2014 ASCO Annual Meeting

CHICAGO – Adding docetaxel chemotherapy to standard management improved survival in men with high-risk, localized, hormone-sensitive prostate cancer, results from the phase III RTOG 0521 study show.

At 4 years, overall survival was 89% without docetaxel and 93% with the addition of docetaxel (Toxotere) and prednisone after completing radiotherapy and long-term hormonal suppression (Hazard ratio, 0.70; P = .04).

“For the first time, improvement in overall survival was observed with adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer,” Dr. Howard Sandler said in a press conference in advance of the formal presentation of the late-breaking study at the annual meeting of the American Society of Clinical Oncology.

The implications of the study are clinically relevant and wide-ranging, particularly in patients with high-risk disease, press briefing moderator Dr. Don Dizon, commented.

Dr. Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, gives details of this practice-changing study in a video interview.

The study was funded by the National Institutes of Health. Dr. Sandler reported financial relationships with several firms including Sanofi Aventis, maker of docetaxel.

[email protected]

On Twitter @pwendl

CHICAGO – Adding docetaxel chemotherapy to standard management improved survival in men with high-risk, localized, hormone-sensitive prostate cancer, results from the phase III RTOG 0521 study show.

At 4 years, overall survival was 89% without docetaxel and 93% with the addition of docetaxel (Toxotere) and prednisone after completing radiotherapy and long-term hormonal suppression (Hazard ratio, 0.70; P = .04).

“For the first time, improvement in overall survival was observed with adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer,” Dr. Howard Sandler said in a press conference in advance of the formal presentation of the late-breaking study at the annual meeting of the American Society of Clinical Oncology.

The implications of the study are clinically relevant and wide-ranging, particularly in patients with high-risk disease, press briefing moderator Dr. Don Dizon, commented.

Dr. Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, gives details of this practice-changing study in a video interview.

The study was funded by the National Institutes of Health. Dr. Sandler reported financial relationships with several firms including Sanofi Aventis, maker of docetaxel.

[email protected]

On Twitter @pwendl

CHICAGO – Adding docetaxel chemotherapy to standard management improved survival in men with high-risk, localized, hormone-sensitive prostate cancer, results from the phase III RTOG 0521 study show.

At 4 years, overall survival was 89% without docetaxel and 93% with the addition of docetaxel (Toxotere) and prednisone after completing radiotherapy and long-term hormonal suppression (Hazard ratio, 0.70; P = .04).

“For the first time, improvement in overall survival was observed with adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer,” Dr. Howard Sandler said in a press conference in advance of the formal presentation of the late-breaking study at the annual meeting of the American Society of Clinical Oncology.

The implications of the study are clinically relevant and wide-ranging, particularly in patients with high-risk disease, press briefing moderator Dr. Don Dizon, commented.

Dr. Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, gives details of this practice-changing study in a video interview.

The study was funded by the National Institutes of Health. Dr. Sandler reported financial relationships with several firms including Sanofi Aventis, maker of docetaxel.

[email protected]

On Twitter @pwendl

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small-cell lung cancer who responded to chemotherapy, according to results from the randomized CREST study.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small-cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small-cell lung cancer (SCLC) who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

Most patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, said Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intrathoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small-cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

[email protected]

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small-cell lung cancer who responded to chemotherapy, according to results from the randomized CREST study.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small-cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small-cell lung cancer (SCLC) who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

Most patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, said Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intrathoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small-cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

[email protected]

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small-cell lung cancer who responded to chemotherapy, according to results from the randomized CREST study.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small-cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small-cell lung cancer (SCLC) who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

Most patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, said Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intrathoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small-cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival (DFS) in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)–positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR-activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median OS in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), New York (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO ( Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation–positive NSCLC, and reached 96% in stage I and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug Aadministration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival (DFS) in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)–positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR-activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median OS in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), New York (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO ( Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation–positive NSCLC, and reached 96% in stage I and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug Aadministration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival (DFS) in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)–positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR-activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median OS in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), New York (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO ( Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation–positive NSCLC, and reached 96% in stage I and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug Aadministration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and improved progression-free survival in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.

The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).

Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks’ follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.

Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.

"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.

Moreover, median progression-free survival (PFS) with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.

"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.

Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.

Study details

Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.

Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.

The KEYNOTE-001 study (clinicaltrials.gov/ show/NCT01295827) http://abstracts.asco.org/144/AbstView_144_132675.html enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.

Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.

Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.

Safety data indicate the regimen is "safe and well tolerated," Dr. Rizvi said.

Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.

Safety data indicate the regimen is "safe and well-tolerated," Dr. Rizvi said.

The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.

[email protected]

CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and improved progression-free survival in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.

The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).

Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks’ follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.

Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.

"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.

Moreover, median progression-free survival (PFS) with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.

"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.

Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.

Study details

Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.

Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.

The KEYNOTE-001 study (clinicaltrials.gov/ show/NCT01295827) http://abstracts.asco.org/144/AbstView_144_132675.html enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.

Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.

Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.

Safety data indicate the regimen is "safe and well tolerated," Dr. Rizvi said.

Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.

Safety data indicate the regimen is "safe and well-tolerated," Dr. Rizvi said.

The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.

[email protected]

CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and improved progression-free survival in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.

The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).

Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks’ follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.

Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.

"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.

Moreover, median progression-free survival (PFS) with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.

"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.

Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.

Study details

Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.

Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.

The KEYNOTE-001 study (clinicaltrials.gov/ show/NCT01295827) http://abstracts.asco.org/144/AbstView_144_132675.html enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.

Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.

Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.

Safety data indicate the regimen is "safe and well tolerated," Dr. Rizvi said.

Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.

Safety data indicate the regimen is "safe and well-tolerated," Dr. Rizvi said.

The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.

[email protected]

CHICAGO – The PARP inhibitor olaparib plus the antiangiogenic cediranib nearly doubled progression-free survival in women with recurrent, platinum-sensitive ovarian cancer in a phase II study.

Median progression-free survival (PFS) was 17.7 months with the combination, compared with 9 months for olaparib alone (hazard ratio, 0.42; P = .005).

Olaparib plus cediranib also significantly increased the overall response rate from 48% to 80% (P = .002), Dr. Joyce F. Liu reported at the annual meeting of the American Society of Clinical Oncology.

