Imetelstat | Myelofibrosis | Myelodysplastic … › file.cfm › 53 › docs ›...
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prospective Telo-FISH assay is predictive of PFS 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 114 106 59 36 27 16 11 10 9 2 2 1 1 Control Imetelstat Improved progression-free survival (PFS) in patients with short tumor telomere length: subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC Chiappori A 7 , Bassett, K 2 , Burington B 2 , Kolevska T 3 , Spigel DR 4 , Hager S 5 , Rarick M 6 , Gadgeel S 8 , Blais N 9 , Von Pawel J 10 , Hart L 11 , Wang H 2 , Eng K 2 , Reck M 12 , and Schiller J 1 promising initial prediction of PFS benefit by retrospective batched qPCR assay conclusions In the original primary analysis of PFS, imetelstat given as maintenance therapy appeared to prolong PFS in patients with advanced NSCLC whose tumors have short telomeres, as measured by a retrospective qPCR assay. Results for Telo-FISH, a prospective assay, show a trend toward increased PFS benefit in the short telomere subgroup. Mature OS analyses suggest a survival benefit in patients with both short telomeres and medium- long telomeres. These data are not consistent with the hypothesis that clinical benefit from telomerase inhibition is potentially greater in patients with tumors possessing short telomeres. The impact of these findings on the development of imetelstat in solid tumors with short telomeres is being evaluated. background & introduction materials & methods Baseline characteristic Short Telomere N=19 (33%) Medium-Long Telomere N=38 (67%) P Age (Median) 65.0 62.5 0.165 EGFR Mutatnt 1 (5.3%) 5 (13.2%) 0.360 Squamous Histology 5 (26.3%) 8 (21.1%) 0.655 Adenocarcinoma 12 (63.2) 28 (73.7%) 0.413 Induction Cycles (Median) 4 4 0.947 Induction Partial Response (vs. SD) 9 (47.4%) 11 (28.9%) 0.170 Days from End Induction to Randomization 34 28 0.030 ECOG 1 (vs. 0) 8 (42.1%) 25 (65.8%) 0.088 Imetelstat Tx 11 (57.9%) 26 (68.4%) 0.433 Bevacizumab Use 5 (26.3%) 10 (26.3%) 1 baseline characteristics references 1. Frink R et al, 2010 AACR Annual Meeting: Abstract #3577 2. Chiappori A et al, 2013 AACR Annual Meeting: Abstract #4660 NSCLC cell lines and other tumor cells with short telomeres appear to be more sensitive to imetelstat in vitro than those with long telomeres. 1 Telomere length varies with tumor type and among individual patients within tumor types. This led to a hypothesis that patients whose tumors have shorter telomeres may be more responsive to imetelstat. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in advanced NSCLC: results for the primary and secondary endpoints are reported separately ( 2 AACR Poster #4660) A planned exploratory analysis to determine PFS as a function of tumor telomere length (TL) was performed. Tumor TL was assessed in archival tumor specimens from pts by quantitative PCR (qPCR) and Telomeric Fluorescence In Situ Hybridization (Telo-FISH). Days of imetelstat treatment Population doublings short telomeres long telomeres 114 patients were evaluable for PFS; archival tumor specimens were obtained from 61 patients; 57 values were obtained from the retrospective qPCR assay, 52 values were obtained from the prospective qPCR assay, 59 values were obtained from Telo-FISH. telomere 1 University of Texas Southwestern Medical Center, Dallas, TX; 2 Geron Corporation, Menlo Park, CA; 3 Kaiser Permanente Medical Center, Vallejo, CA; 4 Sarah Cannon Research Institute, Nashville, TN; 5 Cancer Care Associates of Fresno Medical Group, Fresno, CA; 6 Kaiser Permanente Northwest, Portland, OR; 7 H Lee Moffitt Cancer Center, Tampa, FL; 8 Karmanos Cancer Institute, Detroit, MI; 9 CHUM-Hopital Notre-Dame, Montreal, Quebec; 10 Asklepios Fachkliniken Muenchen-Gauting, Gauting, Bayern, Germany; 11 Sarah Cannon Florida Cancer Specialists, Bonita Springs, FL; 12 Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany Imetelstat + Bevacizumab vs. Bevacizumab Imetelstat vs. Observation Randomize pts (2:1) Stage IV or Recurrent Locally Advanced NSCLC No Progressive Disease Platinum- Based Doublet Induction Chemo- Therapy 1° Efficacy: PFS Imetelstat maintenance study design 5-micron FFPE sections were obtained from each patient. Telomere length was measured on two sections by a modified, retrospective qPCR assay based on the method of Cawthon R. 3 Genomic DNA from FFPE specimen was isolated using FFPE Tissue DNA Extraction Kit (BioChain Institute Inc). DNA concentrations for DNA from FFPE samples were determined by Quant-iT Pico Green dsDNA Assay Kit (Invitrogen). All quantitative PCR reactions were carried out using ABI Prism 7900 HT Sequence Detection System (Applied Biosystems). Two PCR reactions were performed for each sample, one to determine the cycles threshold (Ct) value for telomere (T) amplification and the other to determine the Ct value for the amplification of a single copy gene (Acidic ribosomal phosphoprotein P, 36b4). The primer sequences for telomere amplification and 36B4 amplification are described in Cawthon R. 3 Each PCR reaction for telomere amplification was performed using 1ng of sample. Relative telomere length was calculated as follows: (2 Ct T/2 Ct S) -1 = 2 -(Ct T-Ct S) = 2 -dCt . The patient samples were run in 7 batches. DOE models were used to adjust for plate effects and sample DNA concentrations. Telomere-length analyses were pre-specified for patients grouped into the shortest 1/2, shortest 1/3 and shortest 1/4 of TL. Results in the group with the shortest 1/4 of TL were similar to the shortest 1/3 TL group, while in the shortest 1/2 group the differential benefit appeared diluted, suggesting that that 50% is too large a group size. Kaplan-Meier and Cox PH estimates were used for time-to-event analyses. Wilcoxon rank sum tests were used to test for differences in baseline characteristics. The retrospective assay processed 20 FFPE sections per plate x 2 slides per patient (N=57). The prospective protocol processed 2 sections per patient on a single plate (N=52), with single copy gene (SCG) controls and reference cell lines. Measuring telomere length by Telo-FISH using IN Cell Analyzer and Developer sub-group hazard ratios PFS OS PFS OS In vitro effects of imetelstat on proliferation of NSCLC cell lines with short and long telomeres. 1 Calu-3 Telomere length: ~1.5kb H2882 Telomere length: ~7.7kb Nuclei (DAPI) Telomeres (Cy3) Intensity and area of telomeres (blue outlines) are measured within the nuclei (yellow outlines) + qPCR assay Telo-FISH assay Telo-FISH was performed on one FFPE section per patient. Telomere length was measured based on the method of Meeker R. 4 Cells were hybridized with a telomere-specific probe conjugated to Cy3. Digital images of nuclei and telomeres were obtained using IN Cell Analyzer 2000 (GE Corp). Fluorescent intensities and areas of individual telomeres were measured using IN Cell Developer Toolbox 1.9 (GE Corp). Telomere length was calculated using the equation: By Telo-FISH, PFS benefit was associated with the log 2 intensity-to-area ratio: 1.376 x log 2 (intensity) – 6.215 x √(area), where “intensity” is defined as the intensity of the telomere and “area” is defined as the area of the telomere. Median (95% CI) 2.63 (1.38, 3.59) Median (95% CI) 2.80 (1.58, 4.18) HR (95% CI) 0.77 (0.48, 1.25) P-value 0.295 HR (95% CI) 0.0 0.5 1.0 1.5 2.0 39 20 34 18 38 19 59 N HR (95% CI) 0.0 0.5 1.0 1.5 2.0 Long-TeloFISH Short-TeloFISH Long-Prospective qPCR Short-Prospective qPCR Long-Retrospective qPCR Short-Retrospective qPCR All Patients with Assays HR (95% CI) 0.0 0.5 1.0 1.5 2.0 39 20 34 18 38 19 59 N HR (95% CI) 0.0 0.5 1.0 1.5 2.0 Long-TeloFISH Short-TeloFISH Long-Prospective qPCR Short-Prospective qPCR Long-Retrospective qPCR Short-Retrospective qPCR All Patients with Assays Note that multivariate adjustment for available prognostic factors does not substantially alter the results of subsequent analyses (not shown). Median (95% CI) 2.7 (1.1, 3.6) Median (95% CI) 2.8 (1.5, 