Telomerase Inhibitor Imetelstat for Advanced NSCLC
Eligible patients had pathologically confirmed stage IV (per AJCC) or recurrent locally advanced NSCLC (not eligible for curative intent therapy); had experienced no progression after completing first-line platinum-doublet chemotherapy (four cycles); had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1; were age ≥18 years; had measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and had adequate hematologic (ANC ≥1500/mm, hemoglobin ≥9 g/dl, platelet count ≥75 000 μl), renal (<1.5 mg/dl or creatinine clearance >45 ml/min), and hepatic [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5× the ULN, or <5× the upper limit of normal (ULN) if documented liver metastases, serum bilirubin <2.0 mg/dl and/or alkaline phosphatase <2.5× ULN or ≤5× ULN if liver or bone metastasis documented] function.
Exclusion criteria included patients with progressive disease, symptomatic or untreated central nervous system disease, and clinically significant infections or cardiovascular disease. Owing to bevacizumab use, history of pulmonary hemorrhage, therapeutic anticoagulation, and major surgery within 4 weeks before imetelstat were also exclusionary.
All patients provided written informed consent, and study approval was obtained from the institutional review boards at each of the participating centers. This study was registered with ClinicalTrials.gov (NCT01137968).
This was an open-label, multicenter, randomized phase II study of imetelstat switch maintenance therapy in patients with advanced NSCLC, non-progressive after four cycles of first-line, platinum-doublet chemotherapy, with or without bevacizumab. Patients receiving bevacizumab continued on the drug after randomization, and patients in the control arm had the option of crossover to imetelstat at progression (Figure 1).
(Enlarge Image)
Figure 1.
Study design.
Eligible patients were randomized 2:1 to imetelstat, administered intravenously at 9.4 mg/kg on days 1 and 8 every 21 days in addition to standard of care (bevacizumab or observation) or to standard of care alone. Randomization occurred between 21 and 42 days after the last dose of chemotherapy and was carried out by permuted block design and stratified according to receipt of bevacizumab during first-line chemotherapy.
Therapy continued until disease progression or unacceptable toxicities, and patients receiving both drugs (bevacizumab and imetelstat) could continue on one if the other was stopped. Crossover to imetelstat was allowed upon progressive disease.
Safety evaluations consisted of a history and physical examination, including vital signs and PS, as well as laboratory measurements. Toxicity assessments were carried out using the National Cancer Institute Common Toxicity Criteria (NCI CTCAE) v4.0.
For the study's primary end point (progression-free survival, PFS), tumor status was assessed every 6 weeks for 36 weeks and every 9 weeks thereafter for the remainder of the study. Responses were assessed with RECIST v1.1, and confirmation of a partial or complete response was required. As there was no blinded placebo control group, the lack of a central (independent) radiographic response assessment represented a potential limitation to our primary outcome's measures.
Methods for the assessment of biomarkers are described in supplementary Methods, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/2/354/suppl/DC1.
Criteria for patient dose modifications are described in supplementary Methods, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/2/354/suppl/DC1.
The primary study end point was PFS. Secondary end points included objective response rate (ORR), overall survival (OS), and safety profile. A prespecified exploratory analysis of PFS by tumor TL was also carried out.
Assuming median (m)PFS of 4.5 and 2.6 months for chemotherapy with and without bevacizumab, respectively, and an exponential survival with a hazard ratio (HR) of 0.5 for the imetelstat effect, the estimated mPFS for imetelstat without and with bevacizumab was 5.2 and 9 months, respectively. With a 2:1 randomization ratio in favor of the imetelstat arm, a total of 96 patients were planned and the estimated number of PFS events required was 67.
Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards models were used for PFS and OS (time-to-event) analyses. ORR results, including exact 95% two-sided CIs, were calculated using standard methods; χ and Wilcoxon rank-sum tests were used to test for differences in baseline characteristics.
Efficacy analyses by TL were prespecified for patients grouped into the shortest 1/2, shortest 1/3, and shortest 1/4 of TL.
