Melanoma
Conditions
Keywords
Melanoma, Talimogene Laherparepvec, Pembrolizumab, Oncolytic immunotherapy, Anti-PD-1, Checkpoint inhibitor, MASTERKEY-115
Brief summary
This is a phase 2, open-label, single-arm, multicenter clinical trial designed to evaluate the efficacy and safety of talimogene laherparepvec in combination with pembrolizumab following disease progression on prior anti-programmed cell death protein (anti-PD-1) therapy in unresectable/metastatic melanoma (stage IIIB-IVM1d) or prior anti-PD-1 therapy in the adjuvant setting. Subjects will be treated with talimogene laherparepvec and pembrolizumab until confirmed complete response, disappearance of all injectable lesions, documented confirmed disease progression per modified immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST), intolerance of study treatment, or 102 weeks from the first dose of talimogene laherparepvec and/or pembrolizumab, whichever occurs first.
Interventions
DRUGTalimogene laherparepvec
Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.
DRUGPembrolizumab
Intravenous (IV) infusion.
Sponsors
Merck Sharp & Dohme LLC
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age ≥ 18 years with histologically confirmed diagnosis of stage IIIB to IVM1d melanoma and for whom surgery is not recommended. Subjects with stage IVM1d disease may be enrolled with up to 3 cerebral metastases, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment. * Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions. * Subjects must have had prior treatment (for at least 2 to 3 consecutive cycles within an 8 week period) with a PD-1 inhibitor and have confirmed disease progression (as defined by RECIST v1.1 criteria). The anti-PD-1 therapy must be the immediate prior line of therapy before enrollment and subjects with disease progression on more than 1 line of anti-PD-1 therapy are not eligible. * ECOG performance status of 0 or 1. * Adequate hematologic, renal, hepatic, and coagulation function. Key
Exclusion criteria
* Subjects considered by the investigator to have rapid clinical progression due to melanoma * Subjects with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy * Stage IVM1d subjects must not have greater than 3 cerebral melanoma metastases, or clinically active cerebral melanoma metastases requiring therapy, and/or carcinomatous meningitis regardless of clinical stability. * Primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years. * Subjects must not have history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression. * Subjects may not have been previously treated with talimogene laherparepvec or any other oncolytic virus. * Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1: * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iCRR was defined as the incidence of a best overall response (iBOR) of a complete response (iCR) per modified irRC-RECIST: * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have had a reduction in short axis to \< 10 mm. Confirmation of iCR was required per modified irRC-RECIST. |
| BOR Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | BOR was the best overall visit response up to & including the first overall visit response of PD: * CR: Disappearance of all target & non-target lesions. Any pathological lymph nodes must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size. * PR: ≥30% decrease in the sum of diameters of target lesions. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR/CR nor sufficient increase to qualify for PD. * PD: ≥20% increase in the sum of diameters of target lesions and an increase of ≥5mm. Progression of existing non-target lesions. * Unable to evaluate (UE): Any lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to determine the status of that particular tumor. * Non-CR/Non-PD: Persistence of 1+ non-target lesion(s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline. Confirmation of CR, PR & PD were not required per modified RECIST 1.1. |
| Best Overall Response (iBOR) Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iBOR was defined as the best overall visit response up to and including the first overall visit response of progressive disease (iPD) per modified irRC-RECIST: * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. * Stable disease (iSD): Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. * iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. * Unable to evaluate (iUE): Any lesion present at baseline or a new measurable lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor for that time point. Confirmation of iCR, iPR and iPD was required per modified irRC-RECIST. |
| Durable Response Rate (DRR) Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | DRR was defined as the percentage of participants with a CR or PR per modified RECIST v1.1 with a duration of response (DOR) ≥ 6 months. One month was calculated based on 365.25 days per year. * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmation of CR and PR were not required per modified RECIST v1.1. |
| Durable Response Rate (iDRR) Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iDRR was defined as the percentage of participants with an iCR or iPR per modified irRC-RECIST with a duration of response (iDOR) ≥ 6 months. One month was calculated based on 365.25 days per year. * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. |
| DOR Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/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 first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. * CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to \<10 mm. Any pathological lymph nodes must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size (\<10mm short axis). * PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Confirmation of CR, PR and PD were not required per modified RECIST v1.1. |
| iDOR Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. * iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to \< 10 mm. * iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. |