This included 5 complete responses and 30 partial responses in the 44 women assigned combination therapy, versus 2 complete and 20 partial responses in the 46 treated with olaparib alone.

"One very exciting possibility about this combination is that it can offer an alternative to standard chemotherapy for women in this setting," she said in an interview. "It offers us more options."

Typically, these patients will receive platinum-based doublets containing carboplatin plus paclitaxel or pegylated liposomal doxorubicin, or gemcitabine, resulting in a median PFS of 8-13 months in phase III studies, said Dr. Liu of Dana-Farber Cancer Institute, Boston, during a press briefing.

Women with platinum-sensitive ovarian cancer are also the patients most likely to be considered for surgical debulking, commented Dr. Don Dizon, director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center, Boston. For these women, targeted agents like olaparib and cediranib may provide an alternative if the drugs are able to reset the disease.

Preclinical data have suggested a synergy between PARP (poly-ADP-ribose polymerase) inhibitors and antiangiogenics, and Dr. Liu previously reported phase I data showing an overall response rate of 44% with olaparib plus cediranib in recurrent ovarian cancer (Eur. J. Cancer 2013;49;2972-8).

Study details

The open-label, phase II study randomly assigned 90 women (median age, 58 years) with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer to olaparib 400 mg twice daily or cediranib 30 mg daily plus olaparib 200 mg twice daily, all until disease progression by RECIST criteria.

All patients had high-grade serous or endometrioid histology or other high-grade histological subtypes, if a germ-line BRCA mutation was documented.

There was a slight trend for patients treated with olaparib alone to have higher baseline CA125 levels than patients treated with the combination (115.3 vs. 68 U/mL) and to have received more prior lines of therapy (two lines: 39% vs. 22.7%; 3 or more lines: 24% vs. 18.2%), Dr. Liu observed.

Randomization was stratified by BRCA status, with 52% of participants being BRCA carriers.

Several PARP inhibitors, including the highly potent BMN 673, have shown promising activity in the treatment of breast and ovarian cancers that have BRCA1 or BRCA2 mutations.

The influence of BRCA

A post hoc analysis revealed a trend toward prolonged PFS with olaparib plus cediranib in BRCA mutation carriers (19.4 vs. 16.5 months; HR, 0.55; P = .16).

Surprisingly, the difference was more marked and statistically significant, however, in women without a BRCA mutation or unknown mutation status (16.5 vs. 5.7 months; HR, 0.32; P = .008), Dr. Liu reported.

The finding was "unexpected," but it should be kept in mind that this was a post hoc analysis of a phase II trial and that the finding needs to be confirmed, she told reporters.

When asked whether olaparib plus cediranib is superior to cediranib alone, Dr. Liu said the current findings of a 17.7-month PFS would at least suggest that the combination is more active than cediranib monotherapy, which has demonstrated a 5.2-month PFS in recurrent platinum-sensitive or platinum-resistant disease.

Adverse events

Treatment with olaparib plus cediranib increased the rate of adverse events, but overall the toxicity profile was acceptable, she said. The most common grade 3/4 toxicities with combination therapy versus olaparib alone were hypertension (17 grade 3 and 1 grade 4 events vs. 0), diarrhea (10 grade 3 events vs. 0), and fatigue (12 vs. 5 grade 3 events).

Toxicities were generally manageable with aggressive symptom management and dose holds or reductions, the latter required in 77% of olaparib/cediranib patients versus 24% olaparib-alone patients.

Four patients, all in the combination arm, went off treatment for toxicity: 1 myelodysplastic syndrome, 1 weight loss, 1 avascular necrosis in the setting of preexisting avascular necrosis, and 1 vaginal fistula formation.

"The degree of activity observed with this combination supports additional clinical evaluation of cediranib and olaparib together in ovarian cancer," Dr. Liu concluded.

The study was supported by the National Cancer Institute. Dr. Liu and her coauthors reported no relevant financial disclosures.

[email protected]

CHICAGO – The PARP inhibitor olaparib plus the antiangiogenic cediranib nearly doubled progression-free survival in women with recurrent, platinum-sensitive ovarian cancer in a phase II study.

Median progression-free survival (PFS) was 17.7 months with the combination, compared with 9 months for olaparib alone (hazard ratio, 0.42; P = .005).

Olaparib plus cediranib also significantly increased the overall response rate from 48% to 80% (P = .002), Dr. Joyce F. Liu reported at the annual meeting of the American Society of Clinical Oncology.

This included 5 complete responses and 30 partial responses in the 44 women assigned combination therapy, versus 2 complete and 20 partial responses in the 46 treated with olaparib alone.

"One very exciting possibility about this combination is that it can offer an alternative to standard chemotherapy for women in this setting," she said in an interview. "It offers us more options."

Typically, these patients will receive platinum-based doublets containing carboplatin plus paclitaxel or pegylated liposomal doxorubicin, or gemcitabine, resulting in a median PFS of 8-13 months in phase III studies, said Dr. Liu of Dana-Farber Cancer Institute, Boston, during a press briefing.

Women with platinum-sensitive ovarian cancer are also the patients most likely to be considered for surgical debulking, commented Dr. Don Dizon, director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center, Boston. For these women, targeted agents like olaparib and cediranib may provide an alternative if the drugs are able to reset the disease.

Preclinical data have suggested a synergy between PARP (poly-ADP-ribose polymerase) inhibitors and antiangiogenics, and Dr. Liu previously reported phase I data showing an overall response rate of 44% with olaparib plus cediranib in recurrent ovarian cancer (Eur. J. Cancer 2013;49;2972-8).

Study details

The open-label, phase II study randomly assigned 90 women (median age, 58 years) with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer to olaparib 400 mg twice daily or cediranib 30 mg daily plus olaparib 200 mg twice daily, all until disease progression by RECIST criteria.

All patients had high-grade serous or endometrioid histology or other high-grade histological subtypes, if a germ-line BRCA mutation was documented.

There was a slight trend for patients treated with olaparib alone to have higher baseline CA125 levels than patients treated with the combination (115.3 vs. 68 U/mL) and to have received more prior lines of therapy (two lines: 39% vs. 22.7%; 3 or more lines: 24% vs. 18.2%), Dr. Liu observed.

