- Email: [email protected]
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer
original articles
19. Koivunen JP, Mermel C, Zejnullahu K et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008; 14: 4275–4283. 20. Gottschling S, Herpel E, Eberhardt WE et al. The gefitinib long-term responder (LTR)—a cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP). Lung Cancer 2012; 77: 183–191. 21. van der Wekken AJ, Stigt JA, A’T Hart N. A novel EGFR mutation in exon 19 showed stable disease after TKI treatment. J Thorac Oncol 2012; 7: e8. 22. Lee JK, Shin JY, Kim S et al. Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study. Ann Oncol 2013; 24: 2080–2087. 23. Zhou Q, Zhang XC, Chen ZH et al. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 3316–3321. 24. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–2394. 25. Iwasa Y, Nowak MA, Michor F. Evolution of resistance during clonal expansion. Genetics 2006; 172: 2557–2566. 26. Kim S, Kim TM, Kim DW et al. Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 2013; 8: 415–422.
Annals of Oncology 26: 354–362, 2015 doi:10.1093/annonc/mdu550 Published online 2 December 2014
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer A. A. Chiappori1*, T. Kolevska2, D. R. Spigel3, S. Hager4, M. Rarick5, S. Gadgeel6, N. Blais7, J. Von Pawel8, L. Hart9, M. Reck10, E. Bassett11, B. Burington11 & J. H. Schiller12 1
Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa; 2Department of Oncology, Kaiser Permanente Medical Center, Vallejo; Research Consortium, Sarah Cannon Research Institute, Nashville; 4Thoracic Department, Cancer Care Associates of Fresno Medical Group, Fresno; 5Oncology Hematology Department, Kaiser Permanente Northwest, Portland; 6Karmanos Cancer Institute, Detroit, USA; 7CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada; 8 Department of Oncology, Asklepios Fachkliniken Muenchen-Gauting, Gauting, Bayern, Germany; 9Sarah Cannon Florida Cancer Specialists, Bonita Springs, USA; 10 Department of Thoracic Oncology, LungenClinic Grosshansdorf, member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 11Department of Biostatistics, Geron Corporation, Menlo Park; 12Department of Oncology, University of Texas Southwestern Medical Center, Dallas, USA 3
Received 8 August 2014; revised 3 November 2014; accepted 19 November 2014
Background: Continuation or ‘switch’ maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. Patients and methods: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0–1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. *Correspondence to: Dr Alberto A. Chiappori, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA. Tel: +1-813-745-3050; Fax: +1-813-745-3027; E-mail: alberto.chiappori@ moffitt.org
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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12. Cabillic F, Gros A, Dugay F et al. Parallel FISH and immunohistochemical studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances. J Thorac Oncol 2014; 9: 295–306. 13. Santelmo C, Ravaioli A, Barzotti E et al. Coexistence of EGFR mutation and ALK translocation in NSCLC: literature review and case report of response to gefitinib. Lung Cancer 2013; 81: 294–296. 14. Chen X, Zhang J, Hu Q et al. A case of lung adenocarcinoma harboring exon 19 EGFR deletion and EML4-ALK fusion gene. Lung Cancer 2013; 81: 308–310. 15. Miyanaga A, Shimizu K, Noro R et al. Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small-cell lung cancer harbored coexisting EGFR mutation. BMC Cancer 2013; 13: 262. 16. Yang JJ, Zhang XC, Su J et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014; 20: 1383–1392. 17. Doebele RC, Pilling AB, Aisner DL et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472–1482. 18. Bai H, Wang Z, Wang Y et al. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One 2013; 8: e54170.
Annals of Oncology
Annals of Oncology
original articles
Results: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54–1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14–1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11–1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39–1.88; and HR = 0.51; 95% CI 0.2–1.28; P = 0.145). Conclusions: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat. Key words: non-small-cell lung cancer, biomarker, imetelstat
Telomeres consist of tandem repeats of the TTAGGG DNA sequence, which function to cap the ends of all mammalian chromosomes. Capping prevents chromosomal fusion and also prevents their ends from being misinterpreted as DNA double-strand breaks [1]. When telomeres get critically short, they can no longer cap the telomere ends, triggering a DNA damage signal and resulting in senescence and/or apoptosis [2, 3]. Telomere loss is prevented by the enzyme telomerase, which counters this loss by adding TTAGGG repeats to the chromosome ends [4]. Telomerase inhibition leads to the loss of a cancer cell’s ability to maintain telomere length (TL), similarly resulting in cell cycle arrest or apoptosis/senescence. Imetelstat is a covalently lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. Imetelstat’s mechanism of action is not an antisense-based approach. Rather, it binds with high affinity and acts as a competitive inhibitor of human telomerase enzymatic activity [5, 6]. Preclinical studies with imetelstat have shown its ability to inhibit telomerase in tumor cells and to compromise cancer cell viability in vitro. Imetelstat has broad tumor growth inhibition activity in multiple xenograft models, including metastatic nonsmall-cell lung cancer (NSCLC) and breast cancer [7, 8]. Platinum-based doublet, first-line chemotherapy [9, 10], with or without bevacizumab [11, 12], is the current treatment standard for patients with advanced NSCLC. Additional randomized data with pemetrexed and erlotinib have demonstrated that ‘maintenance therapy’ in NSCLC, either as continuation [13] or switch [14, 15], is effective. In this study, we evaluated the efficacy of switch maintenance therapy with imetelstat in advanced NSCLC patients and explored the potential use of TL as a surrogate (predictive biomarker) of imetelstat activity.
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 [16]; and had adequate hematologic (ANC 1500/mm3, 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). 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
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)
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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 [17]. 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,
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introduction
original articles
Annals of Oncology
Registration period 2 Stage IV NSCLC who are eligible for platinum based doublet therapy
Platinum based doublet +/– Bevacizumab x 4–6 cycles
If no PD
R A N D O M I Z E
Imetelstat (9.4mg/kg IV d1,8) + Bevacizumab (d1)
Imetelstat (9.4mg/kg IV d1,8)
Continue until PD or excessive toxicity
Bevacizumab (d1) 1
2:1 randomization Stratification based on bevacizumab
Optional cross over to imetelstat for standard therapy arm
Figure 1. Study design.
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.
dose modifications Criteria for patient dose modifications are described in supplementary Methods, available at Annals of Oncology online.
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 2 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.
results patient characteristics Originally, the protocol specified enrollment of 96 patients, with the primary analysis to be conducted after 67 PFS events. However, a retrospective review of all CT scan reports identified
| Chiappori et al.
seven ineligible patients (disease progression by RECIST v1.1 at randomization). For this reason, enrollment was increased to 116 and the primary analysis of PFS was conducted after 77 events. Exclusion of these seven patients from the analyses did not change the results substantially. Similarly, results using only the first 67 events were similar to those reported for the 77 events. A final and mature analysis of survival data was also conducted with 66 OS events. Thus, between July 2010 and April 2012, 116 patients were randomized and 114 completed a post-screening visit, including administration of protocol-specified therapy (i.e. efficacy population). Fifty-two patients received imetelstat alone, 24 received imatelstat plus bevacizumab, 12 received bevacizumab only, and 26 patients received neither. Baseline patient characteristics were well balanced between arms (Table 1). Squamous histology was present in 18.4%; 31.6% received concomitant bevacizumab.