4.2) HR (95% CI) 0.83 (0.36, 1.9) P-value 0.623 0 1 2 3 4 5 6 7 8 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 19 18 9 7 6 3 3 2 2 Control Imetelstat 0 1 2 3 4 5 6 7 8 9 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 38 36 20 13 10 6 6 6 5 2 Control Imetelstat all patients Median (95% CI) 1.5 (1.2, 2.8) Median (95% CI) 4.0 (1.3, NA) HR (95% CI) 0.32 (0.1, 1.0) P-value 0.042 N=19 (33%), Events=15 N=38 (67%), Events=29 0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 114 106 62 39 31 22 18 17 16 7 5 3 3 1 1 1 1 1 1 Control Imetelstat 0 1 2 3 4 5 6 7 8 9 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 20 20 8 6 6 4 4 3 2 1 Control Imetelstat 0 1 2 3 4 5 6 7 8 9 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Progression-free Survival Rate N at risk 39 35 22 14 10 6 6 6 6 2 Control Imetelstat N=20, Events=16 N=39, Events=32 short telomeres † medium-long telomeres † N=114, Events=77 N=114, Events=92 Updated PFS July 9, 2012 median FU=2.8mn February 11, 2013: Mature OS Time Point July 9, 2012: Primary PFS Time Point Median (95% CI) 2.57 (1.41, 3.62) Median (95% CI) 2.76 (1.58, 3.03) HR (95% CI) 0.84 (0.54, 1.31) P-value 0.446 Median (95% CI) 1.94 (1.09, NA) Median (95% CI) 1.84 (1.48, 6.12) HR (95% CI) 0.45 (0.14, 1.48) P-value 0.177 Median (95% CI) 2.66 (1.25, 3.75) Median (95% CI) 2.80 (1.45, 4.18) HR (95% CI) 0.92 (0.45, 1.89) P-value 0.820 Primary PFS Feb. 11, 2013 median FU=2.6mn all patients short telomeres † medium-long telomeres † prospective Telo-FISH assay is not predictive for overall survival Mature OS Feb. 11, 2013 median FU=10.5mn 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Overall Survival Rate N at risk 114 114 106 104 100 91 88 84 74 69 58 50 44 41 33 25 19 18 14 11 8 5 5 1 1 1 Control Imetelstat N=114, Events=66 Median (95% CI) 11.5 (7.6, 15.5) Median (95% CI) 14.3 (9.9, 18.9) HR (95% CI) 0.68 (0.41, 1.12) P-value 0.129 all patients short telomeres † medium-long telomeres † N=20, Events=8 Median (95% CI) 11.79 (4.18, NA) Median (95% CI) NA (4.93, NA) HR (95% CI) 0.44 (0.11, 1.87) P-value 0.256 0 2 4 6 8 10 13 16 19 22 25 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Overall Survival Rate N at risk 39 39 36 35 34 31 29 25 22 21 19 14 13 12 9 7 6 6 4 4 3 3 3 1 1 1 Control Imetelstat N=39, Events=24 Median (95% CI) 7.99 (4.67, 14.87) Median (95% CI) 14.24 (7.76, 22.66) HR (95% CI) 0.58 (0.25, 1.36) P-value 0.200 Magnitude of short tumor telomere effect on HR is reduced and median PFS is no longer different between arms AACR abstract #2376 We thank all of the patients, caregivers, principal investigators and staff who have participated in this study. This study was sponsored by Geron Corporation 3. Cawthon R et al, 2009 Nucleic Acids Res. 37(3): e21 4. Meeker A et al, 2002 Am J Path 160(4): 1259 For retrospective qPCR, prospective qPCR and prospective Telo-FISH Nuclei (DAPI) Telomeres (Cy3) Stromal cells Tumor cells 0 2 4 6 8 10 12 14 16 18 20 Months Since Randomization 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Overall Survival Rate N at risk 20 20 19 19 18 15 15 15 13 13 12 11 9 8 7 3 3 3 3 2 2 1 1 Control Imetelstat † Interaction P=0.160 † Interaction P=0.175 † Interaction P=0.689 ↓ Stratify on bevacizumab use ↑ Telomeres are protective caps that maintain the stability and integrity of chromosomes. When telomeres reach a critically short length, chromosome ends are exposed to DNA damage mechanisms, which lead to senescence or apoptosis. The enzyme telomerase is upregulated in malignant cells and sustains indefinite replication by maintaining telomere length. Inhibition of telomerase may be a novel approach to treating cancer by limiting the proliferative capacity of malignant cells. Imetelstat, a lipidated 13-mer oligonucleotide, is a potent and specific inhibitor of telomerase. Imetelstat Telomerase --TTAGGGTTAGGGTTAG-3’ hTR (RNA) IMETELSTAT UGUU Telomere: hTERT (protein) x
Transcript of Imetelstat | Myelofibrosis | Myelodysplastic … › file.cfm › 53 › docs ›...
