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Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02211131
Recruitment Status : Completed
First Posted : August 7, 2014
Results First Posted : May 28, 2020
Last Update Posted : June 5, 2023
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma
Interventions Drug: Talimogene Laherparepvec
Procedure: Immediate surgical resection of melanoma lesion(s)
Enrollment 150
Recruitment Details This study was conducted at 35 centers in Australia, Brazil, Europe, Russia, and the United States. Participants were enrolled between 03 February 2015 and 28 April 2022.
Pre-assignment Details Participants were randomized 1:1 to receive either talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesions or immediate surgical resection of melanoma tumor lesion(s). Randomization was stratified by disease stage and planned adjuvant therapy.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Period Title: Overall Study
Started 74 76
Completed 40 48
Not Completed 34 28
Reason Not Completed
Death             26             16
Lost to Follow-up             4             3
Decision by Sponsor             1             1
Withdrawal by Subject             3             8
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery Total
Hide Arm/Group Description Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.

 Total of all reporting groups
Overall Number of Baseline Participants 74 76 150
Hide Baseline Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 74 participants 76 participants 150 participants
59.1  (16.1) 62.6  (12.6) 60.9  (14.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 74 participants 76 participants 150 participants
Female
27
  36.5%
27
  35.5%
54
  36.0%
Male
47
  63.5%
49
  64.5%
96
  64.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 74 participants 76 participants 150 participants
Hispanic or Latino
5
   6.8%
5
   6.6%
10
   6.7%
Not Hispanic or Latino
69
  93.2%
70
  92.1%
139
  92.7%
Unknown or Not Reported
0
   0.0%
1
   1.3%
1
   0.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 74 participants 76 participants 150 participants
American Indian or Alaska Native
0
   0.0%
1
   1.3%
1
   0.7%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
1
   1.4%
0
   0.0%
1
   0.7%
Black or African American
0
   0.0%
1
   1.3%
1
   0.7%
White
73
  98.6%
73
  96.1%
146
  97.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
1
   1.3%
1
   0.7%
Stratification Factor: Disease Stage   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 74 participants 76 participants 150 participants
Stage IIIB Nodal 14 15 29
Stage IIIB In-Transit 17 16 33
Stage IIIC Nodal 14 13 27
Stage IIIC In-Transit With Nodal 17 17 34
Stage IV M1a 12 15 27
[1]
Measure Description:

The clinical participants were staged according to the American Joint Committee of Cancer (AJCC) 7th edition Melanoma Staging System, which combines tumor staging, nodal staging and metastasis to derive an overall stage. The order of prognostication is as follows: stage IIIB (better prognosis) > stage IIIC > stage IV M1a (worse prognosis).