| Complete Response Rate (CRR) Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | CRR was defined as the incidence of a BOR of CR per modified RECIST v1.1: * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). Confirmation of CR was not required per modified RECIST v1.1. |
| Disease Control Rate (iDCR) Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iDCR per modified irRC-RECIST was defined as the incidence of an iBOR of iCR, iPR or iSD. * iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to \< 10 mm. * iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * iSD: Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. Confirmation of iCR and iPR were required per modified irRC-RECIST. |
| Objective Response Rate (iORR) Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iORR was defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. |
| Progression Free Survival (PFS) Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. \- PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. |
| Progression Free Survival (iPFS) Per Modified irRC-RECIST | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. \- iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. |
| Overall Survival (OS) | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year. |
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks. | Evaluation of TEAEs included the number of participants with at least 1: * TEAE * Treatment-related TEAE * Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 TEAE * Treatment-related CTCAE grade ≥ 3 TEAE * Serious TEAE * Serious treatment-related TEAE * Fatal TEAE * Fatal treatment-related TEAE * TEAE of interest Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. A CTCAE grade ≥ 3 was determined using the CTCAE grading systems based on CTCAE version 5.0 per the below definitions: * Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. * Grade 4: Life-threatening consequences; urgent intervention indicated. * Grade 5: Death related to TEAE. Abnormal laboratory tests were also recorded as TEAEs. |
| Time to First Subsequent Anti-cancer Therapy | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year. |
| Disease Control Rate (DCR) Per Modified RECIST v1.1 | Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months | DCR per modified RECIST v1.1 was defined as the incidence of a BOR of CR, PR or SD. * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * SD: Neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD. Confirmation of CR and PR were not required per modified RECIST v1.1. |
Countries
Australia, Canada, France, Germany, Greece, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
72 participants were enrolled at 28 centers in Australia, Canada, France, Germany, Greece, Italy, the Netherlands, Poland, Spain and the United States from 22 January 2020 to 26 February 2024.
Pre-assignment details
Participants must have received prior anti-programmed cell death protein (anti-PD-1) therapy for at least 2 to 3 consecutive cycles within an 8-week period and have disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The anti-PD-1 therapy must have been the immediate prior line of therapy before enrollment, and participants with disease progression on more than 1 line of anti-PD-1 therapy were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression.
Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10\^6 plaque-forming units (PFU)/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10\^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an intravenous (IV) infusion every 3 weeks for up to 35 cycles. | 26 |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy.
Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10\^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10\^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles. | 15 |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months Included participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of \< 6 months after starting the adjuvant anti-PD-1 therapy.
Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10\^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10\^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles. | 15 |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months Included participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor.
Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10\^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10\^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles. | 15 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 17 | 12 | 4 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal of consent from study | 3 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Total | Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance |
|---|---|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 14.6 | 62.9 Years STANDARD_DEVIATION 13.1 | 63.5 Years STANDARD_DEVIATION 10.3 | 59.4 Years STANDARD_DEVIATION 13 | 65.5 Years STANDARD_DEVIATION 13.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 68 Participants | 15 Participants | 14 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Black (or African American) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Other | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race White | 25 Participants | 68 Participants | 15 Participants | 14 Participants | 14 Participants |
| Sex: Female, Male Female | 8 Participants | 23 Participants | 2 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 18 Participants | 48 Participants | 13 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 27 | 12 / 15 | 4 / 15 | 7 / 15 |
| other Total, other adverse events | 20 / 26 | 15 / 15 | 15 / 15 | 14 / 15 |
| serious Total, serious adverse events | 12 / 26 | 7 / 15 | 4 / 15 | 7 / 15 |
Outcome results
Primary
Objective Response Rate (ORR) Per Modified RECIST v1.1
ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1: * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s).
