Unresected Stage IIIb to IVM1c Melanoma
Conditions
Keywords
T-VEC, CD8+ cell density, objective response rate, unresected, Melanoma
Brief summary
The study is a phase 2, multi centered, single arm study designed to evaluate the correlation between cluster of differentiation 8-positive (CD8+) cell density and objective response rate in adults with unresected stage IIIB to IVM1c melanoma. This study will also evaluate the safety and tolerability profile of talimogene laherparepvec.
Detailed description
The study will explore the hypothesis that intratumoral CD8+ cell density at baseline correlates with objective response rate in adults with unresected stage IIIB to IVMIc melanoma treated with talimogene laherparepvec.
Interventions
DRUGTalimogene Laherparepvec
The initial dose of talimogene laherparepvec is up to 4.0 mL of 10\^6 PFU/mL. Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 10\^8 PFU/mL.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provided informed consent prior to initiation of any study-specific activities/procedures 2. Subject with stage IIIB to IVM1c melanoma for whom surgery is not recommended 3. Candidate for intralesional therapy 4. Measurable disease with greatest diameter ≥ 10 mm 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 6. Adequate organ function Other Inclusion Criteria May Apply
Exclusion criteria
1. Clinically active cerebral metastases. 2. Bone metastases 3. Primary ocular or mucosal melanoma 4. Active herpetic skin lesions or prior complications of herpes simplex virus type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) 5. Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use 6. Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec 7. Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at primary completion = 59 weeks (min 3 to max 116 weeks) | A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of objective response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) according to the modified WHO criteria. The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for objective response rate is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate | Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6) | A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of durable response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy. The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for durable response rate is reported. Primary completion is defined as PC and final analysis is defined as FA. |
| Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response | Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | A Cox proportional hazards regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of duration of response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). The unadjusted hazard ratio of log2(baseline intratumoral CD8+ cell density) for duration of response is reported. |
| Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden | Intratumoral CD8+ cell density: Baseline; Tumor burden: First dose of study drug until primary completion date (26 June 2017) or end of follow-up; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | Pearson's correlation coefficient (r) was estimated to assess the relationship between baseline log2(CD8+ cell density) and the maximum decrease in measurable tumor burden. Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. The Pearson's correlation coefficient (r) of log2(baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. Primary completion is defined as PC and final analysis is defined as FA. |
| Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected tumors as a predictor of objective response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response or partial response according to the modified WHO criteria. The unadjusted odds ratio of log2(change from baseline intratumoral CD8+ cell density) for objective response rate is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA. |
| Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate | CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected lesions as a predictor of durable response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy. The unadjusted odds ratio of log2(change from baseline in intratumoral CD8+ cell density) for durable response rate is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA. |
| Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response | CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | A Cox proportional hazards regression model was performed to evaluate change from baseline in log2(CD8+ cell density) as a predictor of duration of response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). The unadjusted hazard ratio of log2(change from baseline intratumoral CD8+ cell density) for duration of response is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA. |
| Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden | CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks) | Pearson's correlation coefficient (r) was estimated to assess the relationship between change from baseline in log2(CD8+ cell density) in uninjected lesions and the maximum decrease in measurable tumor burden. Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. The Pearson's correlation coefficient (r) of log2(change from baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA. |
| Objective Response Rate | Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks) | Objective Response rate is defined as the percentage of participants with either a CR or PR based on Modified WHO Response Criteria. CR: Complete disappearance of all index lesions, all non-index lesions, and any new tumors which might have appeared. Any residual cutaneous or subcutaneous index lesions must be documented by representative biopsy to not contain viable tumor. PR: Disappearance of all index lesions with persistence of one or more non-index tumor(s), or, 50% or greater reduction in the 2 largest perpendicular diameters (SPD) of all index lesions as compared to baseline, and disappearance or persistence of non-index lesions. |
| Duration of Response | Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks) | Duration of response (DOR) was defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for objective response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). SD: Neither sufficient tumor shrinkage of index lesion to qualify for response (PR or CR) nor sufficient tumor increase of index lesion to qualify for PD, with no increase in size of non-index lesions. PD: A \> 25% increase in the sum of the SPD of all index tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point, or unequivocal progression of one or more non-index lesions. Participants last reported to be either a CR or PR were censored at that time point. |
| Time to Treatment Failure | From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks) | Time to treatment failure (TTF) was calculated from first dosing until one or more of the following: (1) clinically relevant disease progression (PDr); (2) death from any cause; (3) non clinically relevant disease progression (PDn) associated with a requirement for alternative therapy as the reason for ending treatment or start of new anti-cancer therapy. Participants with no event were censored at their last evaluable tumor assessment. |
| Durable Response Rate | Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks) | Durable response rate (DRR) was defined as the percentage of participants with an objective response (CR or PR) based on modified WHO response criteria lasting continuously for 6 months and starting any time within 12 months of initiating therapy. |
| Overall Survival | From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks) | Overall survival (OS) was defined as the time from the date of first dose to the date of death from any cause. OS time was censored at the last date the participant was known to be alive when the confirmation of death is absent or unknown. |
| Change From Baseline in Tumor Burden | Baseline and Day 1 of cycle 6, 12 , 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, and 120. The first cycle was 21 days and all subsequent cycles were 14 days. | Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. Change from baseline in tumor burden was assessed in participants with an objective response. |
| Number of Participants With Adverse Events | From first dose through 30 days after last dose of talimogene laherparepvec; median duration of treatment was 25.143 weeks (range 0.14 to 241.43 weeks) | The severity of each adverse event (AE) was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 grading scale, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE Treatment-related adverse events (TRAE) were those assessed by the investigator as possibly related to talimogene laherparepvec. |
Countries
Austria, Belgium, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 36 centers across 12 countries in Europe from 07 April 2015 to 25 December 2020.
