Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma (MASTERKEY-265)

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.