OPTiM
Talimogene laherparepvec versus GM-CSF in unresectable stage IIIB to IV melanoma: OPTiM, randomised open-label phase 3 trial (ClinicalTrials.gov NCT00769704; study 005/05)
Phase 3N = 436NCT00769704
- Population
- Patients with injectable melanoma that was not surgically resectable, stage IIIB to IV (the final-analysis abstract gives stage IIIB to IVM1c).
- Design
- Randomised, open-label phase 3 trial, 2:1, intralesional talimogene laherparepvec versus subcutaneous GM-CSF. Primary endpoint durable response rate (objective response lasting continuously 6 months or more) per independent assessment.
- Primary endpoint
- DRR
- Arms
- Talimogene laherparepvec (experimental, n = 295): Intralesional talimogene laherparepvec
- GM-CSF (control, n = 141): Subcutaneous GM-CSF
- People
- Andtbacka RH, senior author Coffin RS
Δ DRR+14.2 pointsΔ ORR+20.7 pointsOSHR 0.79 (95% CI 0.62–1.00)Δ median OS+4.4 monthsΔ DRR+17.9 pointsOSHR 0.79 (95% CI 0.62–1.00)
Show the numbers
| Endpoint | Analysis | Talimogene laherparepvec | GM-CSF | Effect |
|---|---|---|---|---|
| DRRRandomised patients (436 in total); the 2015 abstract does not use the term ITT (the 2019 final-analysis abstract describes the 436 as the intent-to-treat population)Durable response rate: objective response lasting continuously for at least 6 months, per independent assessment | primaryAndtbacka 2015 | 16.3% (12.1–20.5%) | 2.1% (0.0–4.5%) | P<.001Odds ratio 8.9. Arm sizes (295 and 141) are from the 2019 final-analysis abstract; the 2015 abstract gives only the total. |
| ORRRandomised patients (436 in total)Overall response rate (key secondary endpoint) | primaryAndtbacka 2015 | 26.4% (21.4–31.5%) | 5.7% (1.9–9.5%) | — |
| OSRandomised patients (436 in total)Overall survival (key secondary endpoint), primary analysis | primaryAndtbacka 2015 | median 23.3 months (19.5–29.6) | median 18.9 months (16.0–23.7) | HR 0.79 (95% CI 0.62–1.00)P=.051The reported P value is above 0.05. Per the 2019 final-analysis paper, this primary OS analysis followed 290 deaths at a median follow-up of 44 months. The FDA Summary Basis for Regulatory Action reports that reviewers were concerned about informative censoring and, from additional survival data requested from the applicant, a revised P value of 0.116 (median OS 22.9 vs 19.0 months). |
| DRRDurable response rate, final planned analysis (descriptive; investigator-assessed); responses lasting at least 6 months with onset within 12 months of randomisation | finalmedian follow-up 49 monthsAndtbacka 2019 | 19.3% | 1.4% | P<0.0001T-VEC 57 of 295 (19.3%) and GM-CSF 2 of 141 (1.4%) in the full text (Results and Table 1); the abstract prints 19.0% for T-VEC, which differs from 57/295. Unadjusted odds ratio 16.6 (95% CI 4.0 to 69.2). The paper states that all final analyses are descriptive and that responses were assessed by the investigators; median follow-up is that of the final overall survival analysis. |
| OSOverall survival, final planned analysis (descriptive) | finalmedian follow-up 49 monthsAndtbacka 2019 | median 23.3 months (19.5–29.6) | median 18.9 months (16.0–23.7) | HR 0.79 (95% CI 0.62–1.00)P=0.0494 [descriptive]Unstratified hazard ratio; the abstract labels the P value descriptive. Median follow-up is that of the final overall survival analysis. |
| Endpoint | Analysis | Talimogene laherparepvec | GM-CSF | Effect |
|---|---|---|---|---|
| DRRRandomised patients (436 in total); the 2015 abstract does not use the term ITT (the 2019 final-analysis abstract describes the 436 as the intent-to-treat population)Durable response rate: objective response lasting continuously for at least 6 months, per independent assessment | primaryAndtbacka 2015 | 16.3% (12.1–20.5%) | 2.1% (0.0–4.5%) | P<.001Odds ratio 8.9. Arm sizes (295 and 141) are from the 2019 final-analysis abstract; the 2015 abstract gives only the total. |
| ORRRandomised patients (436 in total)Overall response rate (key secondary endpoint) | primaryAndtbacka 2015 | 26.4% (21.4–31.5%) | 5.7% (1.9–9.5%) | — |
| OSRandomised patients (436 in total)Overall survival (key secondary endpoint), primary analysis | primaryAndtbacka 2015 | median 23.3 months (19.5–29.6) | median 18.9 months (16.0–23.7) | HR 0.79 (95% CI 0.62–1.00)P=.051The reported P value is above 0.05. Per the 2019 final-analysis paper, this primary OS analysis followed 290 deaths at a median follow-up of 44 months. The FDA Summary Basis for Regulatory Action reports that reviewers were concerned about informative censoring and, from additional survival data requested from the applicant, a revised P value of 0.116 (median OS 22.9 vs 19.0 months). |
| DRRDurable response rate, final planned analysis (descriptive; investigator-assessed); responses lasting at least 6 months with onset within 12 months of randomisation | finalmedian follow-up 49 monthsAndtbacka 2019 | 19.3% | 1.4% | P<0.0001T-VEC 57 of 295 (19.3%) and GM-CSF 2 of 141 (1.4%) in the full text (Results and Table 1); the abstract prints 19.0% for T-VEC, which differs from 57/295. Unadjusted odds ratio 16.6 (95% CI 4.0 to 69.2). The paper states that all final analyses are descriptive and that responses were assessed by the investigators; median follow-up is that of the final overall survival analysis. |
| OSOverall survival, final planned analysis (descriptive) | finalmedian follow-up 49 monthsAndtbacka 2019 | median 23.3 months (19.5–29.6) | median 18.9 months (16.0–23.7) | HR 0.79 (95% CI 0.62–1.00)P=0.0494 [descriptive]Unstratified hazard ratio; the abstract labels the P value descriptive. Median follow-up is that of the final overall survival analysis. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.79 | 0.62–1 |
| OS | 0.79 | 0.62–1 |
- Talimogene laherparepvec (experimental)
- GM-CSF (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Talimogene laherparepvec | GM-CSF |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 15 | 64.0% | 57.7% |
| 29 | 42.2% | 34.5% |
| 44 | 27.0% | 19.9% |
| 58 | 17.8% | 11.9% |
- Talimogene laherparepvec (experimental)
- GM-CSF (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Talimogene laherparepvec | GM-CSF |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 15 | 64.0% | 57.7% |
| 29 | 42.2% | 34.5% |
| 44 | 27.0% | 19.9% |
| 58 | 17.8% | 11.9% |
Appears in
Sources
Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780-8.
Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019;7(1):145.