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Objective Response Rate (ORR) Per Modified RECIST v1.1 | 3.8 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Objective Response Rate (ORR) Per Modified RECIST v1.1 | 6.7 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Objective Response Rate (ORR) Per Modified RECIST v1.1 | 40.0 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Objective Response Rate (ORR) Per Modified RECIST v1.1 | 46.7 Percentage of Participants |
Secondary
Best Overall Response (iBOR) Per Modified irRC-RECIST
iBOR was defined as the best overall visit response up to and including the first overall visit response of progressive disease (iPD) per modified irRC-RECIST: * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. * Stable disease (iSD): Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. * iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. * Unable to evaluate (iUE): Any lesion present at baseline or a new measurable lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor for that time point. Confirmation of iCR, iPR and iPD was required per modified irRC-RECIST.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPR | 3 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iUE | 2 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPD | 5 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | Not Done | 6 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iCR | 0 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iSD | 10 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iCR | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPR | 1 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iSD | 5 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPD | 4 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | iUE | 1 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Best Overall Response (iBOR) Per Modified irRC-RECIST | Not Done | 4 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iCR | 4 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | Not Done | 1 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPR | 7 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iUE | 2 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPD | 1 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iSD | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPD | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iUE | 1 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | Not Done | 1 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iPR | 4 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iCR | 3 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Best Overall Response (iBOR) Per Modified irRC-RECIST | iSD | 6 Participants |
Secondary
BOR Per Modified RECIST v1.1
BOR was the best overall visit response up to & including the first overall visit response of PD: * CR: Disappearance of all target & non-target lesions. Any pathological lymph nodes must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size. * PR: ≥30% decrease in the sum of diameters of target lesions. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR/CR nor sufficient increase to qualify for PD. * PD: ≥20% increase in the sum of diameters of target lesions and an increase of ≥5mm. Progression of existing non-target lesions. * Unable to evaluate (UE): Any lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to determine the status of that particular tumor. * Non-CR/Non-PD: Persistence of 1+ non-target lesion(s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline. Confirmation of CR, PR & PD were not required per modified RECIST 1.1.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | SD | 7 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | PR | 1 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | UE | 0 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | PD | 11 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | Non-CR/Non-PD | 1 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | Not Done | 6 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | BOR Per Modified RECIST v1.1 | CR | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | UE | 1 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | PD | 5 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | Non-CR/Non-PD | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | CR | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | Not Done | 4 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | PR | 1 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | BOR Per Modified RECIST v1.1 | SD | 4 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | PR | 3 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | PD | 9 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | SD | 0 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | Not Done | 0 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | UE | 0 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | CR | 3 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | BOR Per Modified RECIST v1.1 | Non-CR/Non-PD | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | Not Done | 1 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | CR | 3 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | PR | 4 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | SD | 6 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | UE | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | Non-CR/Non-PD | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | BOR Per Modified RECIST v1.1 | PD | 1 Participants |
Secondary
Complete Response Rate (CRR) Per Modified RECIST v1.1
CRR was defined as the incidence of a BOR of CR per modified RECIST v1.1: * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). Confirmation of CR was not required per modified RECIST v1.1.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Complete Response Rate (CRR) Per Modified RECIST v1.1 | 0 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Complete Response Rate (CRR) Per Modified RECIST v1.1 | 0 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Complete Response Rate (CRR) Per Modified RECIST v1.1 | 20.0 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Complete Response Rate (CRR) Per Modified RECIST v1.1 | 20.0 Percentage of Participants |
Secondary
Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1
