Safety and Efficacy of IMCgp100 Versus Investigator Choice in Advanced Uveal Melanoma

• ClinicalTrials.gov Identifier: NCT03070392
• Recruitment Status: Active, not recruiting
• First Posted: March 3, 2017
• Results First Posted: September 14, 2021
• Last Update Posted: November 9, 2021
• Sponsor: Immunocore Ltd
• Information provided by (Responsible Party): Immunocore Ltd

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Uveal Melanoma
• Interventions: Biological: IMCgp100; Drug: Dacarbazine; Biological: Ipilimumab; Biological: Pembrolizumab
• Enrollment: 378

Participant Flow

Recruitment Details	A total of 378 patients were randomly assigned (2:1) to Tebentafusp (n=252) or Investigator's Choice (n=126) at 58 sites in 14 countries.
Pre-assignment Details	The data cut-off date for this analysis was 13 October 2020. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design.

Arm/Group Title	Tebentafusp	Investigator's Choice: Dacarbazine	Investigator's Choice: Ipilimumab	Investigator's Choice: Pembrolizumab
Arm/Group Description	Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	Dacarbazine administered at 1,000 mg/m^2 of body surface area IV infusion every 3 weeks until confirmed disease progression or unacceptable toxicity.	Ipilimumab administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments.	Pembrolizumab administered at 2 mg/kg IV infusion over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Period Title: Overall Study
Started	252	7	16	103
Completed	0	0	10	0
Not Completed	252	7	6	103
Reason Not Completed
Not Treated	7	0	3	12
Death	3	0	0	1
Withdrawal by Subject	7	0	0	3
Physician Decision	1	0	0	2
Progressive Disease	154	6	2	70
Adverse Event	6	1	1	3
Alternate anticancer treatment	1	0	0	1
Ongoing	73	0	0	11

Baseline Characteristics

Arm/Group Title		Tebentafusp	Investigator's Choice	Total
Arm/Group Description		Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Number of Baseline Participants		252	126	378
Baseline Analysis Population Description		The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	252 participants	126 participants	378 participants
		61.3 (11.9)	63.6 (10.7)	62.1 (11.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	252 participants	126 participants	378 participants
	Female	124 49.2%	64 50.8%	188 49.7%
	Male	128 50.8%	62 49.2%	190 50.3%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	252 participants	126 participants	378 participants
	American Indian or Alaska Native	0 0.0%	1 0.8%	1 0.3%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	222 88.1%	107 84.9%	329 87.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	30 11.9%	18 14.3%	48 12.7%

Outcome Measures

1. Primary Outcome

Title	Efficacy: Overall Survival
Description	Overall survival is defined as the time from randomization to date of death due to any cause.
Time Frame	From randomization to the data cut off date of 13-Oct-2020; median follow-up duration was 14.1 months.

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title	Tebentafusp	Investigator's Choice
Arm/Group Description:	Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	252	126
Median (95% Confidence Interval); Unit of Measure: Months
	21.7; (18.6 to 28.6)	16.0; (9.7 to 18.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tebentafusp, Investigator's Choice
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.71
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Safety: Number of Participants With Treatment Emergent Adverse Events
Description	Safety was defined as the number of participants with treatment emergent adverse events, including laboratory abnormalities, ECG changes, and/or physical examination findings.
Time Frame	Safety was assessed from informed consent through 90 days after end of treatment, up to 36 months.

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set includes all randomized participants who received at least 1 full or partial dose of tebentafusp or investigator's choice. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title	Tebentafusp	Investigator's Choice
Arm/Group Description:	Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	245	111
Measure Type: Count of Participants; Unit of Measure: Participants
	245 100.0%	105 94.6%

3. Secondary Outcome

Title	Efficacy: Progression Free Survival (PFS)
Description	Progression free survival (PFS) is defined as the time from randomization to the date of progression (RECIST v1.1) or death due to any cause.
Time Frame	PFS was assessed every 3 months from randomization until disease progression or death, up to 36 months.