adverse events Imetelstat was generally well tolerated, with ∼32% and 26% of patients requiring dose reductions and delays, respectively. Grade 3/4 neutropenia and thrombocytopenia were higher in the imetelstat arms, occurring in 17.3% and 12.5% versus 0% and 0% and 34.6% and 12.5% versus 0% and 0% for imetelstat (alone and with bevacizumab) versus control arms, respectively (Table 2). However, neutropenic fever and bleeding episodes (epistaxis, hemoptysis, pulmonary hemorrhage and intracranial hemorrhage) were infrequent (<2% each). All grade anemia adverse events were also more frequent with imetelstat (17.3% and 25% versus 3.8% and 8.3%, respectively), but only one patient experienced grade 3 anemia with imetelstat plus bevacizumab. The most frequent treatment-related non-hematologic adverse events involved the gastrointestinal (57.9%), musculoskeletal (45.6%), respiratory (39.5%), nervous (42.9%), tegumentary (26.3%), and psychiatric systems (21.9%). Constitutional symptoms, metabolic abnormalities, and infections occurred in 50.9%, 35.1%, and 30.7%, respectively, but only 7%, 3.5%, and
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Observation
original articles
Annals of Oncology
Table 1. Patient characteristics
No-bevacizumab
Sub-total
Observation Bevacizumab
No-bevacizumab
Sub-total
Total
24 (21.0)
52 (45.6)
76 (66.7)
12 (10.5)
26 (22.8)
38 (33.3)
56.9 42–76
65.3 44–81
63.1 53–80
65.1 30–84
11 (9.6) 13 (11.4)
27 (23.6) 25 (21.9)
38 (33.3) 38 (33.3)
8 (7.0) 4 (3.5)
19 (16.70 7 (6.1)
27 (23.6) 11 (9.6)
65 (57.0) 49 (43.0)
17 (14.9) 2 (1.7) 5 (4.4)
44 (38.6) 3 (2.6) 5 (4.4)
61 (53.5) 5 (4.4) 10 (8.8)
11 (9.6) 0 (0.0) 1 (0.9)
20 (17.5) 4 (3.5) 2 (1.7)
31 (27.2) 4 (3.5) 3 (2.6)
92 (80.7) 9 (7.9) 13 (11.4)
0 (0.0) 23 (20.1) 1 (0.9)
2 (1.7) 38 (33.3) 12 (10.5)
2 (1.7) 61 (53.5) 13 (11.4)
1 (0.9) 11 (9.6) 0 (0.0)
1 (0.9) 22 (19.3) 3 (2.6)
2 (1.7) 33 (28.9) 3 (2.6)
4 (3.5) 94 (82.5) 16 (14.0)
8 (7.0) 16 (14.0) 0 (0.0)
19 (16.7) 32 (28.1) 1 (0.9)
27 (23.6) 48 (42.1) 1 (0.9)
4 (3.5) 7 (6.1) 1 (0.9)
10 (8.8) 16 (14.0) 0 (0.0)
14 (12.3) 23 (20.2) 1 (0.9)
41 (36.0) 71 (62.3) 2 (1.7)
2 (1.7) 21 (18.4) 1 (0.9)
2 (1.7) 48 (42.1) 2 (1.7)
4 (3.5) 69 (60.5) 3 (2.6)
0 (0.0) 12 (10.5) 0 (0.0)
1 (0.9) 25 (21.9) 0 (0.0)
1 (0.9) 37 (32.5) 0 (0.0)
5 (4.4) 106 (93.0) 3 (2.6)
24 (21.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
37 (32.5) 10 (8.8) 1 (0.9) 0 (0.0) 4 (3.5)
61 (53.5) 10 (8.8) 1 (0.9) 0 (0.0) 4 (3.5)
10 (8.8) 0 (0.0) 0 (0.0) 1 (0.9) 1 (0.9)
13 (11.4) 11 (9.6) 0 (0.0) 1 (0.9) 1 (0.9)
23 (20.2) 11 (9.6) 0 (0.0) 2 (1.7) 2 (1.7)
84 (73.7) 21 (18.4) 1 (0.9) 2 (1.7) 6 (5.3)
0/10 (8.8) 14 (12.3)
0/16 (14.00 36 (31.6)
0/26 (22.8) 50 (43.9)
0/2 (1.7) 10 (8.8)
0/6 (5.3) 20 (17.5)
0/8 (7.0) 30 (26.3)
0/34 (29.8) 80 (70.2)
4 1–6
4 2–6
4 1–6
4 4–6
4 2–6
4 2–6
4 1–6
8 (7.0) 14 (12.3) 24 (21.0)
11 (9.6) 31 (27.2) 52 (45.6)
19 (16.7) 45 (39.5) 76 (66.7)
3 (2.6) 8 (7.0) 12 (10.5)
10 (8.8) 15 (13.2) 26 (22.8)
13 (11.4) 23 (20.2) 38 (33.3)
32 (28.1) 68 (59.6) 114 (100.0)
1/9 1/4
7/14 3/15
8/23 4/19
2/6 1/4
1/7 1/5
3/13 2/9
11/36 6/28
114 (100.0) 63.5 30–84
Curative and palliative included. ECOG, Eastern Cooperative Oncology Group; PS, performance status; NOS, not otherwise specified; CR/PR, complete response/partial response; SD, stable disease; EGFR, epidermal growth factor receptor; KRAS, V-Ki-rase2 Kirsten rat sarcoma viral oncogene homolog.
3.5%, respectively, were of grade 3/4 severity (Table 3). Both hematologic and non-hematologic adverse events were consistently more frequent in patients receiving imetelstat plus bevacizumab compared with imetelstat alone (anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, hypertension, dizziness, and headaches). However, imetelstat affected patients receiving bevacizumab differentially (lower pulmonary hemorrhage
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and proteinura, similar epistaxis and hypertension and higher fatigue, nausea/vomiting, headache, and myelusuppression). Overall, 17 patients discontinued treatment due to imetelstatrelated adverse events as determined by the investigator (10 in the imetelstat arm and 7 in the imetelstat plus bevacizumab arm). The most frequent causes for discontinuation were thrombocytopenia (6 patients), infusion reactions, and fatigue (2 patients each).
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No. (%) Age (years) Median Range Gender Male (%) Female (%) Race White (%) Black (%) Asian (%) Ethnicity Hispanic (%) Non-hispanic (%) Other/na (%) ECOG PS 0 (%) 1 (%) Not available (%) Disease stage IIIB (%) IV (%) Recurrent Dis (%) Histology Adenocarcinoma (%) Squamous (%) Adenosquamous (%) Large cell (%) NOS/other (%) Response to induction CR/PR (%) SD (%) Induction cycles Median Range Prior therapy Radiation (%) Surgery (any) (%) Systemic (%) Mutations (yes/no) EGFR KRAS
Imetelstat Bevacizumab
original articles
Annals of Oncology
Table 2. Hematologic and laboratory adverse events by treatment arm and severity (>5% total incidence) NCI CTCAE Grade
Observation (N = 26)
Imetelstat only (N = 52)
Bevacizumab only (N = 12)
Imetelstat plus bevacizumab (N = 24)
Total (N = 114)
Thrombocytopenia
All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4
0 0 0 0 1 (3.8%) 0 0 0 0 0 0 0 0 0 2 (7.7%) 1 (3.8%) 2 (7.7%) 0
25 (48.1%) 18 (34.6%) 12 (23.1%) 9 (17.3%) 9 (17.3%) 0 6 (11.5%) 3 (5.8%) 6 (11.5%) 0 4 (7.7%) 0 4 (7.7%) 0 1 (1.9%) 0 2 (3.8%) 0
1 (8.3%) 0 1 (8.3%) 0 1 (8.3%) 0 0 0 0 0 0 0 1 (8.3%) 0 1 (8.3%) 0 0 0
13 (54.2%) 3 (12.5%) 10 (41.7%) 3 (12.5%) 6 (25.0%) 1 (4.2%) 3 (12.5%) 0 3 (12.5%) 0 4 (16.7%) 0 3 (12.5%) 0 3 (12.5%) 0 2 (8.3%) 0
39 (34.2%) 21 (18.4%) 23 (20.2%) 12 (10.5%) 17 (14.9%) 1 (<1%) 9 (7.9%) 3 (2.6%) 9 (7.9%) 0 8 (7.0%) 0 8 (7.0%) 0 7 (6.1%) 1 (<1%) 6 (5.3%) 0
Neutropenia Anemia Alanine aminotransferase increased Aspartate aminotransferase increased Hypokalemia Hyponatremia Hyperglycemia Hypoalbuminemia
efficacy The median number of imetelstat maintenance cycles was 3. ORR (additional improvement after the best response to induction) was 3.0% (2/66) in the imetelstat arm and 0% (0/35) in the control arm (P = 0.32), with 51.5% (34/66) and 54.3% (19/35) of patients achieving stable disease, respectively. Analysis of PFS showed a non-significant improvement in favor of the imetelstat arm (HR = 0.844; 95% CI 0.54– 1.31; P = 0.446). Median PFS was 2.76 months (95% CI 1.58–3.03) for imetelstat and 2.57 months (95% CI 1.41– 3.62) for control (Figure 2A). A non-significant trend for improvement in OS was observed in favor of imetelstat (Figure 2B). Median survival time (MST) for imetelstat was 14.3 months (95% CI 9.9–18.9) and 11.5 months (95% CI 7.6–15.5) for the control arm (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). No subgroup analyzed showed significantly superior PFS or MST with imetelstat. In patients receiving imetelstat plus bevacizumab versus bevacizumab alone, median PFS was 4.5 versus 3.8 months (HR = 0.95; 95% CI 0.42–2.14; P = 0.907) and MST was 14.2 versus 11.0 months (HR = 0.54; 95% CI 0.22–1.31; P = 0.167). Imetelstat did not appear effective in patients with squamous tumors, compared with observation, with a median PFS of 1.6 versus 1.7 months (HR = 1.13; 95% CI 0.41–3.07; P = 0.816) and a MST of 10.7 versus 12.0 months (HR = 1.66; 95% CI 0.57–4.85; P = 0.351). However, patients who had nonsquamous tumors and received imetelstat with or without bevacizumab had the best MST and HR versus controls (18.4 versus 11.6 months; 95% CI 9.9–22.7; HR = 0.6; 95% CI 0.33–1.09; P = 0.092).
