2013 ASCO Annual Meeting

Surveillance is sufficient for most men with stage I seminoma after successful orchiectomy, according to the findings of the largest study ever performed to address the issue.

The 1,822 men followed only with surveillance in Denmark had an excellent disease-specific survival of 99.5%, Dr. Mette Saskø Mortensen said at a press briefing highlighting research to be presented at the upcoming American Society of Clinical Oncology annual meeting. Only 10 men died of testicular cancer or treatment-related causes during a median follow-up of 15.4 years.

This finding means that for every 1,000 men followed by a surveillance program, only 4 will die within 10 years, said incoming ASCO president Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York.

He described the study as one of several recent reminders that sometimes "less is more" in patient care and noted that opting for surveillance spares patients from the harmful side effects of chemotherapy and radiation without diminishing their chances for long-term survival.

Seminoma is a relatively rare cancer, but it is the most common solid tumor among young men. Initial treatment is typically orchiectomy, but no standard postoperative management strategy has been established. The current results will likely accelerate the trend toward surveillance in the United States, where roughly 50% of men undergo either radiotherapy or chemotherapy with carboplatin after surgery.

Overall, 355 (19.5%) of the 1,822 men experienced a relapse during surveillance, said Dr. Mortensen, a PhD student in the oncology department at Copenhagen University Hospital.

The median time to relapse was 13.7 months, with the majority of patients (72.4%) relapsing within the first 2 years. Another 20.3% relapsed within years 2-5 and 7.3% after 5 years.

"With only 19.5% of the patients relapsing, the surveillance strategy spares the remaining 80% of patients from unnecessary treatment after orchiectomy," Dr. Mortensen said. "Surveillance is a safe strategy for stage I seminoma patients."

Surveillance has been the main follow-up strategy for stage I seminoma in Denmark since 1984, and consists of 5 years of scheduled clinical visits, computed tomography scans/chest x-rays, and blood measurements of tumor markers. Men in the analysis were diagnosed from 1984 to 2008, and their data were collected up to December 2012 from patient files and linked national registries.

As observed in other smaller studies, the risk for relapse was increased with elevated human chorionic gonadotropin levels of more than 200 IU/L, vascular invasion, and tumors larger than 4 cm, Dr. Mortensen said.

The study was supported in part by the Danish Cancer Society, Danish Research Foundation and the Preben and Anna Simonsen Foundation. Dr. Mortensen reported having no financial disclosures.

pwendling@frontlinemedcom.com

Surveillance is sufficient for most men with stage I seminoma after successful orchiectomy, according to the findings of the largest study ever performed to address the issue.

The 1,822 men followed only with surveillance in Denmark had an excellent disease-specific survival of 99.5%, Dr. Mette Saskø Mortensen said at a press briefing highlighting research to be presented at the upcoming American Society of Clinical Oncology annual meeting. Only 10 men died of testicular cancer or treatment-related causes during a median follow-up of 15.4 years.

This finding means that for every 1,000 men followed by a surveillance program, only 4 will die within 10 years, said incoming ASCO president Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York.

He described the study as one of several recent reminders that sometimes "less is more" in patient care and noted that opting for surveillance spares patients from the harmful side effects of chemotherapy and radiation without diminishing their chances for long-term survival.

Seminoma is a relatively rare cancer, but it is the most common solid tumor among young men. Initial treatment is typically orchiectomy, but no standard postoperative management strategy has been established. The current results will likely accelerate the trend toward surveillance in the United States, where roughly 50% of men undergo either radiotherapy or chemotherapy with carboplatin after surgery.

Overall, 355 (19.5%) of the 1,822 men experienced a relapse during surveillance, said Dr. Mortensen, a PhD student in the oncology department at Copenhagen University Hospital.

The median time to relapse was 13.7 months, with the majority of patients (72.4%) relapsing within the first 2 years. Another 20.3% relapsed within years 2-5 and 7.3% after 5 years.

"With only 19.5% of the patients relapsing, the surveillance strategy spares the remaining 80% of patients from unnecessary treatment after orchiectomy," Dr. Mortensen said. "Surveillance is a safe strategy for stage I seminoma patients."

Surveillance has been the main follow-up strategy for stage I seminoma in Denmark since 1984, and consists of 5 years of scheduled clinical visits, computed tomography scans/chest x-rays, and blood measurements of tumor markers. Men in the analysis were diagnosed from 1984 to 2008, and their data were collected up to December 2012 from patient files and linked national registries.