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title	Tebentafusp	Investigator's Choice
Arm/Group Description:	Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed	252	126
Median (95% Confidence Interval); Unit of Measure: Months
	3.3; (3.0 to 5.0)	2.9; (2.8 to 3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tebentafusp, Investigator's Choice
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0139
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.94
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Quality-of-Life: Change From Baseline in EQ-5D,5L Domain Scores
Description	General health status was assessed using the EQ-5D,5L questionnaire, which includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 scoring levels, where 1 indicates a better health state (no problems) and 3 indicates a worse health state. A positive change indicates improvement.
Time Frame	EQ-5D,5L was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title		Tebentafusp	Investigator's Choice
Arm/Group Description:		Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed		252	126
Mean (Standard Deviation); Unit of Measure: Units on a scale
Mobility - Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		1.2 (0.62)	1.3 (0.55)
Mobility - Change at Cycle 3	Number Analyzed	136 participants	45 participants
		-0.1 (0.66)	0.1 (0.47)
Mobility - Change at Cycle 5	Number Analyzed	108 participants	28 participants
		0.0 (0.73)	0.3 (0.65)
Mobility - Change at Cycle 9	Number Analyzed	71 participants	14 participants
		0.0 (0.91)	0.0 (0.55)
Mobility - Change at Cycle 13	Number Analyzed	47 participants	9 participants
		-0.1 (0.60)	0.3 (0.87)
Mobility - Change at Cycle 17	Number Analyzed	22 participants	6 participants
		0.3 (0.57)	0.2 (0.41)
Mobility - Change at Cycle 21	Number Analyzed	13 participants	2 participants
		0.0 (0.58)	0.5 (0.71)
Mobility - Change at Cycle 25	Number Analyzed	8 participants	1 participants
		0.1 (0.64)	0.0 (0.00)
Mobility - Change at Cycle 29	Number Analyzed	9 participants	2 participants
		0.0 (0.50)	0.0 (0.00)
Mobility - Change at EOT	Number Analyzed	95 participants	45 participants
		0.3 (0.73)	0.4 (0.99)
Self-care - Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		1.1 (0.45)	1.1 (0.29)
Self-care - Change at Cycle 3	Number Analyzed	136 participants	45 participants
		0.0 (0.49)	0.0 (0.26)
Self-care - Change at Cycle 5	Number Analyzed	108 participants	28 participants
		0.0 (0.42)	0.0 (0.00)
Self-care - Change at Cycle 9	Number Analyzed	71 participants	14 participants
		0.0 (0.58)	0.0 (0.00)
Self-care - Change at Cycle 13	Number Analyzed	47 participants	9 participants
		0.1 (0.52)	0.1 (0.33)
Self-care - Change at Cycle 17	Number Analyzed	22 participants	6 participants
		0.1 (0.68)	0.0 (0.00)
Self-care - Change at Cycle 21	Number Analyzed	13 participants	2 participants
		0.0 (0.00)	0.0 (0.00)
Self-care - Change at Cycle 25	Number Analyzed	8 participants	1 participants
		0.0 (0.00)	0.0 (0.00)
Self-care - Change at Cycle 29	Number Analyzed	9 participants	2 participants
		0.0 (0.00)	0.0 (0.00)
Self-care - Change at EOT	Number Analyzed	95 participants	45 participants
		0.1 (0.60)	0.1 (0.56)
Usual activities - Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		1.2 (0.53)	1.3 (0.55)
Usual activities - Change at Cycle 3	Number Analyzed	136 participants	45 participants
		0.2 (0.59)	0.1 (0.73)
Usual activities - Change at Cycle 5	Number Analyzed	108 participants	28 participants
		0.1 (0.61)	0.2 (0.61)
Usual activities - Change at Cycle 9	Number Analyzed	71 participants	14 participants
		0.2 (0.87)	0.1 (0.53)
Usual activities - Change at Cycle 13	Number Analyzed	47 participants	9 participants
		0.3 (0.79)	0.1 (0.60)
Usual activities - Change at Cycle 17	Number Analyzed	22 participants	6 participants
		0.5 (0.80)	0.2 (0.41)
Usual activities - Change at Cycle 21	Number Analyzed	13 participants	2 participants
		0.3 (0.48)	0.0 (0.00)
Usual activities - Change at Cycle 25	Number Analyzed	8 participants	1 participants
		0.3 (0.46)	0.0 (0.00)
Usual activities - Change at Cycle 29	Number Analyzed	9 participants	2 participants
		0.2 (0.44)	0.0 (0.00)
Usual activities - Change at EOT	Number Analyzed	95 participants	45 participants
		0.4 (0.77)	0.5 (0.87)
Pain/Discomfort - Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		1.5 (0.71)	1.5 (0.73)
Pain/Discomfort - Change at Cycle 3	Number Analyzed	136 participants	45 participants
		0.0 (0.75)	0.1 (0.73)
Pain/Discomfort - Change at Cycle 5	Number Analyzed	108 participants	28 participants
		0.0 (0.65)	0.2 (0.72)
Pain/Discomfort - Change at Cycle 9	Number Analyzed	71 participants	14 participants
		0.1 (0.73)	-0.1 (0.73)
Pain/Discomfort - Change at Cycle 13	Number Analyzed	47 participants	9 participants
		0.1 (0.51)	0.1 (0.93)
Pain/Discomfort - Change at Cycle 17	Number Analyzed	22 participants	6 participants
		0.4 (0.85)	0.3 (0.52)
Pain/Discomfort - Change at Cycle 21	Number Analyzed	13 participants	2 participants
		0.2 (0.55)	0.0 (0.00)
Pain/Discomfort - Change at Cycle 25	Number Analyzed	8 participants	1 participants
		0.0 (0.53)	1.0 [1] (NA)
Pain/Discomfort - Change at Cycle 29	Number Analyzed	9 participants	2 participants
		0.1 (0.60)	0.5 (0.71)
Pain/Discomfort - Change at EOT	Number Analyzed	95 participants	45 participants
		0.2 (0.87)	0.4 (1.10)
Anxiety/Depression - Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		1.8 (0.94)	1.7 (0.89)
Anxiety/Depression - Change at Cycle 3	Number Analyzed	136 participants	45 participants
		-0.2 (0.77)	-0.3 (0.55)
Anxiety/Depression - Change at Cycle 5	Number Analyzed	108 participants	28 participants
		-0.2 (0.74)	0.0 (0.61)
Anxiety/Depression - Change at Cycle 9	Number Analyzed	71 participants	14 participants
		-0.3 (0.80)	0.1 (0.77)
Anxiety/Depression - Change at Cycle 13	Number Analyzed	47 participants	9 participants
		-0.4 (0.77)	-0.1 (0.60)
Anxiety/Depression - Change at Cycle 17	Number Analyzed	22 participants	6 participants
		-0.4 (0.85)	0.0 (0.00)
Anxiety/Depression - Change at Cycle 21	Number Analyzed	13 participants	2 participants
		-0.5 (0.88)	0.0 (0.00)
Anxiety/Depression - Change at Cycle 25	Number Analyzed	8 participants	1 participants
		-0.4 (0.74)	0.0 [1] (NA)
Anxiety/Depression - Change at Cycle 29	Number Analyzed	9 participants	2 participants
		-0.6 (0.88)	0.5 (0.71)
Anxiety/Depression - Change at EOT	Number Analyzed	95 participants	45 participants
		0.3 (0.94)	0.2 (1.07)