TL analysis and correlation with efficacy TL data by quantitative PCR (qPCR) were available for 57 patients. Results in the group with the shortest 1/4 and 1/3 of TL
| Chiappori et al.
were similar, with consistent but attenuated results in the shortest 1/2 group, suggesting that a smaller patient subset (shortest 1/3 TL group) might be the one with the most potential to benefit. In the 19 patients with the shortest 1/3 TL, imetelstat maintenance minimally increased mPFS from 1.5 months for the control arm to 1.9 months for the imetelstat-treated arm (HR = 0.43; 95% CI 0.14–1.3; P = 0.124 [un-stratified log-rank]). Among the 38 patients with the longest 2/3 TL, the HR was 0.86 (95% CI 0.39– 1.88). Short TL by qPCR was associated with a worse mPFS (1.5 months), compared with patients with long TL (2.7 months) in the control arm (Figure 3A). Similarly, using telomerase fluorescence in situ hybridization (TeloFISH) (59 samples in total), a non-significant trend toward improved PFS among patients with the shortest 1/3 TL (HR = 0.45; 95% CI 0.14–1.48; P = 0.177) was observed. The OS observed in the imetelstat patients was also superior to that shown in the control arm, when broken down by qPCR TL, although not statistically significant (Figure 3B). Similarly, OS improvements with imetelstat was also observed by TeloFISH in both the patients with short and long TL tumors (HR = 0.44; 95% CI 0.11–1.87; P = 0.256 and HR = 0.58; 95% CI 0.25–1.36; P = 0.200, respectively).
discussion The treatment of advanced NSCLC, particularly non-squamous NSCLC, has seen tremendous changes and paradigm shifts over the past decade, with resulting survival improvements not restricted to the molecular revolution initiated with the discovery of epidermal growth factor receptor mutations and other genetic alterations that have led to the new concept of personalized (lung) cancer therapy [18]. Changes have also been seen in the more traditional ‘one-size-fits-all’ chemotherapy strategies, where the use of bevacizumab and/or pemetrexed and the concept of maintenance chemotherapy are now well accepted and widely applied.
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System organ class preferred term
original articles
Annals of Oncology
Table 3. Non-hematologic adverse events (>10% all grade incidence) NCI CTCAE Grade
Observation (N = 26)
Imetelstat only (N = 52)
Bevacizumab only (N = 12)
Imetelstat plus bevacizumab (N = 24)
Total (N = 114)
Gastrointestinal disorders
All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–5a All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–5b All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 NCI CTCAE Grade
10 (38.5%) 0 2 (7.7%) 0 1 (3.8%) 0 2 (7.7%) 0 7 (26.9%) 1 (3.8%) 3 (11.5%) 0 0 0 6 (23.1%) 0 5 (19.2%) 1 (3.8%) 2 (7.7%) 0 9 (34.6%) 0 3 (11.5%) 0 7 (26.9%) 2 (7.7%) 1 (3.8%) 0 2 (7.7%) 0 3 (11.5%) 0 7 (26.9%) 0 3 (11.5%) 0 0 0 3 (11.5%) 0 1 (3.8%) 0 Observation (N = 26)
32 (61.5%) 1 (1.9%) 21 (40.4%) 0 12 (23.1%) 0 6 (11.5%) 0 32 (61.5%) 5 (9.6%) 22 (42.3%) 3 (5.8%) 7 (13.5%) 0 14 (26.9%) 3 (5.8%) 19 (36.5%) 1 (1.9%) 7 (13.5%) 0 23 (44.2%) 1 (1.9%) 9 (17.3%) 0 22 (42.3%) 2 (3.8%) 7 (13.5%) 1 (1.9%) 5 (9.6%) 0 14 (26.9%) 0 21 (40.4%) 3 (5.8%) 9 (17.3%) 0 6 (11.5%) 1 (1.9%) 6 (11.5%) 0 14 (26.9%) 0 Imetelstat Only (N = 52)
6 (50.0%) 0 3 (25.0%) 0 2 (16.7%) 0 0 0 3 (25.0%) 2 (16.7%) 3 (25.0%) 1 (8.3%) 1 (8.3%) 0 3 (25.0%) 0 5 (41.7%) 1 (8.3%) 3 (25.0%) 1 (8.3%) 7 (58.3%) 0 0 0 5 (41.7%) 1 (8.3%) 1 (8.3%) 0 0 0 2 (16.7%) 1 (8.3%) 6 (50.0%) 0 1 (8.3%) 0 4 (33.3%) 0 1 (8.3%) 0 5 (41.7%) 0 Bevacizumab Only (N = 12)
18 (75.0%) 1 (4.2%) 12 (50.0%) 0 7 (29.2%) 0 6 (25.0%) 0 16 (66.7%) 1 (4.2%) 10 (41.7%) 0 6 (25.0%) 0 14 (58.3%) 1 (4.2%) 11 (45.8%) 1 (4.2%) 1 (4.2%) 0 13 (54.2%) 0 5 (20.8%) 0 16 (66.7%) 0 7 (29.2%) 0 8 (33.3%) 0 6 (25.0%) 0 11 (45.8%) 1 (4.2%) 4 (16.7%) 0 5 (20.8%) 1 (4.2%) 2 (8.3%) 0 10 (41.7%) 0 Imetelstat plus Bevacizumab (N = 24)
66 (57.9%) 2 (1.8%) 38 (33.3%) 0 22 (19.3%) 0 14 (12.3%) 0 58 (50.9%) 9 (7.9%) 38 (33.3%) 4 (3.5%) 14 (12.3%) 0 37 (32.5%) 4 (3.5%) 40 (35.1%) 4 (3.5%) 13 (11.4%) 1 (<1%) 52 (45.6%) 1 (<1%) 17 (14.9%) 0 50 (43.9%) 5 (4.4%) 16 (14.0%) 1 (<1%) 15 (13.2%) 0 25 (21.9%) 1 (<1%) 45 (39.5%) 4 (3.5%) 17 (14.9%) 0 15 (13.2%) 2 (1.8%) 12 (10.5%) 0 30 (26.3%) 0 Total (N = 114)
Nausea Vomiting Constipation Constitutional symptoms Fatigue Peripheral edema Infections and infestations Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Back pain Nervous system disorders Dizziness Headache Psychiatric disorders Respiratory disorders Cough Epistaxis Dyspnea Skin and subcutaneous tissue disorders System Organ Class Preferred Term
a
One fatal intracranial hemorrhage in the imetelstat-only arm was reported as unrelated to imetelstat by the investigator. There was one fatal pneumonia in the observation arm and one fatal sepsis in the imetelstat-only arm that was reported as unrelated to imetelstat by the investigator.
b
It is the latter concept that our trial attempted to address, by utilizing the novel agent imetelstat, which based on preliminary evidence showed that, following chemotherapy, tumor regrowth (or progression) may rely primarily on the proliferation of a cellular subcompartment with progenitor cell or ‘stem cell’-like properties.