Randomization was stratified by BRCA status, with 52% of participants being BRCA carriers.

Several PARP inhibitors, including the highly potent BMN 673, have shown promising activity in the treatment of breast and ovarian cancers that have BRCA1 or BRCA2 mutations.

The influence of BRCA

A post hoc analysis revealed a trend toward prolonged PFS with olaparib plus cediranib in BRCA mutation carriers (19.4 vs. 16.5 months; HR, 0.55; P = .16).

Surprisingly, the difference was more marked and statistically significant, however, in women without a BRCA mutation or unknown mutation status (16.5 vs. 5.7 months; HR, 0.32; P = .008), Dr. Liu reported.

The finding was "unexpected," but it should be kept in mind that this was a post hoc analysis of a phase II trial and that the finding needs to be confirmed, she told reporters.

When asked whether olaparib plus cediranib is superior to cediranib alone, Dr. Liu said the current findings of a 17.7-month PFS would at least suggest that the combination is more active than cediranib monotherapy, which has demonstrated a 5.2-month PFS in recurrent platinum-sensitive or platinum-resistant disease.

Adverse events

Treatment with olaparib plus cediranib increased the rate of adverse events, but overall the toxicity profile was acceptable, she said. The most common grade 3/4 toxicities with combination therapy versus olaparib alone were hypertension (17 grade 3 and 1 grade 4 events vs. 0), diarrhea (10 grade 3 events vs. 0), and fatigue (12 vs. 5 grade 3 events).

Toxicities were generally manageable with aggressive symptom management and dose holds or reductions, the latter required in 77% of olaparib/cediranib patients versus 24% olaparib-alone patients.

Four patients, all in the combination arm, went off treatment for toxicity: 1 myelodysplastic syndrome, 1 weight loss, 1 avascular necrosis in the setting of preexisting avascular necrosis, and 1 vaginal fistula formation.

"The degree of activity observed with this combination supports additional clinical evaluation of cediranib and olaparib together in ovarian cancer," Dr. Liu concluded.

The study was supported by the National Cancer Institute. Dr. Liu and her coauthors reported no relevant financial disclosures.

[email protected]

CHICAGO – The PARP inhibitor olaparib plus the antiangiogenic cediranib nearly doubled progression-free survival in women with recurrent, platinum-sensitive ovarian cancer in a phase II study.

Median progression-free survival (PFS) was 17.7 months with the combination, compared with 9 months for olaparib alone (hazard ratio, 0.42; P = .005).

Olaparib plus cediranib also significantly increased the overall response rate from 48% to 80% (P = .002), Dr. Joyce F. Liu reported at the annual meeting of the American Society of Clinical Oncology.

This included 5 complete responses and 30 partial responses in the 44 women assigned combination therapy, versus 2 complete and 20 partial responses in the 46 treated with olaparib alone.

"One very exciting possibility about this combination is that it can offer an alternative to standard chemotherapy for women in this setting," she said in an interview. "It offers us more options."

Typically, these patients will receive platinum-based doublets containing carboplatin plus paclitaxel or pegylated liposomal doxorubicin, or gemcitabine, resulting in a median PFS of 8-13 months in phase III studies, said Dr. Liu of Dana-Farber Cancer Institute, Boston, during a press briefing.

Women with platinum-sensitive ovarian cancer are also the patients most likely to be considered for surgical debulking, commented Dr. Don Dizon, director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center, Boston. For these women, targeted agents like olaparib and cediranib may provide an alternative if the drugs are able to reset the disease.

Preclinical data have suggested a synergy between PARP (poly-ADP-ribose polymerase) inhibitors and antiangiogenics, and Dr. Liu previously reported phase I data showing an overall response rate of 44% with olaparib plus cediranib in recurrent ovarian cancer (Eur. J. Cancer 2013;49;2972-8).

Study details

The open-label, phase II study randomly assigned 90 women (median age, 58 years) with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer to olaparib 400 mg twice daily or cediranib 30 mg daily plus olaparib 200 mg twice daily, all until disease progression by RECIST criteria.

All patients had high-grade serous or endometrioid histology or other high-grade histological subtypes, if a germ-line BRCA mutation was documented.

There was a slight trend for patients treated with olaparib alone to have higher baseline CA125 levels than patients treated with the combination (115.3 vs. 68 U/mL) and to have received more prior lines of therapy (two lines: 39% vs. 22.7%; 3 or more lines: 24% vs. 18.2%), Dr. Liu observed.

Randomization was stratified by BRCA status, with 52% of participants being BRCA carriers.

Several PARP inhibitors, including the highly potent BMN 673, have shown promising activity in the treatment of breast and ovarian cancers that have BRCA1 or BRCA2 mutations.

The influence of BRCA

A post hoc analysis revealed a trend toward prolonged PFS with olaparib plus cediranib in BRCA mutation carriers (19.4 vs. 16.5 months; HR, 0.55; P = .16).

Surprisingly, the difference was more marked and statistically significant, however, in women without a BRCA mutation or unknown mutation status (16.5 vs. 5.7 months; HR, 0.32; P = .008), Dr. Liu reported.

The finding was "unexpected," but it should be kept in mind that this was a post hoc analysis of a phase II trial and that the finding needs to be confirmed, she told reporters.

When asked whether olaparib plus cediranib is superior to cediranib alone, Dr. Liu said the current findings of a 17.7-month PFS would at least suggest that the combination is more active than cediranib monotherapy, which has demonstrated a 5.2-month PFS in recurrent platinum-sensitive or platinum-resistant disease.

Adverse events

Treatment with olaparib plus cediranib increased the rate of adverse events, but overall the toxicity profile was acceptable, she said. The most common grade 3/4 toxicities with combination therapy versus olaparib alone were hypertension (17 grade 3 and 1 grade 4 events vs. 0), diarrhea (10 grade 3 events vs. 0), and fatigue (12 vs. 5 grade 3 events).

Toxicities were generally manageable with aggressive symptom management and dose holds or reductions, the latter required in 77% of olaparib/cediranib patients versus 24% olaparib-alone patients.