As observed in other smaller studies, the risk for relapse was increased with elevated human chorionic gonadotropin levels of more than 200 IU/L, vascular invasion, and tumors larger than 4 cm, Dr. Mortensen said.

The study was supported in part by the Danish Cancer Society, Danish Research Foundation and the Preben and Anna Simonsen Foundation. Dr. Mortensen reported having no financial disclosures.

pwendling@frontlinemedcom.com

Surveillance is sufficient for most men with stage I seminoma after successful orchiectomy, according to the findings of the largest study ever performed to address the issue.

The 1,822 men followed only with surveillance in Denmark had an excellent disease-specific survival of 99.5%, Dr. Mette Saskø Mortensen said at a press briefing highlighting research to be presented at the upcoming American Society of Clinical Oncology annual meeting. Only 10 men died of testicular cancer or treatment-related causes during a median follow-up of 15.4 years.

This finding means that for every 1,000 men followed by a surveillance program, only 4 will die within 10 years, said incoming ASCO president Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York.

He described the study as one of several recent reminders that sometimes "less is more" in patient care and noted that opting for surveillance spares patients from the harmful side effects of chemotherapy and radiation without diminishing their chances for long-term survival.

Seminoma is a relatively rare cancer, but it is the most common solid tumor among young men. Initial treatment is typically orchiectomy, but no standard postoperative management strategy has been established. The current results will likely accelerate the trend toward surveillance in the United States, where roughly 50% of men undergo either radiotherapy or chemotherapy with carboplatin after surgery.

Overall, 355 (19.5%) of the 1,822 men experienced a relapse during surveillance, said Dr. Mortensen, a PhD student in the oncology department at Copenhagen University Hospital.

The median time to relapse was 13.7 months, with the majority of patients (72.4%) relapsing within the first 2 years. Another 20.3% relapsed within years 2-5 and 7.3% after 5 years.

"With only 19.5% of the patients relapsing, the surveillance strategy spares the remaining 80% of patients from unnecessary treatment after orchiectomy," Dr. Mortensen said. "Surveillance is a safe strategy for stage I seminoma patients."

Surveillance has been the main follow-up strategy for stage I seminoma in Denmark since 1984, and consists of 5 years of scheduled clinical visits, computed tomography scans/chest x-rays, and blood measurements of tumor markers. Men in the analysis were diagnosed from 1984 to 2008, and their data were collected up to December 2012 from patient files and linked national registries.

As observed in other smaller studies, the risk for relapse was increased with elevated human chorionic gonadotropin levels of more than 200 IU/L, vascular invasion, and tumors larger than 4 cm, Dr. Mortensen said.

The study was supported in part by the Danish Cancer Society, Danish Research Foundation and the Preben and Anna Simonsen Foundation. Dr. Mortensen reported having no financial disclosures.

pwendling@frontlinemedcom.com

Hitting metastatic melanoma with two immunotherapies, each targeted to a different metabolic pathway, has shown some preliminary success in an early study.

Ipilimumab (Yervoy) used in combination with the investigational drug nivolumab shrank stage-III and -IV melanomas in approximately half of 37 evaluable patients in a phase-I study. Tumor reductions of at least 80% were seen at 12 weeks in 11 of 37 (30%) of patients and 90% of all patients who have responded continue to respond to therapy, Dr. Jedd D. Wolchok said at a press briefing sponsored by the American Society of Clinical Oncology highlighting research to be presented at its annual meeting.

Phase-I trials are conducted to examine drug safety and give indications of dose ranges; they do not allow conclusions about efficacy. A randomized phase-III trial of the nivolumab/ipilimumab combination as first-line therapy for patients with advanced melanoma is scheduled to begin in June.

Ipilimumab is a CTLA-4 inhibitor approved for the treatment of metastatic melanoma. Nivolumab is an investigational PD-1 inhibitor that has shown activity when used alone against melanoma and other cancers.

"The rapidity and magnitude of the responses are what’s so striking," Dr. Wolchok said. "We were particularly impressed that the drugs work together so well" and show that two immunotherapies offer a promising strategy for advanced melanoma.

For the trial, patients who had inoperable stage-III and stage-IV melanoma and had undergone up to three prior therapies were assigned to one of six treatment arms. Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York, presented results on 37 evaluable patients in three completed treatment arms, in which patients received concurrent treatment with the two drugs.

In the phase-I study, nivolumab and ipilimumab were given every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. At week 24, patients began to receive one concurrent combination treatment every 3 months.

