A Phase 3 interventional study of Talimogene Laherparepvec and Pembrolizumab in Melanoma, sponsored by Amgen. Terminated at 161 sites in 21 countries. Open to participants aged 18 Years to 95 Years. Per ClinicalTrials.gov, last updated 2022-11-14.
Sponsored by Amgen · Phase 3, Interventional, and Treatment
The primary objectives of the Phase 1b part of the study are to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB to IVM1c melanoma.
The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).
3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.
This study's enrollment of 713 is above the median of 38 across 2,351 interventional studies indexed under Melanoma.
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Key Inclusion Criteria:
Key Exclusion Criteria:
Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Drug: Talimogene Laherparepvec · Drug: Pembrolizumab
Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Drug: Pembrolizumab · Drug: Placebo
Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Drug: Talimogene Laherparepvec · Drug: Pembrolizumab
Talimogene laherparepvec administered by intratumoral injection
Also known as: IMLYGIC®, OncoVEX^GM-CSF, T-VEC
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Also known as: MK-3475, Keytruda®
Administered by intratumoral injection
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: * Grade 4 non-hematologic toxicity. * Grade 3 or higher pneumonitis. * Grade 3 non-hematologic toxicity lasting \> 3 days despite optimal supportive care, excluding grade 3 fatigue. * Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for \> 1 week. * Febrile neutropenia grade 3 or grade 4. * Thrombocytopenia \< 25 x 10\^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit. * Grade 5 toxicity (ie, death). * Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
Time frame: The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1
PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
Time frame: From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Overall Survival
Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
Time frame: From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 1b: Objective Response Rate (ORR)
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
Time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Best Overall Response (BOR)
Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
Time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Durable Response Rate (DRR)
DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
Time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Duration of Response (DOR)
Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
Time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Disease Control Rate (DCR)
DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.
Time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
Phase 1b: Progression-free Survival (PFS)
Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.
Time frame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
Phase 1b: Overall Survival (OS)
Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
Time frame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)
Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)
PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
Time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Overall Survival Excluding Stage IVM1c Participants
Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.
Time frame: From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1
BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR. CR: Disappearance of all lesions except lymph node short axis \< 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1
DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1
Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
Time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1
Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)
Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST
BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR. iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization. Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)
Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)
Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
Time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)
Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
Time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
Time frame: Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.
Time frame: From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.
This study was conducted at 134 centers in Australia, Canada, Europe, South Africa, South Korea, and the United States. Phase 1b was an open-label, single-arm study and Phase 3 was a randomized, double-blind, placebo-controlled study.
| Milestone | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| Started | 21 | 346 | 346 |
| Received talimogene laherparepvec/placebo | 21 | 345 | 343 |
| Received pembrolizumab | 21 | 345 | 343 |
| Completed | 0 | 0 | 0 |
| Not completed | 21 | 346 | 346 |
| Withdrew: Withdrawal by subject | 1 | 23 | 17 |
| Withdrew: Sponsor decision | 12 | 165 | 182 |
| Withdrew: Lost to follow-up | 2 | 7 | 7 |
| Withdrew: Death | 6 | 151 | 140 |
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: * Grade 4 non-hematologic toxicity. * Grade 3 or higher pneumonitis. * Grade 3 non-hematologic toxicity lasting \> 3 days despite optimal supportive care, excluding grade 3 fatigue. * Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for \> 1 week. * Febrile neutropenia grade 3 or grade 4. * Thrombocytopenia \< 25 x 10\^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit. * Grade 5 toxicity (ie, death). * Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
| Participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 |
PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
| months | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1 | 8.5 (5.72 to 13.54) | 14.3 (10.25 to 22.11) |
Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
| months | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Overall Survival | NA (NA to NA) | NA (NA to NA) |
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
| percentage of participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Objective Response Rate (ORR) | 61.9 (38.4 to 81.9) |
Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
| Participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Complete Response (CR) | 9 |
| Partial Response (PR) | 4 |
| Stable Disease (SD) | 1 |
| Progressive Disease (PD) | 6 |
| Unable to Evaluate (UE) | 1 |
DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
| percentage of participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Durable Response Rate (DRR) | 57.1 (34.0 to 78.2) |
Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
| months | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Duration of Response (DOR) | NA (NA to NA) |
DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.