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Proliferation of this putative ‘stem cell’ subpopulation is associated with telomerase upregulation, making telomerase inhibitors, like imetelstat, a promising anti-cancer-targeted therapy [19, 20]. Because TL gets critically shorter with each cell division and does not cause immediate cell death (it is not a rapidly acting
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System organ class preferred term
original articles A
Annals of Oncology
1 Control Imetelstat
0.9
Progression-free survival rate
0.8 0.7 0.6 0.5 0.4 0.3
0.1 N = 114, Events = 92
0 0
1
2
3
4
5
6
7
8
9
10
12
14
16
18
Months since randomization No at risk 114
106
62
39
Median (95% CI) Median (95% CI) HR (95% CI) P-value
B
31
22
18
17
16
7
5
3
3
1
1
1
1
1
1
2.57 (1.41, 3.62) 2.76 (1.58, 3.03) 0.84 (0.54, 1.31) 0.446
1 Control Imetelstat
0.9 0.8
Overall survival rate
0.7 0.6 0.5 0.4 0.3 0.2 0.1 N = 114, Events = 66
0 0
2
4
6
8
10
12
14
16
18
20
22
24
Months since randomization No at risk 114 114 106 104 100 91 88 84 74 69 58 50 44 41 33 25 19 18 14 11 8
Median (95% CI) Median (95% CI) HR (95% CI) P-value
5
5
1
1
1
11.5 (7.6,15.5) 14.3 (9.9, 18.9) 0.68 (0.41, 1.12) 0.129
Figure 2. (A) Kaplan–Meier (K–M) plots for progression-free survival (PFS) in the intent-to treat population, broken down by the treatment arm. There was no significant difference in PFS between arms. (B) K–M plots for overall survival (OS) in the intent-to-treat population, broken down by the treatment arm. There was no significant difference in OS between arms.
| Chiappori et al.
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0.2
original articles
Annals of Oncology
Short telomeres † 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Progression-free survival rate
Control Imetelstat
N = 19, Events = 15 0
19
1 2 3 4 5 6 7 8 Months since randomization 17
8
6
5
3
Median (95% CI) Median (95% CI) HR (95% CI) P-value
B
3
2
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
N = 38, Events = 31 0
1
38
36
No at risk
2
1.48 (1.18, 2.76) 1.91 (1.25, NA) 0.43 (0.14, 1.3) 0.124
Control Imetelstat
N = 19, Events = 10
No at risk
2
4 6 8 10 12 14 16 18 20 Months since randomization 7.57 (3.19, 13.45) NA (1.91, NA) 0.41 (0.11, 1.46) 0.155
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
11
7
7
7
6
3
2.7 (1.09, NA) 2.8 (1.55, 4.18) 0.86 (0.39, 1.88) 0.689
Control Imetelstat
N = 38, Events = 21
No at risk
19 19 16 16 15 14 13 13 9 9 8 8 7 6 6 3 2 2 1 1 1
Median (95% CI) Median (95% CI) HR (95% CI) P-value
13
9
Medium-long telomeres†
Control Imetelstat
0
21
Median (95% CI) Median (95% CI) HR (95% CI) P-value
*Interaction P = 0.255
Short telomeres † 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
2 3 4 5 6 7 8 Months since randomization
0 2 4 6 8 10 13 16 19 22 Months since randomization
25
38 38 38 37 36 31 30 28 26 24 22 18 14 13 10 7 7 7 6 5 4 4 4 1 1 1
*Interaction P = 0.690
Median (95% CI) Median (95% CI) HR (95% CI) P-value
7.99 (4.18, NA) 14.51 (9.41, NA) 0.51 (0.2, 1.28) 0.145
Figure 3. (A) K–M plots for PFS broken down by the treatment arm and telomere length (TL) measured by quantitative PCR (qPCR). (B) K–M plots for OS broken down by the treatment arm and TL measured by qPCR. No significant difference between arms was observed in either case.
mechanism), it is logical to combine a telomerase inhibitor with cytotoxic chemotherapy, which has faster anti-tumor effects, and continue the telomerase inhibitor in a continuation maintenance approach. However, our phase I trial showed dose-limiting myelosuppression when combining imetelstat with chemotherapy, necessitating a switch maintenance approach. Although our present trial did not meet the primary end point of improving PFS with the addition of maintenance imetelstat and thus should be considered a negative trial, some of the results obtained are hypotheses-generating and suggest that further investigations are warranted. First, our biomarker analysis is consistent with the hypothesis that clinical benefit from telomerase inhibition should be greater in patients with tumors possessing shorter telomeres. We showed a numerical but not statistically significant improvement in both the mPFS and MST of patients with the shortest 1/3 TL (measured by qPCR)
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receiving imetelstat. However, although imetelstat did not improve PFS for those with the longest TL, again supporting the predictive power of the shortest 1/3 TL, this power is lost with the observation of a similarly higher MST in patients with the longest TL on imetelstat. Whether the latter is the consequence of the crossover design or from subsequent therapies that could have predominantly benefited the longest TL group of patient is a hypothesis that requires confirmatory studies. Secondly, the OS achieved among patients who had non-squamous tumors, including 36 patients who remained on maintenance bevacizumab, almost reached statistical significance (18.4 months, P = 0.092, n = 93). This result compares favorably with the many trials where bevacizumab has been part of the maintenance treatment regimen, including ATLAS [21] and PointBreak [22], and in light of these results, the door opens to a scenario where the maintenance doublet of bevacizumab plus imetelstat could
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No at risk
Overall survival rate
Medium-long telomeres†
Overall survival rate
Progression-free survival rate
A
original articles follow a period of ‘triplet induction’ chemotherapy, including paclitaxel–carboplatin–bevacizumab or pemetrexed–carboplatin–bevacizumab. In conclusion, maintenance imetelstat failed to improve PFS in an advanced NSCLC patient population with diverse TL responding to first-line therapy. There was a trend toward a survival improvement, particularly in patients receiving bevacizumab and those with short telomeres. Prospective confirmation of short TL as a predictive biomarker will be required for further clinical development of imetelstat.
acknowledgements
funding Clinical trial support was provided by Geron Corporation to conduct this study. This work was supported by grants from the National Institutes of Health SPORE (P50 CA70907) and the National Institutes of Health Cancer Center support grant (P30 CA142543-04).
disclosure EB is a previous and BB is a present employee of Geron Corporation and have received travel funding as well as stock options. VP received travel funds for this study. All remaining authors have declared no conflicts of interest.
references 1. McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annu Rev Genet 2000; 34: 331–358. 2. Harley CB. Telomerase is not an oncogene. Oncogene 2002; 21: 494–502. 3. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345: 458–460. 4. Harley CB, Sherwood SW. Telomerase, checkpoints and cancer. Cancer Surv 1997; 29: 263–284. 5. Asai A, Oshima Y, Yamamoto Y et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res 2003; 63: 3931–3939. 6. Herbert BS, Gellert GC, Hochreiter A et al. Lipid modification of GRN163, an N30 →P50 thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene 2005; 24: 5262–5268.
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7. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 1997; 33: 787–791. 8. Herbert B, Pitts AE, Baker SI et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 1999; 96: 14276–14281. 9. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 10. Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543–3551. 11. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542–2550. 12. Reck M, von Pawel J, Zatloukal P et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous nonsmall-cell lung cancer: AVAil. J Clin Oncol 2009; 27: 1227–1234. 13. Zukin M, Barrios CH, Rodrigues Pereira J et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group Performance Status of 2. J Clin Oncol 2013; 31: 2849–2853. 14. Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–1440. 15. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 2010; 11: 521–529. 16. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. 17. National Cancer Institute. Common Terminology Criteria for Adverse Events v.4.0 (CTCAE). 2011. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ ctc.htm. 18. Johnson BE, Kris MG, Berry LD et al. A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2013; 31: (suppl; abstr 8019). 19. Joseph I, Tressler R, Bassett E et al. The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res 2010; 70: 9494–9504. 20. Castelo-Branco P, Zhang C, Lipman T et al. Neural tumor-initiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition. Clin Cancer Res 2011; 17: 111–121. 21. Johnson BE, Kabbinavar F, Fehrenbacher L et al. ATLAS: randomized, doubleblind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2013; 31: 3926–3934. 22. Patel JD, Socinski MA, Garon EB et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013; 31: 4349–4357.
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The authors thank Jerry Shay for his contributions in the preclinical studies leading up to this clinical trial and his helpful suggestions regarding its design. The authors also thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance in the development of this manuscript.