The first arm of 14 patients received 3 mg/kg of ipilimumab plus 0.3 mg/kg of nivolumab, the second arm of 17 patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab, and the third arm of 6 patients received 3 mg/kg of ipilimumab plus 3 mg/kg of nivolumab. In those three arms, tumor shrinkage rates were 21%, 47%, and 50%, respectively. Tumor reductions of at least 80% were seen in 29%, 41%, and 0%, respectively.

The responses to therapy were rapid for an immunotherapy – three out of four patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipilimumab, according to Dr. Wolchok.

Two of the remaining three arms of the study enrolled patients who had undergone prior ipilimumab treatment. Those patients received only nivolumab every 2 weeks for up to 48 treatments. Although the data are still preliminary, 4 of 16 evaluable patients in the study arm given nivolumab at 1 mg/kg had at least 80% tumor shrinkage after 8 weeks, even though they initially had little benefit from ipilimumab.

In the concurrently treated patients, grade 3-4 side effects – primarily due to asymptomatic lipase, AST, and ALT abnormalities – occurred in 28 of 53 patients (53%).

With sequenced treatment, grade 3-4 side effects occurred in 6 of 33 patients (18%).

Side effects were managed using standard protocols and no treatment-related deaths were reported.

The nivolumab/ipilimumab combination also is being investigated in non–small cell lung cancer and renal cell carcinoma.

The research was supported by Bristol-Myers Squibb. Dr. Wolchok serves in consultant or advisory roles with, and receives research funding from, Bristol-Meyers Squibb.

mdales@frontlinemedcom.com

Hitting metastatic melanoma with two immunotherapies, each targeted to a different metabolic pathway, has shown some preliminary success in an early study.

Ipilimumab (Yervoy) used in combination with the investigational drug nivolumab shrank stage-III and -IV melanomas in approximately half of 37 evaluable patients in a phase-I study. Tumor reductions of at least 80% were seen at 12 weeks in 11 of 37 (30%) of patients and 90% of all patients who have responded continue to respond to therapy, Dr. Jedd D. Wolchok said at a press briefing sponsored by the American Society of Clinical Oncology highlighting research to be presented at its annual meeting.

Phase-I trials are conducted to examine drug safety and give indications of dose ranges; they do not allow conclusions about efficacy. A randomized phase-III trial of the nivolumab/ipilimumab combination as first-line therapy for patients with advanced melanoma is scheduled to begin in June.

Ipilimumab is a CTLA-4 inhibitor approved for the treatment of metastatic melanoma. Nivolumab is an investigational PD-1 inhibitor that has shown activity when used alone against melanoma and other cancers.

"The rapidity and magnitude of the responses are what’s so striking," Dr. Wolchok said. "We were particularly impressed that the drugs work together so well" and show that two immunotherapies offer a promising strategy for advanced melanoma.

For the trial, patients who had inoperable stage-III and stage-IV melanoma and had undergone up to three prior therapies were assigned to one of six treatment arms. Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York, presented results on 37 evaluable patients in three completed treatment arms, in which patients received concurrent treatment with the two drugs.

In the phase-I study, nivolumab and ipilimumab were given every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. At week 24, patients began to receive one concurrent combination treatment every 3 months.

The first arm of 14 patients received 3 mg/kg of ipilimumab plus 0.3 mg/kg of nivolumab, the second arm of 17 patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab, and the third arm of 6 patients received 3 mg/kg of ipilimumab plus 3 mg/kg of nivolumab. In those three arms, tumor shrinkage rates were 21%, 47%, and 50%, respectively. Tumor reductions of at least 80% were seen in 29%, 41%, and 0%, respectively.

The responses to therapy were rapid for an immunotherapy – three out of four patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipilimumab, according to Dr. Wolchok.

Two of the remaining three arms of the study enrolled patients who had undergone prior ipilimumab treatment. Those patients received only nivolumab every 2 weeks for up to 48 treatments. Although the data are still preliminary, 4 of 16 evaluable patients in the study arm given nivolumab at 1 mg/kg had at least 80% tumor shrinkage after 8 weeks, even though they initially had little benefit from ipilimumab.

In the concurrently treated patients, grade 3-4 side effects – primarily due to asymptomatic lipase, AST, and ALT abnormalities – occurred in 28 of 53 patients (53%).

With sequenced treatment, grade 3-4 side effects occurred in 6 of 33 patients (18%).

Side effects were managed using standard protocols and no treatment-related deaths were reported.

The nivolumab/ipilimumab combination also is being investigated in non–small cell lung cancer and renal cell carcinoma.