| percentage of participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Disease Control Rate (DCR) | 66.7 (43.0 to 85.4) |
Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.
| months | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Progression-free Survival (PFS) | NA (NA to NA) |
Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
| months | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Phase 1b: Overall Survival (OS) | NA (NA to NA) |
Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR) | 8.1 (5.22 to 10.97) | 14.5 (10.75 to 18.16) |
PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
| months | Phase 3 : Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS) | 25.3 (17.68 to NA) | NA (NA to NA) |
Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.
| months | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Overall Survival Excluding Stage IVM1c Participants | NA (NA to NA) | NA (NA to NA) |
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1 | 41.3 (36.14 to 46.52) | 48.6 (43.29 to 53.82) |
BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR. CR: Disappearance of all lesions except lymph node short axis \< 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
| Participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Complete response (CR) | 40 | 62 |
| Partial response (PR) | 103 | 106 |
| Stable disease (SD) | 30 | 28 |
| Non-CR/Non-PD (NN) | 16 | 11 |
| Progressive disease (PD) | 120 | 106 |
| Unevaluable (UE) | 11 | 3 |
| Missing | 26 | 30 |
DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1 | 34.1 (29.11 to 39.10) | 42.2 (36.99 to 47.40) |
Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
| months | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1 | NA (NA to NA) | 43.7 (NA to NA) |
Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis \< 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1 | 50.0 (44.73 to 55.27) | 56.6 (51.43 to 61.87) |
Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR) | 39.9 (34.72 to 45.04) | 49.1 (43.87 to 54.40) |
BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR. iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization. Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
| Participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Complete response (iCR) | 28 | 50 |
| Partial response (iPR) | 110 | 120 |
| Stable disease (iSD) | 57 | 51 |
| Progressive disease (iPD) | 56 | 65 |
| Unevaluable (iUE) | 69 | 30 |
| Missing | 26 | 30 |
Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR) | 34.4 (29.39 to 39.40) | 45.7 (40.42 to 50.91) |
Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
| months | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR) | NA (NA to NA) | 43.7 (34.53 to 43.73) |
Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
| percentage of participants | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR) | 56.4 (51.13 to 61.58) | 63.9 (58.81 to 68.93) |
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
| score on a scale | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score | -0.20 ± 1.02 | -0.02 ± 1.02 |
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.
| Participants | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| Any treatment-emergent adverse events | 21 | 331 | 338 |
| Grade ≥ 2 | 20 | 279 | 306 |
| Grade ≥ 3 | 13 | 151 | 161 |
| Grade ≥ 4 | 2 | 29 | 33 |
| Serious adverse events | 8 | 141 | 154 |
| Leading to discontinuation of talimogene laherparepvec/Placebo | 0 | 24 | 26 |
| Leading to discontinuation of pembrolizumab | 2 | 41 | 43 |
| Fatal adverse events | 1 | 42 | 45 |