iCRR was defined as the incidence of a best overall response (iBOR) of a complete response (iCR) per modified irRC-RECIST: * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have had a reduction in short axis to \< 10 mm. Confirmation of iCR was required per modified irRC-RECIST.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | 0 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | 0 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | 26.7 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | 20.0 Percentage of Participants |
Secondary
Disease Control Rate (DCR) Per Modified RECIST v1.1
DCR per modified RECIST v1.1 was defined as the incidence of a BOR of CR, PR or SD. * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * SD: Neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD. Confirmation of CR and PR were not required per modified RECIST v1.1.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Disease Control Rate (DCR) Per Modified RECIST v1.1 | 30.8 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Disease Control Rate (DCR) Per Modified RECIST v1.1 | 33.3 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Disease Control Rate (DCR) Per Modified RECIST v1.1 | 40.0 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Disease Control Rate (DCR) Per Modified RECIST v1.1 | 86.7 Percentage of Participants |
Secondary
Disease Control Rate (iDCR) Per Modified irRC-RECIST
iDCR per modified irRC-RECIST was defined as the incidence of an iBOR of iCR, iPR or iSD. * iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to \< 10 mm. * iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * iSD: Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. Confirmation of iCR and iPR were required per modified irRC-RECIST.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Disease Control Rate (iDCR) Per Modified irRC-RECIST | 50.0 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Disease Control Rate (iDCR) Per Modified irRC-RECIST | 40.0 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Disease Control Rate (iDCR) Per Modified irRC-RECIST | 73.3 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Disease Control Rate (iDCR) Per Modified irRC-RECIST | 86.7 Percentage of Participants |
Secondary
DOR Per Modified RECIST v1.1
DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/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 first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. * CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to \<10 mm. Any pathological lymph nodes must have had a reduction in short axis to \<10 mm. All lymph nodes must have been non-pathological in size (\<10mm short axis). * PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Confirmation of CR, PR and PD were not required per modified RECIST v1.1.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination. Only participants who had an initial response of CR or PR were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | DOR Per Modified RECIST v1.1 | 22.768 Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | DOR Per Modified RECIST v1.1 | 7.655 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | DOR Per Modified RECIST v1.1 | NA Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | DOR Per Modified RECIST v1.1 | 13.700 Months |
Secondary
Durable Response Rate (DRR) Per Modified RECIST v1.1
DRR was defined as the percentage of participants with a CR or PR per modified RECIST v1.1 with a duration of response (DOR) ≥ 6 months. One month was calculated based on 365.25 days per year. * CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmation of CR and PR were not required per modified RECIST v1.1.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Durable Response Rate (DRR) Per Modified RECIST v1.1 | 3.8 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Durable Response Rate (DRR) Per Modified RECIST v1.1 | 6.7 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Durable Response Rate (DRR) Per Modified RECIST v1.1 | 40.0 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Durable Response Rate (DRR) Per Modified RECIST v1.1 | 26.7 Percentage of Participants |
Secondary
Durable Response Rate (iDRR) Per Modified irRC-RECIST
iDRR was defined as the percentage of participants with an iCR or iPR per modified irRC-RECIST with a duration of response (iDOR) ≥ 6 months. One month was calculated based on 365.25 days per year. * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Durable Response Rate (iDRR) Per Modified irRC-RECIST | 11.5 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Durable Response Rate (iDRR) Per Modified irRC-RECIST | 6.7 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Durable Response Rate (iDRR) Per Modified irRC-RECIST | 73.3 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Durable Response Rate (iDRR) Per Modified irRC-RECIST | 40.0 Percentage of Participants |
Secondary
iDOR Per Modified irRC-RECIST
iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. * iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to \< 10 mm. * iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination. Only participants who had an initial response of iCR or iPR were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | iDOR Per Modified irRC-RECIST | NA Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | iDOR Per Modified irRC-RECIST | 7.655 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | iDOR Per Modified irRC-RECIST | NA Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | iDOR Per Modified irRC-RECIST | NA Months |
Secondary
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
Evaluation of TEAEs included the number of participants with at least 1: * TEAE * Treatment-related TEAE * Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 TEAE * Treatment-related CTCAE grade ≥ 3 TEAE * Serious TEAE * Serious treatment-related TEAE * Fatal TEAE * Fatal treatment-related TEAE * TEAE of interest Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. A CTCAE grade ≥ 3 was determined using the CTCAE grading systems based on CTCAE version 5.0 per the below definitions: * Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. * Grade 4: Life-threatening consequences; urgent intervention indicated. * Grade 5: Death related to TEAE. Abnormal laboratory tests were also recorded as TEAEs.