The research was supported by Bristol-Myers Squibb. Dr. Wolchok serves in consultant or advisory roles with, and receives research funding from, Bristol-Meyers Squibb.

mdales@frontlinemedcom.com

Hitting metastatic melanoma with two immunotherapies, each targeted to a different metabolic pathway, has shown some preliminary success in an early study.

Ipilimumab (Yervoy) used in combination with the investigational drug nivolumab shrank stage-III and -IV melanomas in approximately half of 37 evaluable patients in a phase-I study. Tumor reductions of at least 80% were seen at 12 weeks in 11 of 37 (30%) of patients and 90% of all patients who have responded continue to respond to therapy, Dr. Jedd D. Wolchok said at a press briefing sponsored by the American Society of Clinical Oncology highlighting research to be presented at its annual meeting.

Phase-I trials are conducted to examine drug safety and give indications of dose ranges; they do not allow conclusions about efficacy. A randomized phase-III trial of the nivolumab/ipilimumab combination as first-line therapy for patients with advanced melanoma is scheduled to begin in June.

Ipilimumab is a CTLA-4 inhibitor approved for the treatment of metastatic melanoma. Nivolumab is an investigational PD-1 inhibitor that has shown activity when used alone against melanoma and other cancers.

"The rapidity and magnitude of the responses are what’s so striking," Dr. Wolchok said. "We were particularly impressed that the drugs work together so well" and show that two immunotherapies offer a promising strategy for advanced melanoma.

For the trial, patients who had inoperable stage-III and stage-IV melanoma and had undergone up to three prior therapies were assigned to one of six treatment arms. Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York, presented results on 37 evaluable patients in three completed treatment arms, in which patients received concurrent treatment with the two drugs.

In the phase-I study, nivolumab and ipilimumab were given every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. At week 24, patients began to receive one concurrent combination treatment every 3 months.

The first arm of 14 patients received 3 mg/kg of ipilimumab plus 0.3 mg/kg of nivolumab, the second arm of 17 patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab, and the third arm of 6 patients received 3 mg/kg of ipilimumab plus 3 mg/kg of nivolumab. In those three arms, tumor shrinkage rates were 21%, 47%, and 50%, respectively. Tumor reductions of at least 80% were seen in 29%, 41%, and 0%, respectively.

The responses to therapy were rapid for an immunotherapy – three out of four patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipilimumab, according to Dr. Wolchok.

Two of the remaining three arms of the study enrolled patients who had undergone prior ipilimumab treatment. Those patients received only nivolumab every 2 weeks for up to 48 treatments. Although the data are still preliminary, 4 of 16 evaluable patients in the study arm given nivolumab at 1 mg/kg had at least 80% tumor shrinkage after 8 weeks, even though they initially had little benefit from ipilimumab.

In the concurrently treated patients, grade 3-4 side effects – primarily due to asymptomatic lipase, AST, and ALT abnormalities – occurred in 28 of 53 patients (53%).

With sequenced treatment, grade 3-4 side effects occurred in 6 of 33 patients (18%).

Side effects were managed using standard protocols and no treatment-related deaths were reported.

The nivolumab/ipilimumab combination also is being investigated in non–small cell lung cancer and renal cell carcinoma.

The research was supported by Bristol-Myers Squibb. Dr. Wolchok serves in consultant or advisory roles with, and receives research funding from, Bristol-Meyers Squibb.

mdales@frontlinemedcom.com

Standard-dose radiation produced better overall survival and locoregional control than did high-dose radiation when given with concurrent chemotherapy in patients with newly diagnosed stage III non–small cell lung cancer in the phase III, randomized RTOG 0617 trial.

Patients on the high dose had a 56% greater risk of death than those on a standard 60 Gy dose. Median overall survival times were 18.5 months with high-dose radiation and 28.7 months with a standard dose (hazard ratio, 1.56; P = .0007).

The risk of local failure also was increased by 37% in the high-dose arm (HR, 1.37; P = .03).

"At this point, there is no clear reason for the poor outcome we experienced on the high-dose arm," lead author Dr. Jeffrey Bradley said in a press briefing highlighting studies to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

The most likely culprit is unreported toxicities, although other possible explanations are increased heart dose, longer duration of therapy, or a combination of these factors, he said.

The results are surprising because conventional thinking has been that higher doses of radiation would more effectively kill the tumor and thereby improve survival.

A phase-III trial in the 1970s established the standard radiation dose of 60 Gy in this setting but, over time, several radiation dose-ranging phase-II studies have reported promising results and improved median survival times with radiation doses up to 74 Gy, explained Dr. Bradley, professor of radiation oncology and chief of the thoracic service at Washington University, St. Louis.