prospective Telo-FISH assay is predictive of PFS
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9 10 11 12
Months Since Randomization
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N at risk114 106 59 36 27 16 11 10 9 2 2 1 1
Control
Imetelstat
Improved progression-free survival (PFS) in patients with short tumor telomere length: subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC
Chiappori A7, Bassett, K2, Burington B2, Kolevska T3, Spigel DR4, Hager S5, Rarick M6, Gadgeel S8, Blais N9, Von Pawel J10, Hart L11, Wang H2, Eng K2, Reck M12, and Schiller J1
promising initial prediction of PFS benefit by retrospective batched qPCR assay
conclusions
In the original primary analysis of PFS, imetelstat given as maintenance therapy appeared to prolong PFS in patients with advanced NSCLC whose tumors have short telomeres, as measured by a retrospective qPCR assay.
Results for Telo-FISH, a prospective assay, show a trend toward increased PFS benefit in the short telomere subgroup.
Mature OS analyses suggest a survival benefit in patients with both short telomeres and medium-long telomeres. These data are not consistent with the hypothesis that clinical benefit from telomerase inhibition is potentially greater in patients with tumors possessing short telomeres.
The impact of these findings on the development of imetelstat in solid tumors with short telomeres is being evaluated.
background & introduction materials & methods
Baseline characteristic Short
Telomere N=19 (33%)
Medium-Long Telomere
N=38 (67%) P
Age (Median) 65.0 62.5 0.165
EGFR Mutatnt 1 (5.3%) 5 (13.2%) 0.360
Squamous Histology 5 (26.3%) 8 (21.1%) 0.655
Adenocarcinoma 12 (63.2) 28 (73.7%) 0.413
Induction Cycles (Median) 4 4 0.947
Induction Partial Response (vs. SD) 9 (47.4%) 11 (28.9%) 0.170
Days from End Induction to Randomization 34 28 0.030
ECOG 1 (vs. 0) 8 (42.1%) 25 (65.8%) 0.088
Imetelstat Tx 11 (57.9%) 26 (68.4%) 0.433
Bevacizumab Use 5 (26.3%) 10 (26.3%) 1
baseline characteristics
references 1. Frink R et al, 2010 AACR Annual Meeting: Abstract #3577
2. Chiappori A et al, 2013 AACR Annual Meeting: Abstract #4660
NSCLC cell lines and other tumor cells with short telomeres appear to be more sensitive to imetelstat in vitro than those with long telomeres.1 Telomere length varies with tumor type and among individual patients within tumor types. This led to a hypothesis that patients whose tumors have shorter telomeres may be more responsive to imetelstat.
A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in advanced NSCLC: results for the primary and secondary endpoints are reported separately (2AACR Poster #4660)
A planned exploratory analysis to determine PFS as a function of tumor telomere length (TL) was performed. Tumor TL was assessed in archival tumor specimens from pts by quantitative PCR (qPCR) and Telomeric Fluorescence In Situ Hybridization (Telo-FISH).
Days of imetelstat treatment
Po
pu
lati
on
do
ub
lings
short telomeres long telomeres
114 patients were evaluable for PFS; archival tumor specimens were obtained from 61 patients; 57 values were obtained from the retrospective qPCR assay, 52 values were obtained from the prospective qPCR assay, 59 values were obtained from Telo-FISH.
telomere
1University of Texas Southwestern Medical Center, Dallas, TX; 2Geron Corporation, Menlo Park, CA; 3Kaiser Permanente Medical Center, Vallejo, CA; 4Sarah Cannon Research Institute, Nashville, TN; 5Cancer Care Associates of Fresno Medical Group, Fresno, CA; 6Kaiser Permanente Northwest, Portland, OR; 7H Lee Moffitt Cancer Center, Tampa, FL; 8Karmanos Cancer Institute, Detroit, MI; 9CHUM-Hopital Notre-Dame, Montreal, Quebec; 10Asklepios Fachkliniken Muenchen-Gauting, Gauting, Bayern, Germany; 11Sarah Cannon Florida Cancer Specialists, Bonita Springs, FL; 12Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany
Imetelstat + Bevacizumab
vs. Bevacizumab
Imetelstat vs.
Observation Ran
do
miz
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ts (
2:1
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Stage IV or
Recurrent Locally
Advanced NSCLC
No
Pro
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sive
Dis
ease
Platinum-Based
Doublet Induction Chemo- Therapy 1°
Effi
cacy
: P
FS
Imetelstat maintenance study design
5-micron FFPE sections were obtained from each patient. Telomere length was measured on two sections by a modified, retrospective qPCR assay based on the method of Cawthon R.3 Genomic DNA from FFPE specimen was isolated using FFPE Tissue DNA Extraction Kit (BioChain Institute Inc). DNA concentrations for DNA from FFPE samples were determined by Quant-iT Pico Green dsDNA Assay Kit (Invitrogen).