Annals of Oncology
19. Koivunen JP, Mermel C, Zejnullahu K et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008; 14: 4275–4283. 20. Gottschling S, Herpel E, Eberhardt WE et al. The gefitinib long-term responder (LTR)—a cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP). Lung Cancer 2012; 77: 183–191. 21. van der Wekken AJ, Stigt JA, A’T Hart N. A novel EGFR mutation in exon 19 showed stable disease after TKI treatment. J Thorac Oncol 2012; 7: e8. 22. Lee JK, Shin JY, Kim S et al. Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study. Ann Oncol 2013; 24: 2080–2087. 23. Zhou Q, Zhang XC, Chen ZH et al. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 3316–3321. 24. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: 2385–2394. 25. Iwasa Y, Nowak MA, Michor F. Evolution of resistance during clonal expansion. Genetics 2006; 172: 2557–2566. 26. Kim S, Kim TM, Kim DW et al. Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 2013; 8: 415–422.
Annals of Oncology 26: 354–362, 2015 doi:10.1093/annonc/mdu550 Published online 2 December 2014
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer A. A. Chiappori1*, T. Kolevska2, D. R. Spigel3, S. Hager4, M. Rarick5, S. Gadgeel6, N. Blais7, J. Von Pawel8, L. Hart9, M. Reck10, E. Bassett11, B. Burington11 & J. H. Schiller12 1
Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa; 2Department of Oncology, Kaiser Permanente Medical Center, Vallejo; Research Consortium, Sarah Cannon Research Institute, Nashville; 4Thoracic Department, Cancer Care Associates of Fresno Medical Group, Fresno; 5Oncology Hematology Department, Kaiser Permanente Northwest, Portland; 6Karmanos Cancer Institute, Detroit, USA; 7CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada; 8 Department of Oncology, Asklepios Fachkliniken Muenchen-Gauting, Gauting, Bayern, Germany; 9Sarah Cannon Florida Cancer Specialists, Bonita Springs, USA; 10 Department of Thoracic Oncology, LungenClinic Grosshansdorf, member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 11Department of Biostatistics, Geron Corporation, Menlo Park; 12Department of Oncology, University of Texas Southwestern Medical Center, Dallas, USA 3
Received 8 August 2014; revised 3 November 2014; accepted 19 November 2014
Background: Continuation or ‘switch’ maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. Patients and methods: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0–1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. *Correspondence to: Dr Alberto A. Chiappori, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA. Tel: +1-813-745-3050; Fax: +1-813-745-3027; E-mail: alberto.chiappori@ moffitt.org
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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12. Cabillic F, Gros A, Dugay F et al. Parallel FISH and immunohistochemical studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances. J Thorac Oncol 2014; 9: 295–306. 13. Santelmo C, Ravaioli A, Barzotti E et al. Coexistence of EGFR mutation and ALK translocation in NSCLC: literature review and case report of response to gefitinib. Lung Cancer 2013; 81: 294–296. 14. Chen X, Zhang J, Hu Q et al. A case of lung adenocarcinoma harboring exon 19 EGFR deletion and EML4-ALK fusion gene. Lung Cancer 2013; 81: 308–310. 15. Miyanaga A, Shimizu K, Noro R et al. Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small-cell lung cancer harbored coexisting EGFR mutation. BMC Cancer 2013; 13: 262. 16. Yang JJ, Zhang XC, Su J et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014; 20: 1383–1392. 17. Doebele RC, Pilling AB, Aisner DL et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18: 1472–1482. 18. Bai H, Wang Z, Wang Y et al. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One 2013; 8: e54170.
Annals of Oncology
Annals of Oncology
original articles
Results: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54–1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14–1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11–1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39–1.88; and HR = 0.51; 95% CI 0.2–1.28; P = 0.145). Conclusions: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat. Key words: non-small-cell lung cancer, biomarker, imetelstat
Telomeres consist of tandem repeats of the TTAGGG DNA sequence, which function to cap the ends of all mammalian chromosomes. Capping prevents chromosomal fusion and also prevents their ends from being misinterpreted as DNA double-strand breaks [1]. When telomeres get critically short, they can no longer cap the telomere ends, triggering a DNA damage signal and resulting in senescence and/or apoptosis [2, 3]. Telomere loss is prevented by the enzyme telomerase, which counters this loss by adding TTAGGG repeats to the chromosome ends [4]. Telomerase inhibition leads to the loss of a cancer cell’s ability to maintain telomere length (TL), similarly resulting in cell cycle arrest or apoptosis/senescence. Imetelstat is a covalently lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. Imetelstat’s mechanism of action is not an antisense-based approach. Rather, it binds with high affinity and acts as a competitive inhibitor of human telomerase enzymatic activity [5, 6]. Preclinical studies with imetelstat have shown its ability to inhibit telomerase in tumor cells and to compromise cancer cell viability in vitro. Imetelstat has broad tumor growth inhibition activity in multiple xenograft models, including metastatic nonsmall-cell lung cancer (NSCLC) and breast cancer [7, 8]. Platinum-based doublet, first-line chemotherapy [9, 10], with or without bevacizumab [11, 12], is the current treatment standard for patients with advanced NSCLC. Additional randomized data with pemetrexed and erlotinib have demonstrated that ‘maintenance therapy’ in NSCLC, either as continuation [13] or switch [14, 15], is effective. In this study, we evaluated the efficacy of switch maintenance therapy with imetelstat in advanced NSCLC patients and explored the potential use of TL as a surrogate (predictive biomarker) of imetelstat activity.
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 [16]; and had adequate hematologic (ANC 1500/mm3, 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). 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
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)
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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 [17]. 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,
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introduction
original articles
Annals of Oncology
Registration period 2 Stage IV NSCLC who are eligible for platinum based doublet therapy
Platinum based doublet +/– Bevacizumab x 4–6 cycles
If no PD
R A N D O M I Z E
Imetelstat (9.4mg/kg IV d1,8) + Bevacizumab (d1)
Imetelstat (9.4mg/kg IV d1,8)
Continue until PD or excessive toxicity
Bevacizumab (d1) 1
2:1 randomization Stratification based on bevacizumab
Optional cross over to imetelstat for standard therapy arm
Figure 1. Study design.
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.
dose modifications Criteria for patient dose modifications are described in supplementary Methods, available at Annals of Oncology online.
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 2 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.
results patient characteristics Originally, the protocol specified enrollment of 96 patients, with the primary analysis to be conducted after 67 PFS events. However, a retrospective review of all CT scan reports identified
| Chiappori et al.
seven ineligible patients (disease progression by RECIST v1.1 at randomization). For this reason, enrollment was increased to 116 and the primary analysis of PFS was conducted after 77 events. Exclusion of these seven patients from the analyses did not change the results substantially. Similarly, results using only the first 67 events were similar to those reported for the 77 events. A final and mature analysis of survival data was also conducted with 66 OS events. Thus, between July 2010 and April 2012, 116 patients were randomized and 114 completed a post-screening visit, including administration of protocol-specified therapy (i.e. efficacy population). Fifty-two patients received imetelstat alone, 24 received imatelstat plus bevacizumab, 12 received bevacizumab only, and 26 patients received neither. Baseline patient characteristics were well balanced between arms (Table 1). Squamous histology was present in 18.4%; 31.6% received concomitant bevacizumab.