At the same time, improvements in technology such as three-dimensional radiation therapy (RT) and intensity-modulated RT techniques have made RT delivery more precise, allowing organs and tissues sensitive to radiation to receive less radiation while the tumor receives more. This technique was explored in Radiation Therapy Oncology Group (RTOG) 0617.

"This is a very surprising result, especially when using these special radiation techniques that were designed to be more precise, you would expect that the outcome would be better," ASCO president Sandra Swain, medical director of the Washington (D.C.) Cancer Institute, told reporters. "This should really put an end to higher-dose treatments, given the better outcomes in the standard-dose arms."

Dr. Bradley said, "A lot of phase-III trials turn out negative when phase-II trials look good, so I think it was good to do a phase-III trial and get this answered."

RTOG 0617 randomly assigned 464 patients with newly diagnosed, unresected stage-III non–small cell lung cancer to conformal RT to 60 Gy, five times per week for 6 weeks or to 74 Gy five times per week for 7.5 weeks. All patients received concurrent chemotherapy with weekly paclitaxel (Taxol) and carboplatin, with a second randomization for patients to receive consolidation chemotherapy with or without cetuximab (Erbitux).

Among the 419 patients available for analysis at 18 months, local failure rates were 25% with standard-dose RT and 34.3% with high-dose RT (P = .03, as noted above), Dr. Bradley reported.

Median 18-month overall survival rates were 67% with the standard radiation dose vs. 54% with the high dose.

Median overall survival times in both groups were higher than expected, but "the overall survival benefit of 60 Gy is independent of the cetuximab question," he said. Data from that portion of the trial are expected to be reported in 2014.

Finally, the only significant difference in physician-reported side effects was a slightly higher rate of esophagitis in the high-dose arms (21% vs. 7%).

Full details of RTOG 0617 (abstract 7501) will be reported 10:15 a.m. on June 4 at ASCO’s annual meeting in Chicago.

The study was supported by the National Cancer Institute. Dr. Bradley reported having no relevant financial disclosures. A coauthor reported research funding from the NCI.

pwendling@frontlinemedcom.com

Standard-dose radiation produced better overall survival and locoregional control than did high-dose radiation when given with concurrent chemotherapy in patients with newly diagnosed stage III non–small cell lung cancer in the phase III, randomized RTOG 0617 trial.

Patients on the high dose had a 56% greater risk of death than those on a standard 60 Gy dose. Median overall survival times were 18.5 months with high-dose radiation and 28.7 months with a standard dose (hazard ratio, 1.56; P = .0007).

The risk of local failure also was increased by 37% in the high-dose arm (HR, 1.37; P = .03).

"At this point, there is no clear reason for the poor outcome we experienced on the high-dose arm," lead author Dr. Jeffrey Bradley said in a press briefing highlighting studies to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

The most likely culprit is unreported toxicities, although other possible explanations are increased heart dose, longer duration of therapy, or a combination of these factors, he said.

The results are surprising because conventional thinking has been that higher doses of radiation would more effectively kill the tumor and thereby improve survival.

A phase-III trial in the 1970s established the standard radiation dose of 60 Gy in this setting but, over time, several radiation dose-ranging phase-II studies have reported promising results and improved median survival times with radiation doses up to 74 Gy, explained Dr. Bradley, professor of radiation oncology and chief of the thoracic service at Washington University, St. Louis.

At the same time, improvements in technology such as three-dimensional radiation therapy (RT) and intensity-modulated RT techniques have made RT delivery more precise, allowing organs and tissues sensitive to radiation to receive less radiation while the tumor receives more. This technique was explored in Radiation Therapy Oncology Group (RTOG) 0617.

"This is a very surprising result, especially when using these special radiation techniques that were designed to be more precise, you would expect that the outcome would be better," ASCO president Sandra Swain, medical director of the Washington (D.C.) Cancer Institute, told reporters. "This should really put an end to higher-dose treatments, given the better outcomes in the standard-dose arms."

Dr. Bradley said, "A lot of phase-III trials turn out negative when phase-II trials look good, so I think it was good to do a phase-III trial and get this answered."

RTOG 0617 randomly assigned 464 patients with newly diagnosed, unresected stage-III non–small cell lung cancer to conformal RT to 60 Gy, five times per week for 6 weeks or to 74 Gy five times per week for 7.5 weeks. All patients received concurrent chemotherapy with weekly paclitaxel (Taxol) and carboplatin, with a second randomization for patients to receive consolidation chemotherapy with or without cetuximab (Erbitux).

