RADIANT offers mixed results for adjuvant erlotinib in NSCLC

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.

pwendling@frontlinemedcom.com

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.

pwendling@frontlinemedcom.com

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.

pwendling@frontlinemedcom.com