All quantitative PCR reactions were carried out using ABI Prism 7900 HT Sequence Detection System (Applied Biosystems). Two PCR reactions were performed for each sample, one to determine the cycles threshold (Ct) value for telomere (T) amplification and the other to determine the Ct value for the amplification of a single copy gene (Acidic ribosomal phosphoprotein P, 36b4). The primer sequences for telomere amplification and 36B4 amplification are described in Cawthon R.3 Each PCR reaction for telomere amplification was performed using 1ng of sample. Relative telomere length was calculated as follows: (2Ct T/2Ct S)-1 = 2 -(Ct T-Ct S) = 2-dCt.
The patient samples were run in 7 batches. DOE models were used to adjust for plate effects and sample DNA concentrations. Telomere-length analyses were pre-specified for patients grouped into the shortest 1/2, shortest 1/3 and shortest 1/4 of TL. Results in the group with the shortest 1/4 of TL were similar to the shortest 1/3 TL group, while in the shortest 1/2 group the differential benefit appeared diluted, suggesting that that 50% is too large a group size. Kaplan-Meier and Cox PH estimates were used for time-to-event analyses. Wilcoxon rank sum tests were used to test for differences in baseline characteristics.
The retrospective assay processed 20 FFPE sections per plate x 2 slides per patient (N=57). The prospective protocol processed 2 sections per patient on a single plate (N=52), with single copy gene (SCG) controls and reference cell lines.
Measuring telomere length by Telo-FISH using IN Cell Analyzer and Developer
sub-group hazard ratios
PFS OS
PFS OS
In vitro effects of imetelstat on proliferation of NSCLC cell lines with short and long telomeres.1
Calu-3 Telomere length:
~1.5kb
H2882 Telomere length:
~7.7kb
Nuclei (DAPI) Telomeres (Cy3)
Intensity and area of telomeres (blue outlines) are measured within the nuclei (yellow outlines)
+
qPCR assay
Telo-FISH assay Telo-FISH was performed on one FFPE section per patient. Telomere
length was measured based on the method of Meeker R.4 Cells were hybridized with a telomere-specific probe conjugated to Cy3. Digital images of nuclei and telomeres were obtained using IN Cell Analyzer 2000 (GE Corp). Fluorescent intensities and areas of individual telomeres were measured using IN Cell Developer Toolbox 1.9 (GE Corp). Telomere length was calculated using the equation:
By Telo-FISH, PFS benefit was associated with the log2 intensity-to-area ratio: 1.376 x log2(intensity) – 6.215 x √(area), where “intensity” is defined as the intensity of the telomere and “area” is defined as the area of the telomere.
Median (95% CI) 2.63 (1.38, 3.59)
Median (95% CI) 2.80 (1.58, 4.18)
HR (95% CI) 0.77 (0.48, 1.25)
P-value 0.295 HR (95% CI)
0.0 0.5 1.0 1.5 2.0
Long-TeloFISH
Short-TeloFISH
Long-Prospective qPCR
Short-Prospective qPCR
Long-Retrospective qPCR
Short-Retrospective qPCR
All Patients with Assays
39
20
34
18
38
19
59N
HR (95% CI)
0.0 0.5 1.0 1.5 2.0
Long-TeloFISH
Short-TeloFISH
Long-Prospective qPCR
Short-Prospective qPCR
Long-Retrospective qPCR
Short-Retrospective qPCR
All Patients with Assays
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20
34
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59N
HR (95% CI)
0.0 0.5 1.0 1.5 2.0
Long-TeloFISH
Short-TeloFISH
Long-Prospective qPCR
Short-Prospective qPCR
Long-Retrospective qPCR
Short-Retrospective qPCR
All Patients with Assays
39
20
34
18
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59N
HR (95% CI)
0.0 0.5 1.0 1.5 2.0
Long-TeloFISH
Short-TeloFISH
Long-Prospective qPCR
Short-Prospective qPCR
Long-Retrospective qPCR
Short-Retrospective qPCR
All Patients with Assays
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Note that multivariate adjustment for available prognostic factors does not substantially alter the results of subsequent analyses (not shown).