Four patients, all in the combination arm, went off treatment for toxicity: 1 myelodysplastic syndrome, 1 weight loss, 1 avascular necrosis in the setting of preexisting avascular necrosis, and 1 vaginal fistula formation.

"The degree of activity observed with this combination supports additional clinical evaluation of cediranib and olaparib together in ovarian cancer," Dr. Liu concluded.

The study was supported by the National Cancer Institute. Dr. Liu and her coauthors reported no relevant financial disclosures.

[email protected]

CHICAGO – Cisplatin, etoposide, and irinotecan provide a significant survival advantage over topotecan as second-line chemotherapy in sensitive relapsed small cell lung cancer, but the toxicity of the combination dampened the overall results of the phase III JCOG0605 trial.

The primary end point of median overall survival was 12.5 months with topotecan (Hycamtin) and 18.2 months with cisplatin (Platinol), etoposide, and irinotecan (PEI) chemotherapy (hazard ratio, 0.67; P = .0079).

"This is the first time that combination chemotherapy has demonstrated a survival benefit, compared with single-agent topotecan," Dr. Koichi Goto reported at the annual meeting of the American Society of Clinical Oncology.

PEI chemotherapy also substantially improved median progression-free survival from 3.6 months with topotecan to 5.7 months (HR, 0.50; P less than .0001) and the overall response rate from 26.7% to 84.3% (P less than .01).

Phase II data from the same investigators showed an overall response rate of 78% and a median survival time of 11.8 months with PEI chemotherapy in 40 patients with sensitive relapsed small cell lung cancer (SCLC) (Br. J. Cancer 2004;91:659-65).

"Combination chemotherapy with cisplatin, etoposide, and irinotecan should be considered the standard second-line treatment for sensitive relapsed small cell lung cancer," said Dr. Goto of the division of thoracic oncology, National Cancer Center Hospital East, Kashiwa, Japan.

At first glance, the results seem impressive, but the higher than expected survival rates in both arms suggest the patients were selected, said Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, who was invited to discuss the results.

Patients in the trial also mostly had progression 6 months after initial treatment, and current National Comprehensive Cancer Network guidelines recommend rechallenging such patients with their original chemotherapy regimen.

"Furthermore, the treatment with the three-drug regimen was given at the cost of severe toxicities," he said.

There were higher rates of grades 3/4 leukopenia (80% vs. 51%), febrile neutropenia (31% vs. 6.7%), and diarrhea (7.8% vs. 0%), and 50% of patients treated with PEI required a dose reduction. Dr. Lee noted that these findings support those in other trials where the addition of a third drug in small cell lung cancer creates greater toxicity without providing any further benefit in outcomes.

"This begs the question of whether the outcomes in this trial would have been the same if patients had been merely rechallenged with the same first-line treatment they’d received," he said. "I think the bigger issue though is that we’ve reached a therapeutic plateau with our current chemotherapy options, and we’re going to need to explore some new, innovative strategies in order to make any real, significant differences in this disease."

Topotecan is the only drug approved by the Food and Drug Administration as second-line chemotherapy for relapsed SCLC.

SCLC accounts for about 15% of lung cancers, and without treatment has a median survival from diagnosis of only 2-4 months.

The Japan Clinical Oncology Group 0605 trial enrolled 180 patients, who responded to first-line platinum-based chemotherapy or chemoradiotherapy, but relapsed 90 days or more after the completion of treatment. Patients were evenly randomized to topotecan or PEI chemotherapy. Patients also received granulocyte colony-stimulating factor support.

The median time from completion of first-line chemotherapy to relapse/progression was 148 days in the topotecan arm and 181 days in the PEI arm. A performance status of 0 was present in 44% and 58%, respectively. The median age was 64 years.

There were nine complete responses and 61 partial responses to PEI chemotherapy among 83 patients with measurable lesions, compared with no complete responses and 23 partial responses in 86 such patients treated with topotecan.

The study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan. Dr. Goto reported no financial disclosures.

[email protected]

CHICAGO – Cisplatin, etoposide, and irinotecan provide a significant survival advantage over topotecan as second-line chemotherapy in sensitive relapsed small cell lung cancer, but the toxicity of the combination dampened the overall results of the phase III JCOG0605 trial.

The primary end point of median overall survival was 12.5 months with topotecan (Hycamtin) and 18.2 months with cisplatin (Platinol), etoposide, and irinotecan (PEI) chemotherapy (hazard ratio, 0.67; P = .0079).

"This is the first time that combination chemotherapy has demonstrated a survival benefit, compared with single-agent topotecan," Dr. Koichi Goto reported at the annual meeting of the American Society of Clinical Oncology.

PEI chemotherapy also substantially improved median progression-free survival from 3.6 months with topotecan to 5.7 months (HR, 0.50; P less than .0001) and the overall response rate from 26.7% to 84.3% (P less than .01).

Phase II data from the same investigators showed an overall response rate of 78% and a median survival time of 11.8 months with PEI chemotherapy in 40 patients with sensitive relapsed small cell lung cancer (SCLC) (Br. J. Cancer 2004;91:659-65).

"Combination chemotherapy with cisplatin, etoposide, and irinotecan should be considered the standard second-line treatment for sensitive relapsed small cell lung cancer," said Dr. Goto of the division of thoracic oncology, National Cancer Center Hospital East, Kashiwa, Japan.

At first glance, the results seem impressive, but the higher than expected survival rates in both arms suggest the patients were selected, said Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, who was invited to discuss the results.

Patients in the trial also mostly had progression 6 months after initial treatment, and current National Comprehensive Cancer Network guidelines recommend rechallenging such patients with their original chemotherapy regimen.

"Furthermore, the treatment with the three-drug regimen was given at the cost of severe toxicities," he said.

There were higher rates of grades 3/4 leukopenia (80% vs. 51%), febrile neutropenia (31% vs. 6.7%), and diarrhea (7.8% vs. 0%), and 50% of patients treated with PEI required a dose reduction. Dr. Lee noted that these findings support those in other trials where the addition of a third drug in small cell lung cancer creates greater toxicity without providing any further benefit in outcomes.