adverse events Imetelstat was generally well tolerated, with ∼32% and 26% of patients requiring dose reductions and delays, respectively. Grade 3/4 neutropenia and thrombocytopenia were higher in the imetelstat arms, occurring in 17.3% and 12.5% versus 0% and 0% and 34.6% and 12.5% versus 0% and 0% for imetelstat (alone and with bevacizumab) versus control arms, respectively (Table 2). However, neutropenic fever and bleeding episodes (epistaxis, hemoptysis, pulmonary hemorrhage and intracranial hemorrhage) were infrequent (<2% each). All grade anemia adverse events were also more frequent with imetelstat (17.3% and 25% versus 3.8% and 8.3%, respectively), but only one patient experienced grade 3 anemia with imetelstat plus bevacizumab. The most frequent treatment-related non-hematologic adverse events involved the gastrointestinal (57.9%), musculoskeletal (45.6%), respiratory (39.5%), nervous (42.9%), tegumentary (26.3%), and psychiatric systems (21.9%). Constitutional symptoms, metabolic abnormalities, and infections occurred in 50.9%, 35.1%, and 30.7%, respectively, but only 7%, 3.5%, and
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Observation
original articles
Annals of Oncology
Table 1. Patient characteristics
No-bevacizumab
Sub-total
Observation Bevacizumab
No-bevacizumab
Sub-total
Total
24 (21.0)
52 (45.6)
76 (66.7)
12 (10.5)
26 (22.8)
38 (33.3)
56.9 42–76
65.3 44–81
63.1 53–80
65.1 30–84
11 (9.6) 13 (11.4)
27 (23.6) 25 (21.9)
38 (33.3) 38 (33.3)
8 (7.0) 4 (3.5)
19 (16.70 7 (6.1)
27 (23.6) 11 (9.6)
65 (57.0) 49 (43.0)
17 (14.9) 2 (1.7) 5 (4.4)
44 (38.6) 3 (2.6) 5 (4.4)
61 (53.5) 5 (4.4) 10 (8.8)
11 (9.6) 0 (0.0) 1 (0.9)
20 (17.5) 4 (3.5) 2 (1.7)
31 (27.2) 4 (3.5) 3 (2.6)
92 (80.7) 9 (7.9) 13 (11.4)
0 (0.0) 23 (20.1) 1 (0.9)
2 (1.7) 38 (33.3) 12 (10.5)
2 (1.7) 61 (53.5) 13 (11.4)
1 (0.9) 11 (9.6) 0 (0.0)
1 (0.9) 22 (19.3) 3 (2.6)
2 (1.7) 33 (28.9) 3 (2.6)
4 (3.5) 94 (82.5) 16 (14.0)
8 (7.0) 16 (14.0) 0 (0.0)
19 (16.7) 32 (28.1) 1 (0.9)
27 (23.6) 48 (42.1) 1 (0.9)
4 (3.5) 7 (6.1) 1 (0.9)
10 (8.8) 16 (14.0) 0 (0.0)
14 (12.3) 23 (20.2) 1 (0.9)
41 (36.0) 71 (62.3) 2 (1.7)
2 (1.7) 21 (18.4) 1 (0.9)
2 (1.7) 48 (42.1) 2 (1.7)
4 (3.5) 69 (60.5) 3 (2.6)
0 (0.0) 12 (10.5) 0 (0.0)
1 (0.9) 25 (21.9) 0 (0.0)
1 (0.9) 37 (32.5) 0 (0.0)
5 (4.4) 106 (93.0) 3 (2.6)
24 (21.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
37 (32.5) 10 (8.8) 1 (0.9) 0 (0.0) 4 (3.5)
61 (53.5) 10 (8.8) 1 (0.9) 0 (0.0) 4 (3.5)
10 (8.8) 0 (0.0) 0 (0.0) 1 (0.9) 1 (0.9)
13 (11.4) 11 (9.6) 0 (0.0) 1 (0.9) 1 (0.9)
23 (20.2) 11 (9.6) 0 (0.0) 2 (1.7) 2 (1.7)
84 (73.7) 21 (18.4) 1 (0.9) 2 (1.7) 6 (5.3)
0/10 (8.8) 14 (12.3)
0/16 (14.00 36 (31.6)
0/26 (22.8) 50 (43.9)
0/2 (1.7) 10 (8.8)
0/6 (5.3) 20 (17.5)
0/8 (7.0) 30 (26.3)
0/34 (29.8) 80 (70.2)
4 1–6
4 2–6
4 1–6
4 4–6
4 2–6
4 2–6
4 1–6
8 (7.0) 14 (12.3) 24 (21.0)
11 (9.6) 31 (27.2) 52 (45.6)
19 (16.7) 45 (39.5) 76 (66.7)
3 (2.6) 8 (7.0) 12 (10.5)
10 (8.8) 15 (13.2) 26 (22.8)
13 (11.4) 23 (20.2) 38 (33.3)
32 (28.1) 68 (59.6) 114 (100.0)
1/9 1/4
7/14 3/15
8/23 4/19
2/6 1/4
1/7 1/5
3/13 2/9
11/36 6/28
114 (100.0) 63.5 30–84
Curative and palliative included. ECOG, Eastern Cooperative Oncology Group; PS, performance status; NOS, not otherwise specified; CR/PR, complete response/partial response; SD, stable disease; EGFR, epidermal growth factor receptor; KRAS, V-Ki-rase2 Kirsten rat sarcoma viral oncogene homolog.
3.5%, respectively, were of grade 3/4 severity (Table 3). Both hematologic and non-hematologic adverse events were consistently more frequent in patients receiving imetelstat plus bevacizumab compared with imetelstat alone (anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, hypertension, dizziness, and headaches). However, imetelstat affected patients receiving bevacizumab differentially (lower pulmonary hemorrhage
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and proteinura, similar epistaxis and hypertension and higher fatigue, nausea/vomiting, headache, and myelusuppression). Overall, 17 patients discontinued treatment due to imetelstatrelated adverse events as determined by the investigator (10 in the imetelstat arm and 7 in the imetelstat plus bevacizumab arm). The most frequent causes for discontinuation were thrombocytopenia (6 patients), infusion reactions, and fatigue (2 patients each).
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No. (%) Age (years) Median Range Gender Male (%) Female (%) Race White (%) Black (%) Asian (%) Ethnicity Hispanic (%) Non-hispanic (%) Other/na (%) ECOG PS 0 (%) 1 (%) Not available (%) Disease stage IIIB (%) IV (%) Recurrent Dis (%) Histology Adenocarcinoma (%) Squamous (%) Adenosquamous (%) Large cell (%) NOS/other (%) Response to induction CR/PR (%) SD (%) Induction cycles Median Range Prior therapy Radiation (%) Surgery (any) (%) Systemic (%) Mutations (yes/no) EGFR KRAS
Imetelstat Bevacizumab
original articles
Annals of Oncology
Table 2. Hematologic and laboratory adverse events by treatment arm and severity (>5% total incidence) NCI CTCAE Grade
Observation (N = 26)
Imetelstat only (N = 52)
Bevacizumab only (N = 12)
Imetelstat plus bevacizumab (N = 24)
Total (N = 114)
Thrombocytopenia
All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4
0 0 0 0 1 (3.8%) 0 0 0 0 0 0 0 0 0 2 (7.7%) 1 (3.8%) 2 (7.7%) 0
25 (48.1%) 18 (34.6%) 12 (23.1%) 9 (17.3%) 9 (17.3%) 0 6 (11.5%) 3 (5.8%) 6 (11.5%) 0 4 (7.7%) 0 4 (7.7%) 0 1 (1.9%) 0 2 (3.8%) 0
1 (8.3%) 0 1 (8.3%) 0 1 (8.3%) 0 0 0 0 0 0 0 1 (8.3%) 0 1 (8.3%) 0 0 0
13 (54.2%) 3 (12.5%) 10 (41.7%) 3 (12.5%) 6 (25.0%) 1 (4.2%) 3 (12.5%) 0 3 (12.5%) 0 4 (16.7%) 0 3 (12.5%) 0 3 (12.5%) 0 2 (8.3%) 0
39 (34.2%) 21 (18.4%) 23 (20.2%) 12 (10.5%) 17 (14.9%) 1 (<1%) 9 (7.9%) 3 (2.6%) 9 (7.9%) 0 8 (7.0%) 0 8 (7.0%) 0 7 (6.1%) 1 (<1%) 6 (5.3%) 0
Neutropenia Anemia Alanine aminotransferase increased Aspartate aminotransferase increased Hypokalemia Hyponatremia Hyperglycemia Hypoalbuminemia
efficacy The median number of imetelstat maintenance cycles was 3. ORR (additional improvement after the best response to induction) was 3.0% (2/66) in the imetelstat arm and 0% (0/35) in the control arm (P = 0.32), with 51.5% (34/66) and 54.3% (19/35) of patients achieving stable disease, respectively. Analysis of PFS showed a non-significant improvement in favor of the imetelstat arm (HR = 0.844; 95% CI 0.54– 1.31; P = 0.446). Median PFS was 2.76 months (95% CI 1.58–3.03) for imetelstat and 2.57 months (95% CI 1.41– 3.62) for control (Figure 2A). A non-significant trend for improvement in OS was observed in favor of imetelstat (Figure 2B). Median survival time (MST) for imetelstat was 14.3 months (95% CI 9.9–18.9) and 11.5 months (95% CI 7.6–15.5) for the control arm (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). No subgroup analyzed showed significantly superior PFS or MST with imetelstat. In patients receiving imetelstat plus bevacizumab versus bevacizumab alone, median PFS was 4.5 versus 3.8 months (HR = 0.95; 95% CI 0.42–2.14; P = 0.907) and MST was 14.2 versus 11.0 months (HR = 0.54; 95% CI 0.22–1.31; P = 0.167). Imetelstat did not appear effective in patients with squamous tumors, compared with observation, with a median PFS of 1.6 versus 1.7 months (HR = 1.13; 95% CI 0.41–3.07; P = 0.816) and a MST of 10.7 versus 12.0 months (HR = 1.66; 95% CI 0.57–4.85; P = 0.351). However, patients who had nonsquamous tumors and received imetelstat with or without bevacizumab had the best MST and HR versus controls (18.4 versus 11.6 months; 95% CI 9.9–22.7; HR = 0.6; 95% CI 0.33–1.09; P = 0.092).