Median (95% CI) 2.7 (1.1, 3.6)
Median (95% CI) 2.8 (1.5, 4.2)
HR (95% CI) 0.83 (0.36, 1.9)
P-value 0.623
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
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N at risk19 18 9 7 6 3 3 2 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
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N at risk38 36 20 13 10 6 6 6 5 2
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all patients
Median (95% CI) 1.5 (1.2, 2.8)
Median (95% CI) 4.0 (1.3, NA)
HR (95% CI) 0.32 (0.1, 1.0)
P-value 0.042
N=19 (33%), Events=15 N=38 (67%), Events=29
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2012
0 1 2 3 4 5 6 7 8 9 10 12 14 16 18
Months Since Randomization
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N at risk114 106 62 39 31 22 18 17 16 7 5 3 3 1 1 1 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2013
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
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N at risk20 20 8 6 6 4 4 3 2 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2013
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
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N at risk39 35 22 14 10 6 6 6 6 2
Control
Imetelstat
N=20, Events=16 N=39, Events=32
short telomeres† medium-long telomeres†
N=114, Events=77
N=114, Events=92
Updated PFS
July 9, 2012 median FU=2.8mn
February 11, 2013: Mature OS Time Point
July 9, 2012: Primary PFS Time Point
Median (95% CI) 2.57 (1.41, 3.62)
Median (95% CI) 2.76 (1.58, 3.03)
HR (95% CI) 0.84 (0.54, 1.31)
P-value 0.446
Median (95% CI) 1.94 (1.09, NA)
Median (95% CI) 1.84 (1.48, 6.12)
HR (95% CI) 0.45 (0.14, 1.48)
P-value 0.177
Median (95% CI) 2.66 (1.25, 3.75)
Median (95% CI) 2.80 (1.45, 4.18)
HR (95% CI) 0.92 (0.45, 1.89)
P-value 0.820
Primary PFS
Feb. 11, 2013 median FU=2.6mn
all patients short telomeres† medium-long telomeres†
prospective Telo-FISH assay is not predictive for overall survival
Mature OS Feb. 11, 2013 median FU=10.5mn
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2012
0 2 4 6 8 10 12 14 16 18 20 22 24
Months Since Randomization
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N at risk114 114 106 104 100 91 88 84 74 69 58 50 44 41 33 25 19 18 14 11 8 5 5 1 1 1
Control
Imetelstat
N=114, Events=66
Median (95% CI) 11.5 (7.6, 15.5)
Median (95% CI) 14.3 (9.9, 18.9)
HR (95% CI) 0.68 (0.41, 1.12)
P-value 0.129
all patients short telomeres† medium-long telomeres†
N=20, Events=8
Median (95% CI) 11.79 (4.18, NA)
Median (95% CI) NA (4.93, NA)
HR (95% CI) 0.44 (0.11, 1.87)
P-value 0.256
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2013
0 2 4 6 8 10 13 16 19 22 25
Months Since Randomization
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N at risk39 39 36 35 34 31 29 25 22 21 19 14 13 12 9 7 6 6 4 4 3 3 3 1 1 1
Control
Imetelstat
N=39, Events=24
Median (95% CI) 7.99 (4.67, 14.87)
Median (95% CI) 14.24 (7.76, 22.66)
HR (95% CI) 0.58 (0.25, 1.36)
P-value 0.200
Magnitude of short tumor telomere effect on HR is reduced and median PFS is no longer different between arms
AACR abstract #2376 We thank all of the patients, caregivers, principal investigators and staff who have participated in this study.
This study was sponsored by Geron Corporation
3. Cawthon R et al, 2009 Nucleic Acids Res. 37(3): e21
4. Meeker A et al, 2002 Am J Path 160(4): 1259
For retrospective qPCR, prospective qPCR and prospective Telo-FISH
Nuclei (DAPI) Telomeres (Cy3)
Stromal cells
Tumor cells
Imetelstat NSC Phase II (CP14B-012)
Overall Survival as of 11-Feb-2013
0 2 4 6 8 10 12 14 16 18 20
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk20 20 19 19 18 15 15 15 13 13 12 11 9 8 7 3 3 3 3 2 2 1 1
Control
Imetelstat
†Interaction P=0.160
†Interaction P=0.175
†Interaction P=0.689
↓ Stratify on bevacizumab use ↑
Telomeres are protective caps that maintain the stability and integrity of chromosomes. When telomeres reach a critically short length, chromosome ends are exposed to DNA damage mechanisms, which lead to senescence or apoptosis.
The enzyme telomerase is upregulated in malignant cells and sustains indefinite replication by maintaining telomere length.
Inhibition of telomerase may be a novel approach to treating cancer by limiting the proliferative capacity of malignant cells.