Time frame: Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks.
Population: Safety Analysis Set: All enrolled participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious Treatment-related TEAEs | 1 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious TEAEs | 12 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 Treatment-related TEAEs | 2 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 17 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs of Interest | 21 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 24 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal TEAEs | 5 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 TEAEs | 11 Participants |
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal Treatment-related TEAEs | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 15 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 10 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 TEAEs | 8 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 Treatment-related TEAEs | 3 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious TEAEs | 7 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious Treatment-related TEAEs | 2 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal TEAEs | 3 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal Treatment-related TEAEs | 0 Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs of Interest | 14 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious TEAEs | 4 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 TEAEs | 4 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 14 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious Treatment-related TEAEs | 0 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal TEAEs | 1 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal Treatment-related TEAEs | 0 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 15 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs of Interest | 15 Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 Treatment-related TEAEs | 0 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 Treatment-related TEAEs | 6 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal Treatment-related TEAEs | 1 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | CTCAE Grade ≥ 3 TEAEs | 8 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs of Interest | 14 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious Treatment-related TEAEs | 3 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 13 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Fatal TEAEs | 3 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Serious TEAEs | 7 Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 14 Participants |
Secondary
Objective Response Rate (iORR) Per Modified irRC-RECIST
iORR was defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST * iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to \< 10 mm. * iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Objective Response Rate (iORR) Per Modified irRC-RECIST | 11.5 Percentage of Participants |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Objective Response Rate (iORR) Per Modified irRC-RECIST | 6.7 Percentage of Participants |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Objective Response Rate (iORR) Per Modified irRC-RECIST | 73.3 Percentage of Participants |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Objective Response Rate (iORR) Per Modified irRC-RECIST | 46.7 Percentage of Participants |
Secondary
Overall Survival (OS)
OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Overall Survival (OS) | 24.608 Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Overall Survival (OS) | 15.014 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Overall Survival (OS) | NA Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Overall Survival (OS) | NA Months |
Secondary
Progression Free Survival (iPFS) Per Modified irRC-RECIST
iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. \- iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Progression Free Survival (iPFS) Per Modified irRC-RECIST | 6.899 Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Progression Free Survival (iPFS) Per Modified irRC-RECIST | 8.214 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Progression Free Survival (iPFS) Per Modified irRC-RECIST | NA Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Progression Free Survival (iPFS) Per Modified irRC-RECIST | 25.955 Months |
Secondary
Progression Free Survival (PFS) Per Modified RECIST v1.1
PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. \- PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Progression Free Survival (PFS) Per Modified RECIST v1.1 | 3.614 Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Progression Free Survival (PFS) Per Modified RECIST v1.1 | 4.830 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Progression Free Survival (PFS) Per Modified RECIST v1.1 | 2.793 Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Progression Free Survival (PFS) Per Modified RECIST v1.1 | 13.897 Months |
Secondary
Time to First Subsequent Anti-cancer Therapy
Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year.
Time frame: Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
Population: Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance | Time to First Subsequent Anti-cancer Therapy | 11.466 Months |
| Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance | Time to First Subsequent Anti-cancer Therapy | 7.852 Months |
| Cohort 3 - Adjuvant Setting - Disease Free Interval < 6 Months | Time to First Subsequent Anti-cancer Therapy | NA Months |
| Cohort 4 - Adjuvant Setting - Disease Free Interval ≥ 6 Months | Time to First Subsequent Anti-cancer Therapy | 23.097 Months |