TL analysis and correlation with efficacy TL data by quantitative PCR (qPCR) were available for 57 patients. Results in the group with the shortest 1/4 and 1/3 of TL
| Chiappori et al.
were similar, with consistent but attenuated results in the shortest 1/2 group, suggesting that a smaller patient subset (shortest 1/3 TL group) might be the one with the most potential to benefit. In the 19 patients with the shortest 1/3 TL, imetelstat maintenance minimally increased mPFS from 1.5 months for the control arm to 1.9 months for the imetelstat-treated arm (HR = 0.43; 95% CI 0.14–1.3; P = 0.124 [un-stratified log-rank]). Among the 38 patients with the longest 2/3 TL, the HR was 0.86 (95% CI 0.39– 1.88). Short TL by qPCR was associated with a worse mPFS (1.5 months), compared with patients with long TL (2.7 months) in the control arm (Figure 3A). Similarly, using telomerase fluorescence in situ hybridization (TeloFISH) (59 samples in total), a non-significant trend toward improved PFS among patients with the shortest 1/3 TL (HR = 0.45; 95% CI 0.14–1.48; P = 0.177) was observed. The OS observed in the imetelstat patients was also superior to that shown in the control arm, when broken down by qPCR TL, although not statistically significant (Figure 3B). Similarly, OS improvements with imetelstat was also observed by TeloFISH in both the patients with short and long TL tumors (HR = 0.44; 95% CI 0.11–1.87; P = 0.256 and HR = 0.58; 95% CI 0.25–1.36; P = 0.200, respectively).
discussion The treatment of advanced NSCLC, particularly non-squamous NSCLC, has seen tremendous changes and paradigm shifts over the past decade, with resulting survival improvements not restricted to the molecular revolution initiated with the discovery of epidermal growth factor receptor mutations and other genetic alterations that have led to the new concept of personalized (lung) cancer therapy [18]. Changes have also been seen in the more traditional ‘one-size-fits-all’ chemotherapy strategies, where the use of bevacizumab and/or pemetrexed and the concept of maintenance chemotherapy are now well accepted and widely applied.
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System organ class preferred term
original articles
Annals of Oncology
Table 3. Non-hematologic adverse events (>10% all grade incidence) NCI CTCAE Grade
Observation (N = 26)
Imetelstat only (N = 52)
Bevacizumab only (N = 12)
Imetelstat plus bevacizumab (N = 24)
Total (N = 114)
Gastrointestinal disorders
All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–5a All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–5b All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 All grades 3–4 NCI CTCAE Grade
10 (38.5%) 0 2 (7.7%) 0 1 (3.8%) 0 2 (7.7%) 0 7 (26.9%) 1 (3.8%) 3 (11.5%) 0 0 0 6 (23.1%) 0 5 (19.2%) 1 (3.8%) 2 (7.7%) 0 9 (34.6%) 0 3 (11.5%) 0 7 (26.9%) 2 (7.7%) 1 (3.8%) 0 2 (7.7%) 0 3 (11.5%) 0 7 (26.9%) 0 3 (11.5%) 0 0 0 3 (11.5%) 0 1 (3.8%) 0 Observation (N = 26)
32 (61.5%) 1 (1.9%) 21 (40.4%) 0 12 (23.1%) 0 6 (11.5%) 0 32 (61.5%) 5 (9.6%) 22 (42.3%) 3 (5.8%) 7 (13.5%) 0 14 (26.9%) 3 (5.8%) 19 (36.5%) 1 (1.9%) 7 (13.5%) 0 23 (44.2%) 1 (1.9%) 9 (17.3%) 0 22 (42.3%) 2 (3.8%) 7 (13.5%) 1 (1.9%) 5 (9.6%) 0 14 (26.9%) 0 21 (40.4%) 3 (5.8%) 9 (17.3%) 0 6 (11.5%) 1 (1.9%) 6 (11.5%) 0 14 (26.9%) 0 Imetelstat Only (N = 52)
6 (50.0%) 0 3 (25.0%) 0 2 (16.7%) 0 0 0 3 (25.0%) 2 (16.7%) 3 (25.0%) 1 (8.3%) 1 (8.3%) 0 3 (25.0%) 0 5 (41.7%) 1 (8.3%) 3 (25.0%) 1 (8.3%) 7 (58.3%) 0 0 0 5 (41.7%) 1 (8.3%) 1 (8.3%) 0 0 0 2 (16.7%) 1 (8.3%) 6 (50.0%) 0 1 (8.3%) 0 4 (33.3%) 0 1 (8.3%) 0 5 (41.7%) 0 Bevacizumab Only (N = 12)
18 (75.0%) 1 (4.2%) 12 (50.0%) 0 7 (29.2%) 0 6 (25.0%) 0 16 (66.7%) 1 (4.2%) 10 (41.7%) 0 6 (25.0%) 0 14 (58.3%) 1 (4.2%) 11 (45.8%) 1 (4.2%) 1 (4.2%) 0 13 (54.2%) 0 5 (20.8%) 0 16 (66.7%) 0 7 (29.2%) 0 8 (33.3%) 0 6 (25.0%) 0 11 (45.8%) 1 (4.2%) 4 (16.7%) 0 5 (20.8%) 1 (4.2%) 2 (8.3%) 0 10 (41.7%) 0 Imetelstat plus Bevacizumab (N = 24)
66 (57.9%) 2 (1.8%) 38 (33.3%) 0 22 (19.3%) 0 14 (12.3%) 0 58 (50.9%) 9 (7.9%) 38 (33.3%) 4 (3.5%) 14 (12.3%) 0 37 (32.5%) 4 (3.5%) 40 (35.1%) 4 (3.5%) 13 (11.4%) 1 (<1%) 52 (45.6%) 1 (<1%) 17 (14.9%) 0 50 (43.9%) 5 (4.4%) 16 (14.0%) 1 (<1%) 15 (13.2%) 0 25 (21.9%) 1 (<1%) 45 (39.5%) 4 (3.5%) 17 (14.9%) 0 15 (13.2%) 2 (1.8%) 12 (10.5%) 0 30 (26.3%) 0 Total (N = 114)
Nausea Vomiting Constipation Constitutional symptoms Fatigue Peripheral edema Infections and infestations Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Back pain Nervous system disorders Dizziness Headache Psychiatric disorders Respiratory disorders Cough Epistaxis Dyspnea Skin and subcutaneous tissue disorders System Organ Class Preferred Term
a
One fatal intracranial hemorrhage in the imetelstat-only arm was reported as unrelated to imetelstat by the investigator. There was one fatal pneumonia in the observation arm and one fatal sepsis in the imetelstat-only arm that was reported as unrelated to imetelstat by the investigator.
b
It is the latter concept that our trial attempted to address, by utilizing the novel agent imetelstat, which based on preliminary evidence showed that, following chemotherapy, tumor regrowth (or progression) may rely primarily on the proliferation of a cellular subcompartment with progenitor cell or ‘stem cell’-like properties.