Imetelstat, a lipidated 13-mer oligonucleotide, is a potent and specific inhibitor of telomerase.
Imetelstat Telomerase
--TTAGGGTTAGGGTTAG-3’
hTR (RNA) IMETELSTAT
UGUU
Telomere:
hTERT (protein)
x
prospective qPCR assay
Improved progression-free survival (PFS) in patients with short tumor telomere length: subgroup analysis from a randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced NSCLC
analyses prospective TeloFISH assay
Primary PFS
retrospective qPCR assay
Median (95% CI) 2.7 (1.1, 3.6)
Median (95% CI) 2.8 (1.5, 4.2)
HR (95% CI) 0.83 (0.36, 1.9)
P-value 0.623
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk19 18 9 7 6 3 3 2 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk38 36 20 13 10 6 6 6 5 2
Control
Imetelstat
Median (95% CI) 1.5 (1.2, 2.8)
Median (95% CI) 4.0 (1.3, NA)
HR (95% CI) 0.32 (0.1, 1.0)
P-value 0.042
N=19 (33%), Events=15 N=38 (67%), Events=29
short telomeres†
†Interaction P=0.160
Supplemental data for AACR abstract #2376
medium-long telomeres†
overall patient population
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9 10 11 12
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk114 106 59 36 27 16 11 10 9 2 2 1 1
Control
Imetelstat
Median (95% CI) 2.63 (1.38, 3.59)
Median (95% CI) 2.80 (1.58, 4.18)
HR (95% CI) 0.77 (0.48, 1.25)
P-value 0.295
N=114, Events=77
July 9, 2012
median follow-up = 2.8 months
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2012
0 1 2 3 4 5 6 7 8 9 10 12 14 16 18
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk114 106 62 39 31 22 18 17 16 7 5 3 3 1 1 1 1 1 1
Control
Imetelstat
Median (95% CI) 2.57 (1.41, 3.62)
Median (95% CI) 2.76 (1.58, 3.03)
HR (95% CI) 0.84 (0.54, 1.31)
P-value 0.446
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2012
0 2 4 6 8 10 12 14 16 18 20 22 24
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk114 114 106 104 100 91 88 84 74 69 58 50 44 41 33 25 19 18 14 11 8 5 5 1 1 1
Control
Imetelstat
Median (95% CI) 11.5 (7.6, 15.5)
Median (95% CI) 14.3 (9.9, 18.9)
HR (95% CI) 0.68 (0.41, 1.12)
P-value 0.129
N=114, Events=92
N=114, Events=66
Updated PFS
Mature OS
short telomeres† medium-long telomeres†
Median (95% CI) 11.79 (4.18, NA)
Median (95% CI) NA (4.93, NA)
HR (95% CI) 0.44 (0.11, 1.87)
P-value 0.256
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2013
0 2 4 6 8 10 13 16 19 22 25
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk39 39 36 35 34 31 29 25 22 21 19 14 13 12 9 7 6 6 4 4 3 3 3 1 1 1
Control
Imetelstat
N=39, Events=24
Median (95% CI) 7.99 (4.67, 14.87)
Median (95% CI) 14.24 (7.76, 22.66)
HR (95% CI) 0.58 (0.25, 1.36)
P-value 0.200
Imetelstat NSC Phase II (CP14B-012)
Overall Survival as of 11-Feb-2013
0 2 4 6 8 10 12 14 16 18 20
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk20 20 19 19 18 15 15 15 13 13 12 11 9 8 7 3 3 3 3 2 2 1 1
Control
Imetelstat
†Interaction P=0.689
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2013
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk20 20 8 6 6 4 4 3 2 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2013
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk39 35 22 14 10 6 6 6 6 2
Control
Imetelstat
N=20, Events=16 N=39, Events=32
Median (95% CI) 1.94 (1.09, NA)
Median (95% CI) 1.84 (1.48, 6.12)
HR (95% CI) 0.45 (0.14, 1.48)
P-value 0.177
Median (95% CI) 2.66 (1.25, 3.75)
Median (95% CI) 2.80 (1.45, 4.18)
HR (95% CI) 0.92 (0.45, 1.89)
P-value 0.820
short telomeres† medium-long telomeres†
†Interaction P=0.175
February 11, 2013
median follow-up = 2.6 months
February 11, 2013
median follow-up = 10.5 months
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk19 17 8 6 5 3 3 2 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk38 36 21 13 11 7 7 7 6 3