"This begs the question of whether the outcomes in this trial would have been the same if patients had been merely rechallenged with the same first-line treatment they’d received," he said. "I think the bigger issue though is that we’ve reached a therapeutic plateau with our current chemotherapy options, and we’re going to need to explore some new, innovative strategies in order to make any real, significant differences in this disease."

Topotecan is the only drug approved by the Food and Drug Administration as second-line chemotherapy for relapsed SCLC.

SCLC accounts for about 15% of lung cancers, and without treatment has a median survival from diagnosis of only 2-4 months.

The Japan Clinical Oncology Group 0605 trial enrolled 180 patients, who responded to first-line platinum-based chemotherapy or chemoradiotherapy, but relapsed 90 days or more after the completion of treatment. Patients were evenly randomized to topotecan or PEI chemotherapy. Patients also received granulocyte colony-stimulating factor support.

The median time from completion of first-line chemotherapy to relapse/progression was 148 days in the topotecan arm and 181 days in the PEI arm. A performance status of 0 was present in 44% and 58%, respectively. The median age was 64 years.

There were nine complete responses and 61 partial responses to PEI chemotherapy among 83 patients with measurable lesions, compared with no complete responses and 23 partial responses in 86 such patients treated with topotecan.

The study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan. Dr. Goto reported no financial disclosures.

[email protected]

CHICAGO – Cisplatin, etoposide, and irinotecan provide a significant survival advantage over topotecan as second-line chemotherapy in sensitive relapsed small cell lung cancer, but the toxicity of the combination dampened the overall results of the phase III JCOG0605 trial.

The primary end point of median overall survival was 12.5 months with topotecan (Hycamtin) and 18.2 months with cisplatin (Platinol), etoposide, and irinotecan (PEI) chemotherapy (hazard ratio, 0.67; P = .0079).

"This is the first time that combination chemotherapy has demonstrated a survival benefit, compared with single-agent topotecan," Dr. Koichi Goto reported at the annual meeting of the American Society of Clinical Oncology.

PEI chemotherapy also substantially improved median progression-free survival from 3.6 months with topotecan to 5.7 months (HR, 0.50; P less than .0001) and the overall response rate from 26.7% to 84.3% (P less than .01).

Phase II data from the same investigators showed an overall response rate of 78% and a median survival time of 11.8 months with PEI chemotherapy in 40 patients with sensitive relapsed small cell lung cancer (SCLC) (Br. J. Cancer 2004;91:659-65).

"Combination chemotherapy with cisplatin, etoposide, and irinotecan should be considered the standard second-line treatment for sensitive relapsed small cell lung cancer," said Dr. Goto of the division of thoracic oncology, National Cancer Center Hospital East, Kashiwa, Japan.

At first glance, the results seem impressive, but the higher than expected survival rates in both arms suggest the patients were selected, said Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, who was invited to discuss the results.

Patients in the trial also mostly had progression 6 months after initial treatment, and current National Comprehensive Cancer Network guidelines recommend rechallenging such patients with their original chemotherapy regimen.

"Furthermore, the treatment with the three-drug regimen was given at the cost of severe toxicities," he said.

There were higher rates of grades 3/4 leukopenia (80% vs. 51%), febrile neutropenia (31% vs. 6.7%), and diarrhea (7.8% vs. 0%), and 50% of patients treated with PEI required a dose reduction. Dr. Lee noted that these findings support those in other trials where the addition of a third drug in small cell lung cancer creates greater toxicity without providing any further benefit in outcomes.

"This begs the question of whether the outcomes in this trial would have been the same if patients had been merely rechallenged with the same first-line treatment they’d received," he said. "I think the bigger issue though is that we’ve reached a therapeutic plateau with our current chemotherapy options, and we’re going to need to explore some new, innovative strategies in order to make any real, significant differences in this disease."

Topotecan is the only drug approved by the Food and Drug Administration as second-line chemotherapy for relapsed SCLC.

SCLC accounts for about 15% of lung cancers, and without treatment has a median survival from diagnosis of only 2-4 months.

The Japan Clinical Oncology Group 0605 trial enrolled 180 patients, who responded to first-line platinum-based chemotherapy or chemoradiotherapy, but relapsed 90 days or more after the completion of treatment. Patients were evenly randomized to topotecan or PEI chemotherapy. Patients also received granulocyte colony-stimulating factor support.

The median time from completion of first-line chemotherapy to relapse/progression was 148 days in the topotecan arm and 181 days in the PEI arm. A performance status of 0 was present in 44% and 58%, respectively. The median age was 64 years.

There were nine complete responses and 61 partial responses to PEI chemotherapy among 83 patients with measurable lesions, compared with no complete responses and 23 partial responses in 86 such patients treated with topotecan.

The study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan. Dr. Goto reported no financial disclosures.

[email protected]

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)-positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median overall survival (OS) in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), N.Y. (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO (Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation-positive NSCLC, and reached 96% in stage 1 and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug administration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)-positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median overall survival (OS) in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), N.Y. (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO (Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation-positive NSCLC, and reached 96% in stage 1 and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug administration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – The phase III RADIANT trial of adjuvant erlotinib failed to meet its primary endpoint in early-stage, resected non–small cell lung cancer, but shores up support for adjuvant EGFR tyrosine kinase inhibitors in patients with an EGFR mutation.

RADIANT sought to determine whether adjuvant erlotinib (Tarceva) 150 mg/day, with or without chemotherapy, would prolong disease-free survival in patients with completely resected stage IB to IIIA epidermal growth factor receptor (EGFR)-positive non–small cell lung cancer (NSCLC).

Erlotinib, an EGFR tyrosine kinase inhibitor (TKI), has proven efficacy in advanced-stage NSCLC in several settings: as second- and third-line therapy in unselected patients, first-line maintenance therapy in unselected patients, and first-line therapy in patients with EGFR activating mutations.

Among all 973 randomized patients, however, the study’s primary endpoint of median disease-free survival (DFS) was not significantly different at 48.2 months for placebo and 50.5 months for erlotinib (hazard ratio, 0.90; P = .32), Dr. Karen Kelly reported at the annual meeting of the American Society of Clinical Oncology.

The median duration of treatment was noticeably shorter with erlotinib (11.9 months vs. 21.9 months).