[1]

Not calculable due to single participant.

5. Secondary Outcome

Title	Quality-of-life: Change From Baseline in EQ-5D Visual Analogue Score (VAS)
Description	The EQ-5D VAS score records the participant's self-rated health on a vertical visual analogue scale, with 0 being the worst imaginable health state and 100 being the best imaginable health state. A positive change indicates improvement.
Time Frame	EQ-5D,5L VAS was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title		Tebentafusp	Investigator's Choice
Arm/Group Description:		Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed		252	126
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline Cycle 1	Number Analyzed	194 participants	78 participants
		81.0 (16.36)	80.4 (18.31)
Change at Cycle 3	Number Analyzed	136 participants	45 participants
		0.4 (14.69)	-0.8 (14.28)
Change at Cycle 5	Number Analyzed	108 participants	28 participants
		0.6 (15.61)	-0.7 (14.38)
Change at Cycle 9	Number Analyzed	71 participants	14 participants
		-0.9 (19.81)	-3.3 (13.30)
Change at Cycle 13	Number Analyzed	47 participants	9 participants
		-2.0 (16.48)	-2.6 (8.37)
Change at Cycle 17	Number Analyzed	22 participants	6 participants
		-10.2 (20.93)	-8.5 (33.82)
Change at Cycle 21	Number Analyzed	13 participants	2 participants
		-1.8 (14.52)	-1.0 (5.66)
Change at Cycle 25	Number Analyzed	8 participants	1 participants
		-13.6 (19.43)	-4.0 [1] (NA)
Change at Cycle 29	Number Analyzed	9 participants	2 participants
		0.0 (9.25)	-2.0 (1.41)
Change at EOT	Number Analyzed	95 participants	45 participants
		-10.1 (22.53)	-11.7 (21.40)

[1]

Not calculable due to single participant

6. Secondary Outcome

Title	Quality-of-Life: Change From Baseline in EORTC QLQ-C30 Global Health Status
Description	Global health status and quality of life was assessed using the EORTC QLQ-C30 questionnaire. The score range for the EORTC QLQ-C30 is from 0 to 100, with higher scores indicating better functioning and better global health status and health-related quality of life. A positive change indicates improvement.
Time Frame	EORTC QLQ-C30 was assessed at baseline (Cycle 1 Day 1) and on Day 1 of every other cycle to Cycle 5 Day 1, every fourth cycle thereafter, beginning with Cycle 9 Day 1 and End of Treatment (EOT), up to 36 months. Each cycle is 21 days.