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2012
0 1 2 3 4 5 6 7 8
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk18 15 7 5 4 2 2 2 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 11-Feb-2012
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk34 33 20 13 11 7 7 6 5 3
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2012
0 2 4 6 8 10 13 16 19 22 25
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk34 34 34 33 32 29 28 25 23 23 22 18 16 15 12 8 7 7 6 5 4 4 4 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2012
0 2 4 6 8 10 12 14 16 18 20
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk18 18 15 15 14 12 11 10 8 7 6 6 5 4 3 2 2 2 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
OS as of 11-Feb-2013
0 2 4 6 8 10 13 16 19 22 25
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk38 38 38 37 36 31 30 26 25 24 22 16 14 13 10 7 7 7 6 5 4 4 4 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
Overall Survival as of 11-Feb-2013
0 2 4 6 8 10 12 14 16 18 20
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Ove
rall
Su
rviv
al R
ate
N at risk19 19 16 16 15 14 13 13 9 9 8 8 7 6 5 3 2 2 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk18 16 7 5 4 1 1 1 1
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk34 33 20 14 11 7 7 6 5 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk20 19 9 7 7 4 4 3 2
Control
Imetelstat
Imetelstat NSC Phase II (CP14B-012)
PFS as of 09-July-2012
0 1 2 3 4 5 6 7 8 9
Months Since Randomization
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Pro
gre
ssio
n-f
ree
Su
rviv
al R
ate
N at risk39 36 21 14 9 5 5 5 5 2
Control
Imetelstat
short telomeres† medium-long telomeres†
short telomeres† medium-long telomeres† short telomeres† medium-long telomeres†
short telomeres† medium-long telomeres†
short telomeres† medium-long telomeres† short telomeres† medium-long telomeres†
Median (95% CI) 1.48 (1.18, 2.76)
Median (95% CI) 1.91 (1.25, NA)
HR (95% CI) 0.43 (0.14, 1.3)
P-value 0.124
N=19, Events=15
Median (95% CI) 2.7 (1.09, NA)
Median (95% CI) 2.8 (1.55, 4.18)
HR (95% CI) 0.86 (0.39, 1.88)
P-value 0.689
N=38, Events=31
Median (95% CI) 7.57 (3.19, 13.45)
Median (95% CI) NA (1.91, NA)
HR (95% CI) 0.41 (0.11, 1.46)
P-value 0.155
N=19, Events=10 N=38, Events=21
Median (95% CI) 7.99 (4.18, NA)
Median (95% CI) 14.51 (9.41, NA)
HR (95% CI) 0.51 (0.2, 1.28)
P-value 0.145
Median (95% CI) 2.57 (1.18, NA)
Median (95% CI) 1.91 (1.22, NA)
HR (95% CI) 0.55 (0.17, 1.84)
P-value 0.325
N=18 (35%), Events=13 N=34 (65%), Events=26
Median (95% CI) 2.66 (0.92, NA)
Median (95% CI) 3.03 (1.58, 4.47)
HR (95% CI) 0.65 (0.27, 1.56)
P-value 0.334
Median (95% CI) 2.57 (1.18, 3.98)
Median (95% CI) 1.51 (0.72, NA)
HR (95% CI) 0.97 (0.32, 2.93)
P-value 0.962
N=18 (35%), Events=13 N=34 (65%), Events=28
Median (95% CI) 2.53 (0.92, 3.62)
Median (95% CI) 3.03 (1.58, 4.47)
HR (95% CI) 0.55 (0.24, 1.27)
P-value 0.154
Median (95% CI) 9.77 (3.19, NA)
Median (95% CI) NA (1.22, NA)
HR (95% CI) 0.67 (0.19, 2.37)
P-value 0.529
N=18 (35%), Events=10
Median (95% CI) 10.79 (4.67, NA)
Median (95% CI) 19.54 (9.08, NA)
HR (95% CI) 0.47 (0.17, 1.33)
P-value 0.144
N=34 (65%), Events=17
N=20, Events=14 N=39, Events=30
Median (95% CI) 2.66 (1.25, 3.98)
Median (95% CI) 2.8 (1.45, 4.18)
HR (95% CI) 0.95 (0.44, 2.06)
P-value 0.88
Median (95% CI) 1.94 (1.09, NA)
Median (95% CI) 4.05 (1.41, NA)
HR (95% CI) 0.34 (0.1, 1.18)
P-value 0.067
N=20, Events=8
Legend:
Control
Imetelstat
†Interaction P=0.092
†Interaction P=0.804
†Interaction P=0.419
†Interaction P=0.777
†Interaction P=0.255
†Interaction P=0.690