Participants by arm
| Arm | Count |
|---|---|
| Talimogene Laherparepvec Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first. | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 41 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol-specified criteria | 3 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Talimogene Laherparepvec |
|---|---|
| Age, Continuous | 65.7 years STANDARD_DEVIATION 15.1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active, no restrictions) | 87 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restricted but ambulatory) | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Log2(Intratumoral Cluster of Differentiation 8-positive (CD8+) Cell Density) Final analysis | 8.109 Log2 CD8+ cells/mm² STANDARD_DEVIATION 1.94 |
| Log2(Intratumoral Cluster of Differentiation 8-positive (CD8+) Cell Density) Primary completion | 8.041 Log2 CD8+ cells/mm² STANDARD_DEVIATION 1.903 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 111 Participants |
| Sex: Female, Male Female | 62 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 112 |
| other Total, other adverse events | 97 / 111 |
| serious Total, serious adverse events | 33 / 111 |
Outcome results
Primary
Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate
A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of objective response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) according to the modified WHO criteria. The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for objective response rate is reported.
Time frame: Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at primary completion = 59 weeks (min 3 to max 116 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with non-missing baseline CD8+ cell density data. Data is available for 91 participants who had data available for analysis at the time of primary completion (26 June 2017).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talimogene Laherparepvec | Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | 1.11 ratio |
p-value: 0.387Regression, Logistic
Secondary
Change From Baseline in Tumor Burden
Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. Change from baseline in tumor burden was assessed in participants with an objective response.
Time frame: Baseline and Day 1 of cycle 6, 12 , 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, and 120. The first cycle was 21 days and all subsequent cycles were 14 days.
Population: Participants who received at least 1 dose of talimogene laherparepvec with an objective response (CR or PR)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Baseline | 16.420 cm² | Standard Deviation 41.269 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 6 day 1 | -5.883 cm² | Standard Deviation 12.158 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 12 day 1 | -10.085 cm² | Standard Deviation 22.862 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 18 day 1 | -13.074 cm² | Standard Deviation 27.798 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 48 day 1 | -11.396 cm² | Standard Deviation 14.885 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 84 day 1 | -17.022 cm² | Standard Deviation 14.992 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 90 day 1 | -13.916 cm² | Standard Deviation 14.381 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 96 day 1 | -16.505 cm² | Standard Deviation 15.244 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 102 day 1 | -17.793 cm² | Standard Deviation 18.413 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 108 day 1 | -17.733 cm² | Standard Deviation 18.426 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 114 day 1 | -1.694 cm² | — |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 120 day 1 | -39.930 cm² | — |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 24 day 1 | -21.407 cm² | Standard Deviation 42.221 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 30 day 1 | -30.404 cm² | Standard Deviation 55.593 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 36 day 1 | -31.803 cm² | Standard Deviation 69.358 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 42 day 1 | -10.208 cm² | Standard Deviation 14.188 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 54 day 1 | -11.693 cm² | Standard Deviation 15.72 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 60 day 1 | -13.122 cm² | Standard Deviation 17.791 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 66 day 1 | -16.797 cm² | Standard Deviation 14.659 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 72 day 1 | -16.797 cm² | Standard Deviation 14.659 |
| Talimogene Laherparepvec | Change From Baseline in Tumor Burden | Change from baseline at Cycle 78 day 1 | -16.858 cm² | Standard Deviation 14.73 |
Secondary
Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden
Pearson's correlation coefficient (r) was estimated to assess the relationship between baseline log2(CD8+ cell density) and the maximum decrease in measurable tumor burden. Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. The Pearson's correlation coefficient (r) of log2(baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: Intratumoral CD8+ cell density: Baseline; Tumor burden: First dose of study drug until primary completion date (26 June 2017) or end of follow-up; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with available tumor burden data at primary completion or final analysis, and baseline CD8+ cell density data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden | Primary completion | 0.03 Pearson's correlation coefficient |