Randomization was stratified by disease stage and planned adjuvant therapy (adjuvant systemic therapy with or without radiotherapy vs radiotherapy without adjuvant systemic therapy vs none).
Stratification Factor: Planned Adjuvant Therapy   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 74 participants 76 participants 150 participants
Adjuvant Systemic Therapy W/ or W/O Radiotherapy 9 9 18
Radiotherapy W/O Adjuvant Systemic Therapy 3 3 6
None 62 64 126
[1]
Measure Description: Randomization was stratified by disease stage (IIIB nodal vs IIIB in-transit vs IIIC nodal vs IIIC in-transit with nodal vs IVM1a) and planned adjuvant therapy (adjuvant systemic therapy with (W/) or without (W/O) radiotherapy vs radiotherapy without (W/O) adjuvant systemic therapy vs none).
1.Primary Outcome
Title Recurrence-Free Survival (RFS)
Hide Description Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
Time Frame 24 months after last participant was randomized (data cutoff date of 30 April 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
0.0 [1] 
(NA to NA)
0.0
(0.0 to 6.5)
[1]
NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals (CIs) are not estimable.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Surgery, Talimogene Laherparepvec Plus Surgery
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.070
Comments Unstratified log-rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 80%
0.58 to 0.96
Estimation Comments Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)
2.Secondary Outcome
Title RFS
Hide Description Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
0.03 [1] 
(NA to NA)
0.03
(0.03 to 6.54)
[1]
NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals (CIs) are not estimable.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Surgery, Talimogene Laherparepvec Plus Surgery
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.092
Comments Unstratified log-rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 80%
0.60 to 0.97
Estimation Comments Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)
3.Secondary Outcome
Title Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years
Hide Description Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
RFS at 1 Year
21.95
(15.88 to 28.65)
33.73
(26.82 to 40.76)
RFS at 2 Years
16.88
(11.44 to 23.23)
29.51
(22.91 to 36.40)
RFS at 3 Years
16.88
(11.44 to 23.23)
28.11
(21.62 to 36.94)
RFS at 5 Years
15.19
(10.01 to 21.38)
22.32
(16.39 to 28.84)
4.Secondary Outcome
Title Histopathology Tumor-Free Margin (R0) Surgical Resection Rate
Hide Description Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.
Time Frame 18 weeks after last participant randomized (data cutoff date of 30 April 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
37.8
(30.3 to 45.9)
42.1
(34.4 to 50.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Surgery, Talimogene Laherparepvec Plus Surgery
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.594
Comments The two-sided p-value is based on the Pearson's Chi-square test.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 4.3
Confidence Interval (2-Sided) 80%
-6.9 to 15.3
Estimation Comments An 80% approximate exact CI for between-arm differences in binary rate is calculated using Wilson's score method with continuity correction.
5.Secondary Outcome
Title Pathological Complete Response (pCR) Rate
Hide Description Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.
Time Frame 18 weeks after last participant randomized (data cutoff date of 30 April 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
2.7
(0.7 to 7.0)
17.1
(11.6 to 24.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Surgery, Talimogene Laherparepvec Plus Surgery
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments The two-sided p-value is based on the Pearson's Chi-square test.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 14.4
Confidence Interval (2-Sided) 80%
7.4 to 21.6
Estimation Comments 80% exact CI for binary rate of each arm is calculated using the Clopper Pearson method.
6.Secondary Outcome
Title Local Recurrence-Free Survival (LRFS)
Hide Description Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
0.0 [1] 
(NA to NA)
0.0
(0.0 to 7.1)
[1]
NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.
7.Secondary Outcome
Title Regional Recurrence-Free Survival (RRFS)
Hide Description Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
0.0 [1] 
(NA to NA)
0.0
(0.0 to 12.9)
[1]
NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.
8.Secondary Outcome
Title Distant Metastases-Free Survival (DMFS)
Hide Description Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
0.0 [1] 
(NA to NA)
0.0
(0.0 to 6.5)
[1]
NA = not estimable. There are not enough events to estimate a standard error for the median survival time, confidence intervals are not estimable.
9.Secondary Outcome
Title Overall Survival (Kaplan-Meier)
Hide Description Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Median (80% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
NA=not estimable. Not enough events occurred to estimate the median and the confidence intervals.
[2]
NA=not estimable. There are not enough events to estimate a standard error for the median survival time, confidence interval is not estimable.
10.Secondary Outcome
Title Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years
Hide Description Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.
Time Frame 5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 74 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
Year 1
85.92
(79.63 to 90.38)
95.89
(91.58 to 98.02)
Year 2
77.44
(70.29 to 83.08)
88.94
(83.16 to 92.82)
Year 3
71.59
(64.03 to 77.84)
83.27
(76.70 to 88.13)
Year 5
62.29
(54.75 to 69.62)
77.32
(70.12 to 83.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Surgery, Talimogene Laherparepvec Plus Surgery
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.050
Comments Unstratified log-rank test
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.54
Confidence Interval (2-Sided) 80%
0.36 to 0.81
Estimation Comments Unstratified Hazard Ratio (T-VEC + Surgery / Surgery)
11.Secondary Outcome
Title Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)
Hide Description Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.
Time Frame 18 months after last participant randomized (data cutoff date of 30 April 2019).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
13.2
(8.3 to 19.5)
12.Secondary Outcome
Title Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)
Hide Description The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
Time Frame 18 months after last participant randomized (data cutoff date of 30 April 2019).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of lesions
26.3
(19.7 to 33.9)
13.Secondary Outcome
Title Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)
Hide Description The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
Time Frame 18 months after last participant randomized (data cutoff date of 30 April 2019).
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat Analysis Set: all participants who were randomized to either treatment group.
Arm/Group Title Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 76
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of lesions
3.9
(1.5 to 8.6)
14.Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions
Hide Description Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
Time Frame Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks).
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Safety Analysis Set: all participants who received talimogene laherparepvec (TL) or surgical resection of melanoma tumor lesion(s).
Arm/Group Title Surgery Talimogene Laherparepvec: Pre-Surgery Talimogene Laherparepvec: Post-Surgery Talimogene Laherparepvec Plus Surgery
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Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.

Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 69 57 57 73
Measure Type: Count of Participants
Unit of Measure: Participants
All TEAEs
32
  46.4%
53
  93.0%
19
  33.3%
70
  95.9%
Grade ≥2
19
  27.5%
20
  35.1%
12
  21.1%
38
  52.1%
Grade ≥3
4
   5.8%
1
   1.8%
7
  12.3%
11
  15.1%
Grade ≥4
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.4%
Serious TEAEs
2
   2.9%
1
   1.8%
8
  14.0%
13
  17.8%
Leading to DC of TL NA [1] 
1
   1.8%
0
   0.0%
3
   4.1%
Leading to Interruption of TL NA [1] 
0
   0.0%
0
   0.0%
0
   0.0%
Leading to <4 ml TL Administered NA [1] 
1
   1.8%
1
   1.8%
3
   4.1%
Leading to <4 ml TL Administered: Serious NA [1] 
1
   1.8%
0
   0.0%
2
   2.7%
Leading to <4 ml TL Administered: Nonserious NA [1] 
0
   0.0%
1
   1.8%
1
   1.4%
Fatal Adverse Events
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
no TL administered
15.Secondary Outcome
Title Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions
Hide Description Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
Time Frame Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
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Hide Analysis Population Description
Safety Analysis Set: all participants who received talimogene laherparepvec (TL).
Arm/Group Title Talimogene Laherparepvec: Pre-Surgery Talimogene Laherparepvec: Post-Surgery Talimogene Laherparepvec Plus Surgery
Hide Arm/Group Description:

Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.

Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Limited to participants who received at least 1 dose of talimogene laherparepvec and protocol-specified surgery.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
Overall Number of Participants Analyzed 57 57 73
Measure Type: Count of Participants
Unit of Measure: Participants
All TEAEs
51
  89.5%
0
   0.0%
64
  87.7%
Grade ≥2
13
  22.8%
0
   0.0%
20
  27.4%
Grade ≥3
1
   1.8%
0
   0.0%
3
   4.1%
Grade ≥4
0
   0.0%
0
   0.0%
0
   0.0%
Serious TEAEs
1
   1.8%
0
   0.0%
2
   2.7%
Leading to DC of TL
1
   1.8%
0
   0.0%
1
   1.4%
Leading to Interruption of TL
0
   0.0%
0
   0.0%
0
   0.0%
Leading to <4 ml TL Administered
1
   1.8%
0
   0.0%
1
   1.4%
Leading to <4 ml TL Administered: Serious
1
   1.8%
0
   0.0%
1
   1.4%
Leading to <4 ml TL Administered: Nonserious
0
   0.0%
0
   0.0%
0
   0.0%
Fatal Adverse Events
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks). All-cause mortality was reported from enrollment through end of follow-up (up to 5 years after randomization).
Adverse Event Reporting Description All-cause mortality is reported for all participants enrolled in the study. Serious adverse events and other adverse events are reported for all randomized subjects who received talimogene laherparepvec or surgical resection of melanoma tumor lesion(s).
 
Arm/Group Title Surgery TALIMOGENE LAHERPAREPVEC PLUS SURGERY
Hide Arm/Group Description Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6.

Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first.

Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18.
All-Cause Mortality
Surgery TALIMOGENE LAHERPAREPVEC PLUS SURGERY
Affected / at Risk (%) Affected / at Risk (%)
Total   26/74 (35.14%)   16/76 (21.05%) 
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Surgery TALIMOGENE LAHERPAREPVEC PLUS SURGERY
Affected / at Risk (%) Affected / at Risk (%)
Total   2/69 (2.90%)   13/73 (17.81%) 
Gastrointestinal disorders     
Nausea † 1  0/69 (0.00%)  1/73 (1.37%) 
Small intestinal obstruction † 1  0/69 (0.00%)  1/73 (1.37%) 
General disorders     
Asthenia † 1  0/69 (0.00%)  1/73 (1.37%) 
Pain † 1  0/69 (0.00%)  1/73 (1.37%) 
Pyrexia † 1  0/69 (0.00%)  1/73 (1.37%) 
Hepatobiliary disorders     
Cholecystitis † 1  0/69 (0.00%)  1/73 (1.37%) 
Infections and infestations     
Cellulitis † 1  0/69 (0.00%)  2/73 (2.74%) 
Influenza † 1  0/69 (0.00%)  1/73 (1.37%) 
Postoperative wound infection † 1  0/69 (0.00%)  1/73 (1.37%) 
Urinary tract infection † 1  0/69 (0.00%)  1/73 (1.37%) 
Wound abscess † 1  1/69 (1.45%)  0/73 (0.00%) 
Musculoskeletal and connective tissue disorders     
Neck pain † 1  0/69 (0.00%)  1/73 (1.37%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Glioblastoma † 1  0/69 (0.00%)  1/73 (1.37%) 
Nervous system disorders     
Cerebral ischaemia † 1  0/69 (0.00%)  1/73 (1.37%) 
Pregnancy, puerperium and perinatal conditions     
Anembryonic gestation † 1  0/69 (0.00%)  1/73 (1.37%) 
Product Issues     
Device occlusion † 1  0/69 (0.00%)  1/73 (1.37%) 
Skin and subcutaneous tissue disorders     
Skin ulcer † 1  0/69 (0.00%)  1/73 (1.37%) 
Surgical and medical procedures     
Neck dissection † 1  0/69 (0.00%)  1/73 (1.37%) 
Vascular disorders     
Peripheral embolism † 1  1/69 (1.45%)  0/73 (0.00%) 
1
Term from vocabulary, MedDRA 24.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Surgery TALIMOGENE LAHERPAREPVEC PLUS SURGERY
Affected / at Risk (%) Affected / at Risk (%)
Total   14/69 (20.29%)   62/73 (84.93%) 
Gastrointestinal disorders     
Diarrhoea † 1  0/69 (0.00%)  8/73 (10.96%) 
Nausea † 1  1/69 (1.45%)  7/73 (9.59%) 
Vomiting † 1  0/69 (0.00%)  7/73 (9.59%) 
General disorders     
Chills † 1  0/69 (0.00%)  18/73 (24.66%) 
Fatigue † 1  1/69 (1.45%)  20/73 (27.40%) 
Influenza like illness † 1  0/69 (0.00%)  26/73 (35.62%) 
Injection site erythema † 1  0/69 (0.00%)  4/73 (5.48%) 
Injection site pain † 1  0/69 (0.00%)  6/73 (8.22%) 
Injection site reaction † 1  0/69 (0.00%)  4/73 (5.48%) 
Pain † 1  6/69 (8.70%)  5/73 (6.85%) 
Pyrexia † 1  2/69 (2.90%)  24/73 (32.88%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  0/69 (0.00%)  10/73 (13.70%) 
Myalgia † 1  0/69 (0.00%)  8/73 (10.96%) 
Pain in extremity † 1  4/69 (5.80%)  1/73 (1.37%) 
Nervous system disorders     
Dizziness † 1  0/69 (0.00%)  7/73 (9.59%) 
Headache † 1  0/69 (0.00%)  17/73 (23.29%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  0/69 (0.00%)  4/73 (5.48%) 
Skin and subcutaneous tissue disorders     
Pruritus † 1  1/69 (1.45%)  4/73 (5.48%) 
1
Term from vocabulary, MedDRA 24.1
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
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Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
EMail: medinfo@amgen.com
Publications:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02211131    
Other Study ID Numbers: 20110266
2014-001146-13 ( EudraCT Number )
First Submitted: August 5, 2014
First Posted: August 7, 2014
Results First Submitted: April 21, 2020
Results First Posted: May 28, 2020
Last Update Posted: June 5, 2023