Patients and Methods
Eligibility Criteria
Eligible patients had pathologically confirmed stage IV (per AJCC) or recurrent locally advanced NSCLC (not eligible for curative intent therapy); had experienced no progression after completing first-line platinum-doublet chemotherapy (four cycles); had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1; were age ≥18 years; had measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and had adequate hematologic (ANC ≥1500/mm, hemoglobin ≥9 g/dl, platelet count ≥75 000 μl), renal (<1.5 mg/dl or creatinine clearance >45 ml/min), and hepatic [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5× the ULN, or <5× the upper limit of normal (ULN) if documented liver metastases, serum bilirubin <2.0 mg/dl and/or alkaline phosphatase <2.5× ULN or ≤5× ULN if liver or bone metastasis documented] function.
Exclusion criteria included patients with progressive disease, symptomatic or untreated central nervous system disease, and clinically significant infections or cardiovascular disease. Owing to bevacizumab use, history of pulmonary hemorrhage, therapeutic anticoagulation, and major surgery within 4 weeks before imetelstat were also exclusionary.
All patients provided written informed consent, and study approval was obtained from the institutional review boards at each of the participating centers. This study was registered with ClinicalTrials.gov (NCT01137968).
Study Design and Treatment Plan
This was an open-label, multicenter, randomized phase II study of imetelstat switch maintenance therapy in patients with advanced NSCLC, non-progressive after four cycles of first-line, platinum-doublet chemotherapy, with or without bevacizumab. Patients receiving bevacizumab continued on the drug after randomization, and patients in the control arm had the option of crossover to imetelstat at progression (Figure 1).
(Enlarge Image)
Figure 1.
Study design.
Eligible patients were randomized 2:1 to imetelstat, administered intravenously at 9.4 mg/kg on days 1 and 8 every 21 days in addition to standard of care (bevacizumab or observation) or to standard of care alone. Randomization occurred between 21 and 42 days after the last dose of chemotherapy and was carried out by permuted block design and stratified according to receipt of bevacizumab during first-line chemotherapy.
Therapy continued until disease progression or unacceptable toxicities, and patients receiving both drugs (bevacizumab and imetelstat) could continue on one if the other was stopped. Crossover to imetelstat was allowed upon progressive disease.
Clinical Assessments
Safety evaluations consisted of a history and physical examination, including vital signs and PS, as well as laboratory measurements. Toxicity assessments were carried out using the National Cancer Institute Common Toxicity Criteria (NCI CTCAE) v4.0.
For the study's primary end point (progression-free survival, PFS), tumor status was assessed every 6 weeks for 36 weeks and every 9 weeks thereafter for the remainder of the study. Responses were assessed with RECIST v1.1, and confirmation of a partial or complete response was required. As there was no blinded placebo control group, the lack of a central (independent) radiographic response assessment represented a potential limitation to our primary outcome's measures.
Assessment of Biomarkers
Methods for the assessment of biomarkers are described in supplementary Methods, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/2/354/suppl/DC1.
Dose Modifications
Criteria for patient dose modifications are described in supplementary Methods, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/2/354/suppl/DC1.
Statistical Methods
The primary study end point was PFS. Secondary end points included objective response rate (ORR), overall survival (OS), and safety profile. A prespecified exploratory analysis of PFS by tumor TL was also carried out.
Assuming median (m)PFS of 4.5 and 2.6 months for chemotherapy with and without bevacizumab, respectively, and an exponential survival with a hazard ratio (HR) of 0.5 for the imetelstat effect, the estimated mPFS for imetelstat without and with bevacizumab was 5.2 and 9 months, respectively. With a 2:1 randomization ratio in favor of the imetelstat arm, a total of 96 patients were planned and the estimated number of PFS events required was 67.
Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards models were used for PFS and OS (time-to-event) analyses. ORR results, including exact 95% two-sided CIs, were calculated using standard methods; χ and Wilcoxon rank-sum tests were used to test for differences in baseline characteristics.
Efficacy analyses by TL were prespecified for patients grouped into the shortest 1/2, shortest 1/3, and shortest 1/4 of TL.
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