Among the 419 patients available for analysis at 18 months, local failure rates were 25% with standard-dose RT and 34.3% with high-dose RT (P = .03, as noted above), Dr. Bradley reported.

Median 18-month overall survival rates were 67% with the standard radiation dose vs. 54% with the high dose.

Median overall survival times in both groups were higher than expected, but "the overall survival benefit of 60 Gy is independent of the cetuximab question," he said. Data from that portion of the trial are expected to be reported in 2014.

Finally, the only significant difference in physician-reported side effects was a slightly higher rate of esophagitis in the high-dose arms (21% vs. 7%).

Full details of RTOG 0617 (abstract 7501) will be reported 10:15 a.m. on June 4 at ASCO’s annual meeting in Chicago.

The study was supported by the National Cancer Institute. Dr. Bradley reported having no relevant financial disclosures. A coauthor reported research funding from the NCI.

pwendling@frontlinemedcom.com

Standard-dose radiation produced better overall survival and locoregional control than did high-dose radiation when given with concurrent chemotherapy in patients with newly diagnosed stage III non–small cell lung cancer in the phase III, randomized RTOG 0617 trial.

Patients on the high dose had a 56% greater risk of death than those on a standard 60 Gy dose. Median overall survival times were 18.5 months with high-dose radiation and 28.7 months with a standard dose (hazard ratio, 1.56; P = .0007).

The risk of local failure also was increased by 37% in the high-dose arm (HR, 1.37; P = .03).

"At this point, there is no clear reason for the poor outcome we experienced on the high-dose arm," lead author Dr. Jeffrey Bradley said in a press briefing highlighting studies to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

The most likely culprit is unreported toxicities, although other possible explanations are increased heart dose, longer duration of therapy, or a combination of these factors, he said.

The results are surprising because conventional thinking has been that higher doses of radiation would more effectively kill the tumor and thereby improve survival.

A phase-III trial in the 1970s established the standard radiation dose of 60 Gy in this setting but, over time, several radiation dose-ranging phase-II studies have reported promising results and improved median survival times with radiation doses up to 74 Gy, explained Dr. Bradley, professor of radiation oncology and chief of the thoracic service at Washington University, St. Louis.

At the same time, improvements in technology such as three-dimensional radiation therapy (RT) and intensity-modulated RT techniques have made RT delivery more precise, allowing organs and tissues sensitive to radiation to receive less radiation while the tumor receives more. This technique was explored in Radiation Therapy Oncology Group (RTOG) 0617.

"This is a very surprising result, especially when using these special radiation techniques that were designed to be more precise, you would expect that the outcome would be better," ASCO president Sandra Swain, medical director of the Washington (D.C.) Cancer Institute, told reporters. "This should really put an end to higher-dose treatments, given the better outcomes in the standard-dose arms."

Dr. Bradley said, "A lot of phase-III trials turn out negative when phase-II trials look good, so I think it was good to do a phase-III trial and get this answered."

RTOG 0617 randomly assigned 464 patients with newly diagnosed, unresected stage-III non–small cell lung cancer to conformal RT to 60 Gy, five times per week for 6 weeks or to 74 Gy five times per week for 7.5 weeks. All patients received concurrent chemotherapy with weekly paclitaxel (Taxol) and carboplatin, with a second randomization for patients to receive consolidation chemotherapy with or without cetuximab (Erbitux).

Among the 419 patients available for analysis at 18 months, local failure rates were 25% with standard-dose RT and 34.3% with high-dose RT (P = .03, as noted above), Dr. Bradley reported.

Median 18-month overall survival rates were 67% with the standard radiation dose vs. 54% with the high dose.

Median overall survival times in both groups were higher than expected, but "the overall survival benefit of 60 Gy is independent of the cetuximab question," he said. Data from that portion of the trial are expected to be reported in 2014.

Finally, the only significant difference in physician-reported side effects was a slightly higher rate of esophagitis in the high-dose arms (21% vs. 7%).

Full details of RTOG 0617 (abstract 7501) will be reported 10:15 a.m. on June 4 at ASCO’s annual meeting in Chicago.

The study was supported by the National Cancer Institute. Dr. Bradley reported having no relevant financial disclosures. A coauthor reported research funding from the NCI.

pwendling@frontlinemedcom.com

An investigational drug that targets the PD-L1 pathway was associated with tumor shrinkage in about 20% of patients who had a wide array of incurable or metastatic solid cancers in a phase I study.

