Biomarker unreliability scratches trial of customized chemotherapy

Customized adjuvant chemotherapy for non–small-cell lung cancer proved feasible in a phase II trial in 150 patients, but the unreliability of some biomarker tests led to cancellation of a planned phase III study of the efficacy of individualizing treatment based on biomarker status.

The prospective phase II trial at 29 French centers enrolled patients who had completely resected nonsquamous cell, stage II or IIIA (non-N2) tumors and had no prior chemotherapy. Within 2 months of surgery, 80% of all patients had complete biomarker status results and were able to start adjuvant treatment, showing that timely customized adjuvant therapy is feasible, Dr. Marie Wislez and her associates reported in the Journal of Clinical Oncology.

The study randomized 74 patients to a control group receiving conventional treatment with four courses of cisplatin (75 mg/m²) plus pemetrexed (500 mg/m²) every 21 days plus vitamin B₁₂ supplements and corticosteroids. Among 76 patients randomized to the customized treatment group, 7 patients with activated epidermal growth factor receptor (mutations were treated with oral erlotinib 150 mg/day for 1 year. In the customized group, 53 patients who were negative for excision repair cross-complementation group 1 (ERCC1) were to receive the same cisplatin/pemetrexed regimen as the control group, and 16 ERCC1-positive patients were simply followed, the investigators reported (J. Clin. Oncol. 2014 March 17 [doi:10.1200/JCO.2013.53.1525]).

Patients were to be followed every 6 months for the first 5 years after surgery. The adjuvant therapies generally were well tolerated.

The investigators discovered unexpectedly, however, that assays for ERCC1 expression were unreliable, reported Dr. Wislez of Tenon Hospital, Paris, and her associates. ERCC1-positive patients made up 25% of patients in the study, compared with 44% of patients with non–small-cell lung cancer in the previous IALT (International Adjuvant Lung Cancer) trial (N. Engl. J. Med. 2006;355:983-91).

When Dr. Wislez and her associates restained biosamples from the IALT trial using the 8F1 antibody test commercially available in 2011, they found important discrepancies between the IALT’s results from 2006 and those obtained in 2001.The unreliability of the ERCC1 immunohistochemical readouts led them to cancel the planned phase III TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial until ERCC1 testing methodology can be improved.

The current phase II trial also found that the epidermal growth factor receptor mutation rate (6.7%) was lower than expected based on previously published data, whether analyzed using probe-specific polymerase chain reaction or by direct sequencing methodology.

Some of Dr. Wislez’s associates in the study reported financial associations with Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Pfizer, and/or Amgen.

[email protected]

On Twitter @sherryboschert

Customized adjuvant chemotherapy for non–small-cell lung cancer proved feasible in a phase II trial in 150 patients, but the unreliability of some biomarker tests led to cancellation of a planned phase III study of the efficacy of individualizing treatment based on biomarker status.

The prospective phase II trial at 29 French centers enrolled patients who had completely resected nonsquamous cell, stage II or IIIA (non-N2) tumors and had no prior chemotherapy. Within 2 months of surgery, 80% of all patients had complete biomarker status results and were able to start adjuvant treatment, showing that timely customized adjuvant therapy is feasible, Dr. Marie Wislez and her associates reported in the Journal of Clinical Oncology.

The study randomized 74 patients to a control group receiving conventional treatment with four courses of cisplatin (75 mg/m²) plus pemetrexed (500 mg/m²) every 21 days plus vitamin B₁₂ supplements and corticosteroids. Among 76 patients randomized to the customized treatment group, 7 patients with activated epidermal growth factor receptor (mutations were treated with oral erlotinib 150 mg/day for 1 year. In the customized group, 53 patients who were negative for excision repair cross-complementation group 1 (ERCC1) were to receive the same cisplatin/pemetrexed regimen as the control group, and 16 ERCC1-positive patients were simply followed, the investigators reported (J. Clin. Oncol. 2014 March 17 [doi:10.1200/JCO.2013.53.1525]).

Patients were to be followed every 6 months for the first 5 years after surgery. The adjuvant therapies generally were well tolerated.

The investigators discovered unexpectedly, however, that assays for ERCC1 expression were unreliable, reported Dr. Wislez of Tenon Hospital, Paris, and her associates. ERCC1-positive patients made up 25% of patients in the study, compared with 44% of patients with non–small-cell lung cancer in the previous IALT (International Adjuvant Lung Cancer) trial (N. Engl. J. Med. 2006;355:983-91).

When Dr. Wislez and her associates restained biosamples from the IALT trial using the 8F1 antibody test commercially available in 2011, they found important discrepancies between the IALT’s results from 2006 and those obtained in 2001.The unreliability of the ERCC1 immunohistochemical readouts led them to cancel the planned phase III TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial until ERCC1 testing methodology can be improved.

The current phase II trial also found that the epidermal growth factor receptor mutation rate (6.7%) was lower than expected based on previously published data, whether analyzed using probe-specific polymerase chain reaction or by direct sequencing methodology.

Some of Dr. Wislez’s associates in the study reported financial associations with Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Pfizer, and/or Amgen.

[email protected]

On Twitter @sherryboschert

Customized adjuvant chemotherapy for non–small-cell lung cancer proved feasible in a phase II trial in 150 patients, but the unreliability of some biomarker tests led to cancellation of a planned phase III study of the efficacy of individualizing treatment based on biomarker status.

The prospective phase II trial at 29 French centers enrolled patients who had completely resected nonsquamous cell, stage II or IIIA (non-N2) tumors and had no prior chemotherapy. Within 2 months of surgery, 80% of all patients had complete biomarker status results and were able to start adjuvant treatment, showing that timely customized adjuvant therapy is feasible, Dr. Marie Wislez and her associates reported in the Journal of Clinical Oncology.

The study randomized 74 patients to a control group receiving conventional treatment with four courses of cisplatin (75 mg/m²) plus pemetrexed (500 mg/m²) every 21 days plus vitamin B₁₂ supplements and corticosteroids. Among 76 patients randomized to the customized treatment group, 7 patients with activated epidermal growth factor receptor (mutations were treated with oral erlotinib 150 mg/day for 1 year. In the customized group, 53 patients who were negative for excision repair cross-complementation group 1 (ERCC1) were to receive the same cisplatin/pemetrexed regimen as the control group, and 16 ERCC1-positive patients were simply followed, the investigators reported (J. Clin. Oncol. 2014 March 17 [doi:10.1200/JCO.2013.53.1525]).

Patients were to be followed every 6 months for the first 5 years after surgery. The adjuvant therapies generally were well tolerated.

The investigators discovered unexpectedly, however, that assays for ERCC1 expression were unreliable, reported Dr. Wislez of Tenon Hospital, Paris, and her associates. ERCC1-positive patients made up 25% of patients in the study, compared with 44% of patients with non–small-cell lung cancer in the previous IALT (International Adjuvant Lung Cancer) trial (N. Engl. J. Med. 2006;355:983-91).

When Dr. Wislez and her associates restained biosamples from the IALT trial using the 8F1 antibody test commercially available in 2011, they found important discrepancies between the IALT’s results from 2006 and those obtained in 2001.The unreliability of the ERCC1 immunohistochemical readouts led them to cancel the planned phase III TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial until ERCC1 testing methodology can be improved.

The current phase II trial also found that the epidermal growth factor receptor mutation rate (6.7%) was lower than expected based on previously published data, whether analyzed using probe-specific polymerase chain reaction or by direct sequencing methodology.

Some of Dr. Wislez’s associates in the study reported financial associations with Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Pfizer, and/or Amgen.

[email protected]

On Twitter @sherryboschert