has been observed in other common malignancies.

"These findings will help physicians develop guidelines for following patients who are in remission from DLBCL and will spare patients from the costs and excessive radiation exposure of unnecessary CT scans, not to mention the impact of false-positive findings on such scans," Dr. Hudis said.

Dr. Thomson reported having no financial disclosures.

[email protected]