MPDL3280A, a PD-L1 targeted antibody with an Fc-domain designed to optimize efficacy and safety, shrank tumors by at least 50% in 29 of 140 patients, for an overall response rate of 21%. Further, there have been additional delayed responses, and the treatment responses are ongoing, with 26 of 29 patients continuing to respond at follow-ups of 3-15 months.

"We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors," especially given that this is a phase I study designed to assess the drug’s safety and guide selection of dosing for phase II study, lead investigator Dr. Roy S. Herbst said May 15 during a presscast sponsored by the American Society of Clinical Oncology in advance of its annual meeting,

The drug also met safety measures, with no maximum tolerated dose, dose-limiting toxicities, or treatment-related deaths in an analysis of 171 patients. One patient discontinued MPDL3280A because of an immune-related adverse event; importantly, no cases of grade 3-5 pneumonitis occurred. The most common grade 3-4 adverse events, each seen in 3%-5% of patients, were hyperglycemia, fatigue, increased ALT, dyspnea, and hypoxia. These included all adverse events, irrespective of whether they were from disease, the drug, or other factors, reported Dr. Herbst, Ensign Professor of medical oncology at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale, both in New Haven, Conn.

PD-L1 is a protein that can essentially hide cancer cells from the immune system, When MPDL3280A attaches to the protein PD-L1, it essentially reveals the cancer cell to T cells, eliciting an immune response. MPDL3280A was specifically engineered for enhanced safety and efficacy, compared with earlier PD-L1 or PD-1 targeted agents.

Based on diagnostic testing for PD-L1 expression in archived tumor tissue from 103 patients, tumor shrinkage occurred after MPDL3280A treatment in 13 of 36 (36%) of patients with PD-L1–positive tumors and in 9 of 67 (13%) of patients with PD-L1–negative tumors. The diagnostic test for PD-L1 is still evolving, so a negative result on the PD-L1 test could simply mean that tumors have less PD-L1 than the test currently detects, according to Dr. Herbst.

The study has been expanded to include more than 275 patients to date. Phase II and phase III studies are planned to confirm MPDL3280A’s anticancer activity and to validate the PD-L1 diagnostic test.

For the phase I study, MPDL3280A was administered intravenously 3 times weekly. Administered doses included 1 mg/kg or less (9 patients), 3 mg/kg (3 patients), 10 mg/kg (35 patients), 15 mg/kg (57 patients), and 20 mg/kg (67 patients). Responses were observed in multiple tumor types, including non–small cell lung cancer, renal cell carcinoma melanoma, colorectal cancer, and gastric cancer. The 24-week progression-free survival was 44%. No maximum tolerated dose was identified, and patients received MPDL3280A for a median duration of 127 days (range 1-330 days). Pharmacokinetics supports thrice-weekly dosing at 15 mg/kg or a fixed-dose equivalent.

The study was supported by Genentech. Dr. Herbst receives research support from Genentech.

mdales@frontlinemedcom.com

An investigational drug that targets the PD-L1 pathway was associated with tumor shrinkage in about 20% of patients who had a wide array of incurable or metastatic solid cancers in a phase I study.

MPDL3280A, a PD-L1 targeted antibody with an Fc-domain designed to optimize efficacy and safety, shrank tumors by at least 50% in 29 of 140 patients, for an overall response rate of 21%. Further, there have been additional delayed responses, and the treatment responses are ongoing, with 26 of 29 patients continuing to respond at follow-ups of 3-15 months.

"We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors," especially given that this is a phase I study designed to assess the drug’s safety and guide selection of dosing for phase II study, lead investigator Dr. Roy S. Herbst said May 15 during a presscast sponsored by the American Society of Clinical Oncology in advance of its annual meeting,

The drug also met safety measures, with no maximum tolerated dose, dose-limiting toxicities, or treatment-related deaths in an analysis of 171 patients. One patient discontinued MPDL3280A because of an immune-related adverse event; importantly, no cases of grade 3-5 pneumonitis occurred. The most common grade 3-4 adverse events, each seen in 3%-5% of patients, were hyperglycemia, fatigue, increased ALT, dyspnea, and hypoxia. These included all adverse events, irrespective of whether they were from disease, the drug, or other factors, reported Dr. Herbst, Ensign Professor of medical oncology at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale, both in New Haven, Conn.

PD-L1 is a protein that can essentially hide cancer cells from the immune system, When MPDL3280A attaches to the protein PD-L1, it essentially reveals the cancer cell to T cells, eliciting an immune response. MPDL3280A was specifically engineered for enhanced safety and efficacy, compared with earlier PD-L1 or PD-1 targeted agents.