At a median follow-up of 47 months, overall survival (OS) data were immature, she said. At the time of the analysis, there were 95 events in the placebo arm and 182 events in the erlotinib arm (HR, 1.13; P = .33), with the median not yet reached.

It was hoped the results of RADIANT would also clarify the broader question of whether adjuvant treatment with EGFR TKIs improves outcomes for patients whose tumors harbor an EGFR mutation.

In a subset analysis of 161 patients with deletion 19 or L858R EGFR mutations, median DFS favored erlotinib at 46.4 months vs. 28.5 months for placebo (HR, 0.61; P = .0391).

This 18-month difference, however, was not statistically significant because the study’s hierarchical testing procedure dictated that if the primary endpoint was not met all subsequent endpoints would be deemed nonsignificant, explained Dr. Kelly of the University of California–Davis Comprehensive Cancer Center, Sacramento.

Exposure to erlotinib and placebo was similar in the EGFR-mutated subgroup (median 21.2 months vs. 21.9 months). Importantly, patients treated with placebo had more stage IIIA disease at baseline (30.5% vs. 17.6%), she noted.

Median overall survival (OS) in the mutation-positive subset was also not reached, with 13 events in the placebo arm and 22 in the erlotinib arm (HR, 1.09; P = .81).

Invited discussant Dr. Nasser Hanna of the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, called the data of adjuvant erlotinib in patients with an activating EGFR mutation "persuasive and compelling."

Enthusiasm for adjuvant EGFR TKI therapy for early-stage NSCLC has wavered in light of the consistent development of acquired resistance to EGFR TKIs in metastatic disease, and data from two randomized trials showing that the EGFR TKI gefitinib (Iressa) did not improve survival in advanced NSCLC and was potentially detrimental after chemoradiotherapy plus docetaxel in stage III disease.

The results prompted the premature closure of the Canadian phase III BR19 trial of adjuvant gefitinib in completely resected stage 1B-IIIA NSCLC, which reported no DFS or OS benefits from gefitinib in the total population or in the 15 patients with EGFR mutations (J. Clin. Oncol. 2013;31:3320-6).

To put the current subset analysis in perspective, however, Dr. Hanna pointed out that the magnitude of gain in DFS with adjuvant EGFR TKI therapy is now consistent across three datasets: RADIANT, the phase II SELECT trial, and an analysis by Memorial Sloan-Kettering Cancer Center (MSKCC), N.Y. (J. Thorac. Oncol. 2011;6:569-75).

Two-year DFS with adjuvant erlotinib was 89% in patients with completely resected stage I-III NSCLC with EGFR exon 19 or 21 mutations treated at MSKCC, after controlling for stage, type of surgery, and adjuvant platinum chemotherapy.

Data reported from SELECT at this year’s ASCO (Ab. 7514) showed 2-year DFS was also 89% with adjuvant erlotinib in EGFR mutation-positive NSCLC, and reached 96% in stage 1 and 91% in stage III disease, he said.

"We don’t have just one data point; we have three data points that are consistent," Dr. Hanna said. "This magnitude of gain is substantial and it is significant, and it appears potentially far more than with adjuvant chemotherapy."

He said the jury is still out on overall survival, but observed that the Food and Drug administration granted accelerated approval for imatinib (Gleevec) in KIT-mutant gastrointestinal stromal tumors based on DFS alone.

In an interview, Dr. Hanna said he has never used an EGFR TKI in any disease setting except the metastatic setting, and though persuasive, the RADIANT, SELECT, and MSKCC data are not conclusive and that a phase III trial is planned.

"I know that other experts have been using erlotinib in the adjuvant setting, though, off of a clinical trial," he said. "I’ve struggled with the issue, but I don’t think I’m ready to go there yet."

Dr. Kelly said the safety profile of erlotinib was generally consistent with that observed in the advanced disease setting and that additional biomarker analyses are ongoing.

Dr. Kelly and Dr. Hanna reported no relevant disclosures. Several coauthors reported financial relationships with Astellas Pharma, Roche, OSI Pharmaceuticals, or Novella Clinical.

[email protected]

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small cell lung cancer who responded to chemotherapy, according to results from the randomized CREST trial.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small cell lung cancer who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

The vast majority of these patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, explained Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intra-thoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

Dr. Slotman and his coauthors reported no financial disclosures.

[email protected]

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small cell lung cancer who responded to chemotherapy, according to results from the randomized CREST trial.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small cell lung cancer who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

The vast majority of these patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, explained Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intra-thoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

Dr. Slotman and his coauthors reported no financial disclosures.

[email protected]

CHICAGO – Thoracic radiotherapy improved overall survival, progression-free survival, and intrathoracic control in patients with extensive small cell lung cancer who responded to chemotherapy, according to results from the randomized CREST trial.

"Thoracic radiotherapy should be offered in addition to PCI [prophylactic cranial irradiation] to all extensive-stage small cell lung cancer patients responding to initial chemotherapy," Dr. Ben J. Slotman said at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

The rationale for CREST (Chest Radiotherapy Extensive Stage Trial) was based on an earlier trial by Dr. Slotman showing that prophylactic cranial irradiation not only lowered the risk of symptomatic brain metastases but also significantly improved 1-year overall survival compared with no additional therapy in patients with extensive small cell lung cancer who had any response to chemotherapy (N. Engl. J. Med. 2007;357:664-72).

The vast majority of these patients, however, had persistent intrathoracic disease after chemotherapy or intrathoracic progression, explained Dr. Slotman, professor and head of radiation oncology, VU Medical Center, Amsterdam.

CREST investigators at 42 centers in the Netherlands, the United Kingdom, Norway, and Belgium randomly assigned 498 patients with any response after four to six cycles of initial platinum-based chemotherapy to thoracic radiotherapy (TRT) (30 Gy in 10 fractions) plus PCI or PCI only. Treatment began within 2-7 weeks of their last chemotherapy. Patients with brain or plural metastasis, pleuritis carcinomatosa, or prior radiotherapy (RT) to the brain or thorax were excluded.

About 70% of patients had a partial response to chemotherapy, and almost 90% still had persistent intrathoracic disease at the time of randomization. Their median age was 63 years.