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Proliferation of this putative ‘stem cell’ subpopulation is associated with telomerase upregulation, making telomerase inhibitors, like imetelstat, a promising anti-cancer-targeted therapy [19, 20]. Because TL gets critically shorter with each cell division and does not cause immediate cell death (it is not a rapidly acting
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System organ class preferred term
original articles A
Annals of Oncology
1 Control Imetelstat
0.9
Progression-free survival rate
0.8 0.7 0.6 0.5 0.4 0.3
0.1 N = 114, Events = 92
0 0
1
2
3
4
5
6
7
8
9
10
12
14
16
18
Months since randomization No at risk 114
106
62
39
Median (95% CI) Median (95% CI) HR (95% CI) P-value
B
31
22
18
17
16
7
5
3
3
1
1
1
1
1
1
2.57 (1.41, 3.62) 2.76 (1.58, 3.03) 0.84 (0.54, 1.31) 0.446
1 Control Imetelstat
0.9 0.8
Overall survival rate
0.7 0.6 0.5 0.4 0.3 0.2 0.1 N = 114, Events = 66
0 0
2
4
6
8
10
12
14
16
18
20
22
24
Months since randomization No at risk 114 114 106 104 100 91 88 84 74 69 58 50 44 41 33 25 19 18 14 11 8
Median (95% CI) Median (95% CI) HR (95% CI) P-value
5
5
1
1
1
11.5 (7.6,15.5) 14.3 (9.9, 18.9) 0.68 (0.41, 1.12) 0.129
Figure 2. (A) Kaplan–Meier (K–M) plots for progression-free survival (PFS) in the intent-to treat population, broken down by the treatment arm. There was no significant difference in PFS between arms. (B) K–M plots for overall survival (OS) in the intent-to-treat population, broken down by the treatment arm. There was no significant difference in OS between arms.
| Chiappori et al.
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0.2
original articles
Annals of Oncology
Short telomeres † 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Progression-free survival rate
Control Imetelstat
N = 19, Events = 15 0
19
1 2 3 4 5 6 7 8 Months since randomization 17
8
6
5
3
Median (95% CI) Median (95% CI) HR (95% CI) P-value
B
3
2
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
N = 38, Events = 31 0
1
38
36
No at risk
2
1.48 (1.18, 2.76) 1.91 (1.25, NA) 0.43 (0.14, 1.3) 0.124
Control Imetelstat
N = 19, Events = 10
No at risk
2
4 6 8 10 12 14 16 18 20 Months since randomization 7.57 (3.19, 13.45) NA (1.91, NA) 0.41 (0.11, 1.46) 0.155
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
11
7
7
7
6
3
2.7 (1.09, NA) 2.8 (1.55, 4.18) 0.86 (0.39, 1.88) 0.689
Control Imetelstat
N = 38, Events = 21
No at risk
19 19 16 16 15 14 13 13 9 9 8 8 7 6 6 3 2 2 1 1 1
Median (95% CI) Median (95% CI) HR (95% CI) P-value
13
9
Medium-long telomeres†
Control Imetelstat
0
21
Median (95% CI) Median (95% CI) HR (95% CI) P-value
*Interaction P = 0.255
Short telomeres † 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
2 3 4 5 6 7 8 Months since randomization
0 2 4 6 8 10 13 16 19 22 Months since randomization
25
38 38 38 37 36 31 30 28 26 24 22 18 14 13 10 7 7 7 6 5 4 4 4 1 1 1
*Interaction P = 0.690
Median (95% CI) Median (95% CI) HR (95% CI) P-value
7.99 (4.18, NA) 14.51 (9.41, NA) 0.51 (0.2, 1.28) 0.145
Figure 3. (A) K–M plots for PFS broken down by the treatment arm and telomere length (TL) measured by quantitative PCR (qPCR). (B) K–M plots for OS broken down by the treatment arm and TL measured by qPCR. No significant difference between arms was observed in either case.
mechanism), it is logical to combine a telomerase inhibitor with cytotoxic chemotherapy, which has faster anti-tumor effects, and continue the telomerase inhibitor in a continuation maintenance approach. However, our phase I trial showed dose-limiting myelosuppression when combining imetelstat with chemotherapy, necessitating a switch maintenance approach. Although our present trial did not meet the primary end point of improving PFS with the addition of maintenance imetelstat and thus should be considered a negative trial, some of the results obtained are hypotheses-generating and suggest that further investigations are warranted. First, our biomarker analysis is consistent with the hypothesis that clinical benefit from telomerase inhibition should be greater in patients with tumors possessing shorter telomeres. We showed a numerical but not statistically significant improvement in both the mPFS and MST of patients with the shortest 1/3 TL (measured by qPCR)
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receiving imetelstat. However, although imetelstat did not improve PFS for those with the longest TL, again supporting the predictive power of the shortest 1/3 TL, this power is lost with the observation of a similarly higher MST in patients with the longest TL on imetelstat. Whether the latter is the consequence of the crossover design or from subsequent therapies that could have predominantly benefited the longest TL group of patient is a hypothesis that requires confirmatory studies. Secondly, the OS achieved among patients who had non-squamous tumors, including 36 patients who remained on maintenance bevacizumab, almost reached statistical significance (18.4 months, P = 0.092, n = 93). This result compares favorably with the many trials where bevacizumab has been part of the maintenance treatment regimen, including ATLAS [21] and PointBreak [22], and in light of these results, the door opens to a scenario where the maintenance doublet of bevacizumab plus imetelstat could
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No at risk
Overall survival rate
Medium-long telomeres†
Overall survival rate
Progression-free survival rate
A
original articles follow a period of ‘triplet induction’ chemotherapy, including paclitaxel–carboplatin–bevacizumab or pemetrexed–carboplatin–bevacizumab. In conclusion, maintenance imetelstat failed to improve PFS in an advanced NSCLC patient population with diverse TL responding to first-line therapy. There was a trend toward a survival improvement, particularly in patients receiving bevacizumab and those with short telomeres. Prospective confirmation of short TL as a predictive biomarker will be required for further clinical development of imetelstat.
acknowledgements
funding Clinical trial support was provided by Geron Corporation to conduct this study. This work was supported by grants from the National Institutes of Health SPORE (P50 CA70907) and the National Institutes of Health Cancer Center support grant (P30 CA142543-04).
disclosure EB is a previous and BB is a present employee of Geron Corporation and have received travel funding as well as stock options. VP received travel funds for this study. All remaining authors have declared no conflicts of interest.
references 1. McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annu Rev Genet 2000; 34: 331–358. 2. Harley CB. Telomerase is not an oncogene. Oncogene 2002; 21: 494–502. 3. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345: 458–460. 4. Harley CB, Sherwood SW. Telomerase, checkpoints and cancer. Cancer Surv 1997; 29: 263–284. 5. Asai A, Oshima Y, Yamamoto Y et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res 2003; 63: 3931–3939. 6. Herbert BS, Gellert GC, Hochreiter A et al. Lipid modification of GRN163, an N30 →P50 thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene 2005; 24: 5262–5268.
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7. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 1997; 33: 787–791. 8. Herbert B, Pitts AE, Baker SI et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 1999; 96: 14276–14281. 9. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 10. Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543–3551. 11. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542–2550. 12. Reck M, von Pawel J, Zatloukal P et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous nonsmall-cell lung cancer: AVAil. J Clin Oncol 2009; 27: 1227–1234. 13. Zukin M, Barrios CH, Rodrigues Pereira J et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group Performance Status of 2. J Clin Oncol 2013; 31: 2849–2853. 14. Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–1440. 15. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 2010; 11: 521–529. 16. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. 17. National Cancer Institute. Common Terminology Criteria for Adverse Events v.4.0 (CTCAE). 2011. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ ctc.htm. 18. Johnson BE, Kris MG, Berry LD et al. A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2013; 31: (suppl; abstr 8019). 19. Joseph I, Tressler R, Bassett E et al. The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res 2010; 70: 9494–9504. 20. Castelo-Branco P, Zhang C, Lipman T et al. Neural tumor-initiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition. Clin Cancer Res 2011; 17: 111–121. 21. Johnson BE, Kabbinavar F, Fehrenbacher L et al. ATLAS: randomized, doubleblind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2013; 31: 3926–3934. 22. Patel JD, Socinski MA, Garon EB et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013; 31: 4349–4357.
Volume 26 | No. 2 | February 2015
Downloaded from http://annonc.oxfordjournals.org/ at Memorial Univ. of Newfoundland on March 5, 2015
The authors thank Jerry Shay for his contributions in the preclinical studies leading up to this clinical trial and his helpful suggestions regarding its design. The authors also thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance in the development of this manuscript.
Annals of Oncology