| Talimogene Laherparepvec | Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden | Final analysis | 0.01 Pearson's correlation coefficient |
p-value: 0.82Fisher's Z transformation
p-value: 0.9Fisher's Z transformation
Secondary
Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden
Pearson's correlation coefficient (r) was estimated to assess the relationship between change from baseline in log2(CD8+ cell density) in uninjected lesions and the maximum decrease in measurable tumor burden. Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. The Pearson's correlation coefficient (r) of log2(change from baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with available tumor burden data at primary completion or final analysis, and baseline and week 6 CD8+ cell density data for uninjected lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden | Primary completion | -0.18 Pearson's correlation coefficient |
| Talimogene Laherparepvec | Correlation Between Change From Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden | Final analysis | -0.19 Pearson's correlation coefficient |
p-value: 0.18Pearson's correlation coefficient
p-value: 0.14Pearson's correlation coefficient
Secondary
Durable Response Rate
Durable response rate (DRR) was defined as the percentage of participants with an objective response (CR or PR) based on modified WHO response criteria lasting continuously for 6 months and starting any time within 12 months of initiating therapy.
Time frame: Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Durable Response Rate | Primary completion | 13.5 percentage of participants |
| Talimogene Laherparepvec | Durable Response Rate | Final analysis | 21.6 percentage of participants |
Secondary
Duration of Response
Duration of response (DOR) was defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for objective response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). SD: Neither sufficient tumor shrinkage of index lesion to qualify for response (PR or CR) nor sufficient tumor increase of index lesion to qualify for PD, with no increase in size of non-index lesions. PD: A \> 25% increase in the sum of the SPD of all index tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point, or unequivocal progression of one or more non-index lesions. Participants last reported to be either a CR or PR were censored at that time point.
Time frame: Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with an objective response at either primary completion (26 June 2017) or final analysis (25 December 2020).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Talimogene Laherparepvec | Duration of Response | Primary completion | NA months |
| Talimogene Laherparepvec | Duration of Response | Final analysis | NA months |
Secondary
Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response
A Cox proportional hazards regression model was performed to evaluate change from baseline in log2(CD8+ cell density) as a predictor of duration of response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). The unadjusted hazard ratio of log2(change from baseline intratumoral CD8+ cell density) for duration of response is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with an objective response at either primary completion or final analysis, and with baseline and week 6 CD8+ cell density data for uninjected lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response | Primary completion | 1.28 ratio |
| Talimogene Laherparepvec | Hazard Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Duration of Response | Final analysis | 1.12 ratio |
p-value: 0.626Cox proportional hazards
p-value: 0.579Cox proportional hazards
Secondary
Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response
A Cox proportional hazards regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of duration of response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease \[SD\] as compared with baseline or progressive disease \[PD\]). The unadjusted hazard ratio of log2(baseline intratumoral CD8+ cell density) for duration of response is reported.
Time frame: Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with an objective response at the time of primary completion or final analysis, and with baseline CD8+ cell density data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response | Primary completion | 0.74 ratio |
| Talimogene Laherparepvec | Hazards Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response | Final analysis | 0.91 ratio |
p-value: 0.335Cox proportional hazards
p-value: 0.597Cox proportional hazards
Secondary
Number of Participants With Adverse Events
The severity of each adverse event (AE) was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 grading scale, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE Treatment-related adverse events (TRAE) were those assessed by the investigator as possibly related to talimogene laherparepvec.