Overall survival at 1 year was not statistically different between the TRT and no TRT arms (33% vs. 28%; hazard ratio, 0.84; P = .066). The survival curves began to diverge after 9 months, however, leading to a significant overall survival benefit favoring TRT at 18 months (P = .03) and 24 months (13% vs. 3%; P = .004), Dr. Slotman said.

A subgroup analysis found no influence on overall survival for treatment factors such as age, sex, response after chemotherapy, or presence of intra-thoracic disease at randomization.

Discussant Dr. Walter J. Curran Jr., executive director of the Winship Cancer Institute of Emory University, Atlanta, said CREST was a well-executed and adequately powered trial, but argued that its conclusion that thoracic RT improves overall survival "is not supported by the presented data."

The hazard ratio of 0.84 failed to reach the HR goal of 0.76, and the comparison at 2 years was not the primary end point of the trial, he said.

Dr. Curran said there is a rationale for why sequential chemotherapy-radiation would work for patients with more extensive disease, even though every randomized limited disease small cell trial has shown a benefit with concurrent vs. sequential chemotherapy-radiation therapy or early vs. delayed concurrent chemoradiation, and little to no benefit with sequential chemoradiation, compared with chemotherapy alone.

"The rationale behind it, and it’s a reasonable one, is that in the noncurative setting, which is what we’re dealing with if you remember the survival curves Dr. Slotman showed us, we really are probably talking about debulking chemoresistant disease," he said. "If one is able to do that with limited toxicity and without long-lasting morbidity, that might extend survival but certainly is not going to procure cure rates as thoracic radiation can do in limited disease."

Progression-free survival was significantly better in patients receiving TRT vs. no TRT (HR, 0.73; P = .001), Dr. Slotman said.

TRT-treated patients also had significantly less intrathoracic progression overall (43.7% vs. 80%; P less than .001), as the first site of relapse (41.7% vs. 78%; P less than .001), and as the only site of relapse (20% vs. 46%; P less than .001).

Going forward, Dr. Curran said it will be important to know whether patients with extensive-stage disease receiving TRT also have less progression of thoracic disease and to better understand quality of life and toxicity associated with the therapy.

Dr. Slotman said grade 3/4 toxicity was similar between groups, although those receiving radiation had a modest increased risk of grade 3 fatigue (11 vs. 8 events) and grade 3 esophagitis (4 events vs. 0 events).

Dr. Slotman and his coauthors reported no financial disclosures.

[email protected]

CHICAGO – Women with breast cancer and bone metastases previously treated with bisphosphonates can safely reduce the frequency of their zoledronic acid infusions, according to results from the phase III OPTIMIZE-2 study.

At a median follow-up of 11.9 months, the skeletal-related event (SRE) rate, the study’s primary endpoint, was 23.2% with zoledronic acid (Zometa) every 12 weeks and 22% with zoledronic acid every 4 weeks (P = .724).

The upper limit of the 95% confidence interval for the SRE rate difference was 9.8%, which is below the predefined noninferiority margin of 10%, Dr. Gabriel N. Hortobagyi reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Zoledronic acid, a third-generation bisphosphonate, is used to reduce the risk of SREs such as bone fractures and spinal cord compression in patients with bone metastases from solid tumors, and is approved to be administered every 3-4 weeks by intravenous infusion.

It has safety concerns similar to other bisphosphonates such as atypical fractures, chronic kidney impairment, and osteonecrosis of the jaw, and therefore, less frequent dosing could have distinct advantages, Dr. Hortobagyi, professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston, said during a press briefing highlighting the study.

Dr. Patricia Ganz, professor of medicine at the University of California, Los Angeles, told reporters that for women living with advanced breast cancer and bone metastases, the late-breaking abstract results mean they can spend more time with family and friends and less time in their doctor’s office, with less toxicity and less cost.

"Sometimes we have to add things, but sometimes we have to take away to add value to patients’ care," she said.

The noninferiority, double-blind OPTIMIZE-2 trial enrolled 412 patients with breast cancer and bone metastases and randomly assigned 403 patients to 4 mg intravenous zoledronic acid every 4 weeks or every 12 weeks for 1 year. All participants had received at least nine doses of zoledronic acid or pamidronate prior to study entry. Their average age was 59 years.

The mean skeletal morbidity rate was 0.46 with monthly zoledronic acid and 0.50 with quarterly treatment (P = .854), Dr. Hortobagyi said.

Times to first on-study SRE were also similar in the two arms (Hazard ratio, 1.06; P = .792).

The safety profile was similar in both arms, although there were more kidney-related adverse events in the monthly arm than in the quarterly arm (9.6% vs. 7.9%), he said.

Women dosed monthly had more grade 3/4 adverse events (47.5% vs. 42.6%) and were more likely to stop treatment due to these events (11.6% vs. 8.9%).

Two patients treated monthly developed osteonecrosis of the jaw, whereas none did with quarterly treatment.

Bone marker profiles were similar between arms, Dr. Hortobagyi said. Serum bone-specific alkaline phosphatase was not significantly different at any time point and urinary N-telopeptide/creatinine was significantly different at week 36 only.

Because of study limitations, such as its relatively modest size, and statistical concerns, the inferiority claim should be interpreted with caution, he said. The protocol was revised during the course of the trial including a placebo arm that was dropped because of poor accrual. The sample size was also reduced from 705 to 412 patients based on new data that became available from the ZOOM trial.

As previously reported, ZOOM also demonstrated no difference in skeletal morbidity rate, its primary endpoint, between zoledronic acid dosed quarterly or monthly in women with metastatic breast cancer and bone metastases.

Novartis sponsored the trial. Dr. Hortobagyi disclosed serving as a consultant to Antigen Express, Novartis, and Pfizer, and research funds to his institution from Novartis.

[email protected]

CHICAGO – Women with breast cancer and bone metastases previously treated with bisphosphonates can safely reduce the frequency of their zoledronic acid infusions, according to results from the phase III OPTIMIZE-2 study.

At a median follow-up of 11.9 months, the skeletal-related event (SRE) rate, the study’s primary endpoint, was 23.2% with zoledronic acid (Zometa) every 12 weeks and 22% with zoledronic acid every 4 weeks (P = .724).

