A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

pRR was defined as the percentage of participants with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) as determined by an independent pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as > 0 to ≤ 10% of viable tumor cells, and pPR was defined as > 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to complete lymph node dissection (CLND), were classified as non-responders. pRR was calculated for each arm along with 95% confidence intervals (CIs) using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using Clopper-Pearson method.

pRR was defined as the percentage of participants with pCR, pnCR, and pPR as determined by a local pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as > 0 to ≤ 10% of viable tumor cells, and pPR was defined as > 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to CLND, were classified as non-responders. pRR was calculated for each arm along with 95% CIs using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

EFS was defined as the time from randomization to any of the following events (whichever occurs first): documented disease progression (PD) that precludes surgery, as assessed by investigator per RECIST v1.1, local, regional, or distant disease recurrence, or death from any cause. PD = as at least a 20% increase in smallest sum of diameter (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). Local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are > 2 cm from the primary lesion but not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence, progression, or death at the time of analysis were censored at the time of the last tumor assessment. Kaplan-Meier method was used to estimate the median for EFS, and 95% CIs was constructed using Brookmeyer and Crowley method.

RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. Recurrent disease includes local, regional, or distant recurrence: local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence or death at the time of analysis were censored at the last tumor assessment. Kaplan-Meier method was used to estimate the median for RFS, and 95% CIs were constructed using the Brookmeyer and Crowley method.

OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, 95% CIs were constructed using the Brookmeyer and Crowley method.

ORR was defined as the percentage of participants with a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using the Clopper-Pearson method. The difference in ORR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic or mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2:Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant, but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling or limiting self-care ADL; Grade 4: Life-threatening consequences or urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in the same category at the worst (highest) NCIC-CTCAE grade for an individual are counted only once.

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. Participants with immune-related adverse events Grade ≥ 3 were reported.

Rate of delayed surgery due to treatment related AEs was defined as the percentage of participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.

Duration of surgery delay due to treatment related AEs was calculated on the participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.

Surgical complications were scored according to the Clavien-Dindo surgical classification. Complication rates for every grade were reported and scored for participants who underwent CLND. The Surgical complications according to Clavien-Dindo can be classified into the following grades: Grade I: Any complication that does not need pharmacological treatment or surgical, endoscopic, and radiological interventions. Grade II: Complications that require pharmacological treatment with drugs or blood transfusions and total parenteral nutrition. Grade III: Complications that require surgical, endoscopic, or radiological intervention with (Grade IIIb) or without (Grade IIIa) general anesthesia. Grade IV: Life-threatening complications requiring intensive care unit (ICU) management, which may be single organ (Grade IVa) or multiorgan (Grade IVb) dysfunction. Grade V: Complications that might cause the death of a participant. Values have been rounded off to 2 decimal digits.

PFS after randomization/enrollment was defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline) and/or unequivocal progression of a non-target lesion and/or any new lesion. Participants without documented disease progression or death at the time of analysis were censored at the day of the last tumor assessment. Kaplan-Meier method was used to estimate the median for PFS, with 95% CIs constructed by using the Brookmeyer and Crowley method.

OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, with 95% CIs constructed by using the Brookmeyer and Crowley method.

OS was defined as the time from randomization to death from any cause. OS rate is percentage of participants who were event free for OS. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS rate at specific time points were estimated using the Kaplan-Meier method, with 95% CIs calculated based on Greenwood's estimate for the variance.

DOR was defined as the time from the first occurrence of a documented objective response (OR) to disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. OR was defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). Participants without PD or death at time of analysis were censored at time of last tumor assessment. Kaplan-Meier method was used to estimate median for DOR, with 95% CIs constructed using Brookmeyer & Crowley method.

DCR was defined as the percentage of participants with stable disease for ≥ 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). DCR was calculated for each treatment arm, with 95% CIs estimated through use of Clopper-Pearson's exact method.

An AE=any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable & unintended sign, symptom/disease temporally associated with using an investigational product, whether or not considered related to the investigational product. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care ADL; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in 1 individual are counted once at highest grade.