Time frame: From first dose through 30 days after last dose of talimogene laherparepvec; median duration of treatment was 25.143 weeks (range 0.14 to 241.43 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Any adverse event | 108 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 38 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Serious adverse events | 33 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related serious adverse events | 9 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Adverse events ≥ grade 4 | 11 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 4 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Fatal adverse events | 4 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related adverse events | 93 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related adverse events ≥ grade 3 | 11 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related adverse events ≥ grade 4 | 2 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | TRAE leading to discontinuation of study drug | 3 Participants |
| Talimogene Laherparepvec | Number of Participants With Adverse Events | Treatment-related fatal adverse events | 0 Participants |
Secondary
Objective Response Rate
Objective Response rate is defined as the percentage of participants with either a CR or PR based on Modified WHO Response Criteria. CR: Complete disappearance of all index lesions, all non-index lesions, and any new tumors which might have appeared. Any residual cutaneous or subcutaneous index lesions must be documented by representative biopsy to not contain viable tumor. PR: Disappearance of all index lesions with persistence of one or more non-index tumor(s), or, 50% or greater reduction in the 2 largest perpendicular diameters (SPD) of all index lesions as compared to baseline, and disappearance or persistence of non-index lesions.
Time frame: Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up at time of primary completion: 59 weeks (3 to 116 weeks); final analysis: 108 weeks (2.7 to 245.6 weeks)
Population: All participants who received at least 1 dose of talimogene laherparepvec.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Objective Response Rate | Primary completion | 27.0 percentage of participants |
| Talimogene Laherparepvec | Objective Response Rate | Final analysis | 28.8 percentage of participants |
Secondary
Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate
A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of durable response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy. The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for durable response rate is reported. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6)
Population: Participants who received at least 1 dose of talimogene laherparepvec with non-missing baseline CD8+ cell density data. Data is available for 91 participants who had data available for analysis at the time of primary completion (26 June 2017). Data is also presented for 93 participants who had data available at final analysis (25 December 2020).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate | Primary completion | 1.40 ratio |
| Talimogene Laherparepvec | Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate | Final analysis | 1.18 ratio |
p-value: 0.056Regression, Logistic
p-value: 0.222Regression, Logistic
Secondary
Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate
A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected lesions as a predictor of durable response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy. The unadjusted odds ratio of log2(change from baseline in intratumoral CD8+ cell density) for durable response rate is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with baseline and week 6 CD8+ cell density data in uninjected lesions. Data is available for 59 participants who had data available for analysis at the time of primary completion (26 June 2017). Data is also presented for 63 participants who had data available at final analysis (25 December 2020).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate | Final analysis | 0.93 ratio |
| Talimogene Laherparepvec | Odds Ratio of Change From Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate | Primary completion | 0.99 ratio |
p-value: 0.974Regression, Logistic
p-value: 0.612Regression, Logistic
Secondary
Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate
A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected tumors as a predictor of objective response. Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response or partial response according to the modified WHO criteria. The unadjusted odds ratio of log2(change from baseline intratumoral CD8+ cell density) for objective response rate is reported. Intratumoral CD8+ Cell density has been shortened to CD8+ cell density in the time frame due to character limit. Primary completion is defined as PC and final analysis is defined as FA.
Time frame: CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: PC: 59 weeks (3 to 116 weeks); FA: 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec with baseline and week 6 CD8+ cell density data for uninjected lesions. Data is available for 59 participants who had data available for analysis at the time of primary completion (26 June 2017). Data is also presented for 63 participants who had data available at final analysis (25 December 2020).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec | Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | Primary completion | 0.94 ratio |
| Talimogene Laherparepvec | Odds Ratio of Change From Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | Final analysis | 0.98 ratio |
p-value: 0.66Regression, Logistic
p-value: 0.881Regression, Logistic
Secondary
Overall Survival
Overall survival (OS) was defined as the time from the date of first dose to the date of death from any cause. OS time was censored at the last date the participant was known to be alive when the confirmation of death is absent or unknown.
Time frame: From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Talimogene Laherparepvec | Overall Survival | Primary completion | NA months |
| Talimogene Laherparepvec | Overall Survival | Final analysis | NA months |
Secondary
Time to Treatment Failure
Time to treatment failure (TTF) was calculated from first dosing until one or more of the following: (1) clinically relevant disease progression (PDr); (2) death from any cause; (3) non clinically relevant disease progression (PDn) associated with a requirement for alternative therapy as the reason for ending treatment or start of new anti-cancer therapy. Participants with no event were censored at their last evaluable tumor assessment.
Time frame: From first dose of study drug until primary completion date of 26 June 2017, or end of follow-up; median time on follow-up at primary completion was 59 weeks (3 to 116 weeks); final analysis was 108 weeks (2.7 to 245.6 weeks)
Population: Participants who received at least 1 dose of talimogene laherparepvec.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Talimogene Laherparepvec | Time to Treatment Failure | Primary completion | 8.1 months |
| Talimogene Laherparepvec | Time to Treatment Failure | Final analysis | 8.1 months |