The upper limit of the 95% confidence interval for the SRE rate difference was 9.8%, which is below the predefined noninferiority margin of 10%, Dr. Gabriel N. Hortobagyi reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Zoledronic acid, a third-generation bisphosphonate, is used to reduce the risk of SREs such as bone fractures and spinal cord compression in patients with bone metastases from solid tumors, and is approved to be administered every 3-4 weeks by intravenous infusion.

It has safety concerns similar to other bisphosphonates such as atypical fractures, chronic kidney impairment, and osteonecrosis of the jaw, and therefore, less frequent dosing could have distinct advantages, Dr. Hortobagyi, professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston, said during a press briefing highlighting the study.

Dr. Patricia Ganz, professor of medicine at the University of California, Los Angeles, told reporters that for women living with advanced breast cancer and bone metastases, the late-breaking abstract results mean they can spend more time with family and friends and less time in their doctor’s office, with less toxicity and less cost.

"Sometimes we have to add things, but sometimes we have to take away to add value to patients’ care," she said.

The noninferiority, double-blind OPTIMIZE-2 trial enrolled 412 patients with breast cancer and bone metastases and randomly assigned 403 patients to 4 mg intravenous zoledronic acid every 4 weeks or every 12 weeks for 1 year. All participants had received at least nine doses of zoledronic acid or pamidronate prior to study entry. Their average age was 59 years.

The mean skeletal morbidity rate was 0.46 with monthly zoledronic acid and 0.50 with quarterly treatment (P = .854), Dr. Hortobagyi said.

Times to first on-study SRE were also similar in the two arms (Hazard ratio, 1.06; P = .792).

The safety profile was similar in both arms, although there were more kidney-related adverse events in the monthly arm than in the quarterly arm (9.6% vs. 7.9%), he said.

Women dosed monthly had more grade 3/4 adverse events (47.5% vs. 42.6%) and were more likely to stop treatment due to these events (11.6% vs. 8.9%).

Two patients treated monthly developed osteonecrosis of the jaw, whereas none did with quarterly treatment.

Bone marker profiles were similar between arms, Dr. Hortobagyi said. Serum bone-specific alkaline phosphatase was not significantly different at any time point and urinary N-telopeptide/creatinine was significantly different at week 36 only.

Because of study limitations, such as its relatively modest size, and statistical concerns, the inferiority claim should be interpreted with caution, he said. The protocol was revised during the course of the trial including a placebo arm that was dropped because of poor accrual. The sample size was also reduced from 705 to 412 patients based on new data that became available from the ZOOM trial.

As previously reported, ZOOM also demonstrated no difference in skeletal morbidity rate, its primary endpoint, between zoledronic acid dosed quarterly or monthly in women with metastatic breast cancer and bone metastases.

Novartis sponsored the trial. Dr. Hortobagyi disclosed serving as a consultant to Antigen Express, Novartis, and Pfizer, and research funds to his institution from Novartis.

[email protected]

CHICAGO – Women with breast cancer and bone metastases previously treated with bisphosphonates can safely reduce the frequency of their zoledronic acid infusions, according to results from the phase III OPTIMIZE-2 study.

At a median follow-up of 11.9 months, the skeletal-related event (SRE) rate, the study’s primary endpoint, was 23.2% with zoledronic acid (Zometa) every 12 weeks and 22% with zoledronic acid every 4 weeks (P = .724).

The upper limit of the 95% confidence interval for the SRE rate difference was 9.8%, which is below the predefined noninferiority margin of 10%, Dr. Gabriel N. Hortobagyi reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Zoledronic acid, a third-generation bisphosphonate, is used to reduce the risk of SREs such as bone fractures and spinal cord compression in patients with bone metastases from solid tumors, and is approved to be administered every 3-4 weeks by intravenous infusion.

It has safety concerns similar to other bisphosphonates such as atypical fractures, chronic kidney impairment, and osteonecrosis of the jaw, and therefore, less frequent dosing could have distinct advantages, Dr. Hortobagyi, professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston, said during a press briefing highlighting the study.

Dr. Patricia Ganz, professor of medicine at the University of California, Los Angeles, told reporters that for women living with advanced breast cancer and bone metastases, the late-breaking abstract results mean they can spend more time with family and friends and less time in their doctor’s office, with less toxicity and less cost.

"Sometimes we have to add things, but sometimes we have to take away to add value to patients’ care," she said.

The noninferiority, double-blind OPTIMIZE-2 trial enrolled 412 patients with breast cancer and bone metastases and randomly assigned 403 patients to 4 mg intravenous zoledronic acid every 4 weeks or every 12 weeks for 1 year. All participants had received at least nine doses of zoledronic acid or pamidronate prior to study entry. Their average age was 59 years.

The mean skeletal morbidity rate was 0.46 with monthly zoledronic acid and 0.50 with quarterly treatment (P = .854), Dr. Hortobagyi said.

Times to first on-study SRE were also similar in the two arms (Hazard ratio, 1.06; P = .792).

The safety profile was similar in both arms, although there were more kidney-related adverse events in the monthly arm than in the quarterly arm (9.6% vs. 7.9%), he said.

Women dosed monthly had more grade 3/4 adverse events (47.5% vs. 42.6%) and were more likely to stop treatment due to these events (11.6% vs. 8.9%).

Two patients treated monthly developed osteonecrosis of the jaw, whereas none did with quarterly treatment.

Bone marker profiles were similar between arms, Dr. Hortobagyi said. Serum bone-specific alkaline phosphatase was not significantly different at any time point and urinary N-telopeptide/creatinine was significantly different at week 36 only.

Because of study limitations, such as its relatively modest size, and statistical concerns, the inferiority claim should be interpreted with caution, he said. The protocol was revised during the course of the trial including a placebo arm that was dropped because of poor accrual. The sample size was also reduced from 705 to 412 patients based on new data that became available from the ZOOM trial.

As previously reported, ZOOM also demonstrated no difference in skeletal morbidity rate, its primary endpoint, between zoledronic acid dosed quarterly or monthly in women with metastatic breast cancer and bone metastases.

Novartis sponsored the trial. Dr. Hortobagyi disclosed serving as a consultant to Antigen Express, Novartis, and Pfizer, and research funds to his institution from Novartis.

[email protected]