Collected over All-cause mortality: From enrollment (Phase 1b) or randomization (Phase 3) to end of study, up to 75 months in Phase 1b and 58 months in Phase 3. SAEs: From first dose of study drug to 90 days after last dose or 30 days after last dose if new anticancer therapy was started. AEs: From first dose to 30 days after last dose; median (range) duration of exposure was 48 (5.1, 110) weeks in Phase 1b, 39 (0.1, 107) weeks in Placebo + Pembrolizumab and 56 (0.1, 110) weeks in T-VEC + Pembrolizumab arm.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Pembrolizumab | 6/21 (28.6%) | 8/21 (38.1%) | 21/21 (100%) |
| Phase 3: Placebo + Pembrolizumab | 156/346 (45.1%) | 141/344 (41%) | 305/344 (88.7%) |
| Phase 3: Talimogene Laherparepvec + Pembrolizumab | 146/346 (42.2%) | 154/344 (44.8%) | 317/344 (92.2%) |
| Event | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| PyrexiaGeneral disorders | 2/21 | 4/344 | 7/344 |
| Malignant melanomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/21 | 26/344 | 27/344 |
| General physical health deteriorationGeneral disorders | 1/21 | 2/344 | 1/344 |
| Autoimmune hepatitisHepatobiliary disorders | 1/21 | 1/344 | 1/344 |
| CholecystitisHepatobiliary disorders | 1/21 | 1/344 | 1/344 |
| Cytokine release syndromeImmune system disorders | 1/21 | 0/344 | 0/344 |
| Bronchopulmonary aspergillosisInfections and infestations | 1/21 | 0/344 | 0/344 |
| CellulitisInfections and infestations | 1/21 | 4/344 | 4/344 |
| Meningitis asepticInfections and infestations | 1/21 | 0/344 | 0/344 |
| Lumbar spinal stenosisMusculoskeletal and connective tissue disorders | 1/21 | 0/344 | 0/344 |
| Event | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| FatigueGeneral disorders | 15/21 | 94/344 | 137/344 |
| DiarrhoeaGastrointestinal disorders | 13/21 | 73/344 | 70/344 |
| PyrexiaGeneral disorders | 10/21 | 33/344 | 128/344 |
| HeadacheNervous system disorders | 9/21 | 44/344 | 62/344 |
| RashSkin and subcutaneous tissue disorders | 9/21 | 42/344 | 61/344 |
| ChillsGeneral disorders | 8/21 | 17/344 | 73/344 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 8/21 | 66/344 | 82/344 |
| CoughRespiratory, thoracic and mediastinal disorders | 8/21 | 44/344 | 58/344 |
| NauseaGastrointestinal disorders | 7/21 | 61/344 | 92/344 |
| VomitingGastrointestinal disorders | 7/21 | 29/344 | 56/344 |
All enrolled participants
| Age, Continuous(years) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Mean | 60.2 ± 13.4 | 62.3 ± 14.5 | 63.1 ± 13.7 | 62.6 ± 14.1 |
| Sex: Female, Male(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Female | 13 | 127 | 147 | 287 |
| Male | 8 | 219 | 199 | 426 |
| Ethnicity (NIH/OMB)(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 9 | 13 | 22 |
| Not Hispanic or Latino | 21 | 337 | 331 | 689 |
| Unknown or Not Reported | 0 | 0 | 2 | 2 |
| Race/Ethnicity, Customized(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 4 | 7 | 11 |
| Black (or African American) | 0 | 1 | 2 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| White | 21 | 335 | 327 | 683 |
| Other | 0 | 6 | 10 | 16 |
| Disease Stage per the American Joint Committee on Cancer (AJCC) 7th Edition(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Stage IIIB - IVM1a | 9 | 169 | 169 | 347 |
| Stage IVM1b/c | 12 | 177 | 177 | 366 |
| Prior Serine/Threonine Protein Kinase B-Raf (BRAF) Inhibitor Therapy(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Yes | — | 29 | 29 | 58 |
| No | — | 317 | 317 | 634 |
| Programmed Cell Death-1 Ligand 1 (PD-L1) Status(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Positive | 17 | 218 | 231 | 466 |
| Not Positive | 4 | 128 | 115 | 247 |
| BRAF V600 Mutation Status(Participants) | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Mutation | 4 | 116 | 124 | 244 |
| Mutation not present | 17 | 215 | 211 | 443 |
| Missing/unknown | 0 | 15 | 11 | 26 |
Showing the first 100 of 161 sites across 21 countries.
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Plan to share: Yes — De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting information: Study protocol, Sap, Icf, Csr
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