Based on diagnostic testing for PD-L1 expression in archived tumor tissue from 103 patients, tumor shrinkage occurred after MPDL3280A treatment in 13 of 36 (36%) of patients with PD-L1–positive tumors and in 9 of 67 (13%) of patients with PD-L1–negative tumors. The diagnostic test for PD-L1 is still evolving, so a negative result on the PD-L1 test could simply mean that tumors have less PD-L1 than the test currently detects, according to Dr. Herbst.

The study has been expanded to include more than 275 patients to date. Phase II and phase III studies are planned to confirm MPDL3280A’s anticancer activity and to validate the PD-L1 diagnostic test.

For the phase I study, MPDL3280A was administered intravenously 3 times weekly. Administered doses included 1 mg/kg or less (9 patients), 3 mg/kg (3 patients), 10 mg/kg (35 patients), 15 mg/kg (57 patients), and 20 mg/kg (67 patients). Responses were observed in multiple tumor types, including non–small cell lung cancer, renal cell carcinoma melanoma, colorectal cancer, and gastric cancer. The 24-week progression-free survival was 44%. No maximum tolerated dose was identified, and patients received MPDL3280A for a median duration of 127 days (range 1-330 days). Pharmacokinetics supports thrice-weekly dosing at 15 mg/kg or a fixed-dose equivalent.

The study was supported by Genentech. Dr. Herbst receives research support from Genentech.

mdales@frontlinemedcom.com

An investigational drug that targets the PD-L1 pathway was associated with tumor shrinkage in about 20% of patients who had a wide array of incurable or metastatic solid cancers in a phase I study.

MPDL3280A, a PD-L1 targeted antibody with an Fc-domain designed to optimize efficacy and safety, shrank tumors by at least 50% in 29 of 140 patients, for an overall response rate of 21%. Further, there have been additional delayed responses, and the treatment responses are ongoing, with 26 of 29 patients continuing to respond at follow-ups of 3-15 months.

"We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors," especially given that this is a phase I study designed to assess the drug’s safety and guide selection of dosing for phase II study, lead investigator Dr. Roy S. Herbst said May 15 during a presscast sponsored by the American Society of Clinical Oncology in advance of its annual meeting,

The drug also met safety measures, with no maximum tolerated dose, dose-limiting toxicities, or treatment-related deaths in an analysis of 171 patients. One patient discontinued MPDL3280A because of an immune-related adverse event; importantly, no cases of grade 3-5 pneumonitis occurred. The most common grade 3-4 adverse events, each seen in 3%-5% of patients, were hyperglycemia, fatigue, increased ALT, dyspnea, and hypoxia. These included all adverse events, irrespective of whether they were from disease, the drug, or other factors, reported Dr. Herbst, Ensign Professor of medical oncology at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale, both in New Haven, Conn.

PD-L1 is a protein that can essentially hide cancer cells from the immune system, When MPDL3280A attaches to the protein PD-L1, it essentially reveals the cancer cell to T cells, eliciting an immune response. MPDL3280A was specifically engineered for enhanced safety and efficacy, compared with earlier PD-L1 or PD-1 targeted agents.

Based on diagnostic testing for PD-L1 expression in archived tumor tissue from 103 patients, tumor shrinkage occurred after MPDL3280A treatment in 13 of 36 (36%) of patients with PD-L1–positive tumors and in 9 of 67 (13%) of patients with PD-L1–negative tumors. The diagnostic test for PD-L1 is still evolving, so a negative result on the PD-L1 test could simply mean that tumors have less PD-L1 than the test currently detects, according to Dr. Herbst.

The study has been expanded to include more than 275 patients to date. Phase II and phase III studies are planned to confirm MPDL3280A’s anticancer activity and to validate the PD-L1 diagnostic test.

For the phase I study, MPDL3280A was administered intravenously 3 times weekly. Administered doses included 1 mg/kg or less (9 patients), 3 mg/kg (3 patients), 10 mg/kg (35 patients), 15 mg/kg (57 patients), and 20 mg/kg (67 patients). Responses were observed in multiple tumor types, including non–small cell lung cancer, renal cell carcinoma melanoma, colorectal cancer, and gastric cancer. The 24-week progression-free survival was 44%. No maximum tolerated dose was identified, and patients received MPDL3280A for a median duration of 127 days (range 1-330 days). Pharmacokinetics supports thrice-weekly dosing at 15 mg/kg or a fixed-dose equivalent.

The study was supported by Genentech. Dr. Herbst receives research support from Genentech.

mdales@frontlinemedcom.com