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) Analysis Set comprises all participants assigned to treatment analyzed by the treatment assignment whether or not the participant received the assigned treatment. Combining participants into a single group as part of the Investigator's Choice arm was pre-specified as part of the study design; therefore, data per different treatments were not analyzed.

Arm/Group Title		Tebentafusp	Investigator's Choice
Arm/Group Description:		Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.	1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed		252	126
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline Cycle 1	Number Analyzed	173 participants	65 participants
		76.108 (20.233)	74.872 (20.439)
Change at Cycle 3	Number Analyzed	105 participants	35 participants
		0.952 (16.274)	-0.238 (14.919)
Change at Cycle 5	Number Analyzed	94 participants	22 participants
		-1.152 (20.797)	-10.227 (22.557)
Change at Cycle 9	Number Analyzed	57 participants	13 participants
		-2.193 (19.577)	-8.333 (13.176)
Change at Cycle 13	Number Analyzed	40 participants	9 participants
		-5.625 (17.641)	-10.185 (16.017)
Change at Cycle 17	Number Analyzed	18 participants	6 participants
		-10.185 (28.087)	-4.167 (6.972)
Change at Cycle 21	Number Analyzed	11 participants	2 participants
		0.758 (18.429)	-4.167 (5.893)
Change at Cycle 25	Number Analyzed	7 participants	1 participants
		-2.381 (27.936)	0.00 (0.00)
Change at Cycle 29	Number Analyzed	6 participants	1 participants
		-8.333 (19.720)	0.00 (0.00)
Change at EOT	Number Analyzed	76 participants	34 participants
		-10.417 (20.911)	-10.539 (23.148)

7. Secondary Outcome

Title	Pharmacokinetics (PK): Tebentafusp Concentration
Description	Serum PK concentrations of tebentafusp were collected over time.
Time Frame	PK concentrations were assessed at pre-dose, end of infusion and anytime in the 12 to 24 hour window after completion of the infusion in Cycle 1 on Days 1, 8 and 15.

Outcome Measure Data

Analysis Population Description

The PK Analysis Set included participants in the Safety Analysis Set who had at least 1 measurable PK concentration and who had relevant date, time, and dosing data for the sample.

Arm/Group Title		Tebentafusp
Arm/Group Description:		Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.
Overall Number of Participants Analyzed		231
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: pg/mL
Cycle 1 Day 1 - End of Infusion	Number Analyzed	207 participants
		4201.929; (0.6%)
Cycle 1 Day 1 - 12 to 24 hours post-infusion	Number Analyzed	212 participants
		505.100; (0.7%)
Cycle 1 Day 8 - End of Infusion	Number Analyzed	200 participants
		5787.139; (0.4%)
Cycle 1 Day 8 - 12 to 24 hours post-infusion	Number Analyzed	198 participants
		738.602; (0.7%)
Cycle 1 Day 15 - End of Infusion	Number Analyzed	202 participants
		13715.914; (0.5%)
Cycle 1 Day 15 - 12 to 24 hours post-infusion	Number Analyzed	205 participants
		1685.354; (0.6%)

8. Secondary Outcome

Title	Efficacy: Objective Response Rate (ORR)
Description	Objective response rate (ORR) is defined as the proportion of patients achieving an objective response (RECIST v1.1).
Time Frame	ORR will be assessed after every participant has had at least 3 assessments, conducted every 3 months, up to 5.5 years.

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Efficacy: Duration of Response (DOR)
Description	Duration of response (DOR) is defined as the time from first documented objective response (RECIST v1.1) until the date of documented disease progression.
Time Frame	DOR will be assessed every 3 months from randomization until disease progression, assessed up to 5.5 years.

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Efficacy: Disease Control Rate (DCR)
Description	Disease control rate (DCR) is defined as the proportion of patients with either an objective response or stable disease (RECIST v1.1)
Time Frame	DCR will be assessed every 3 months from randomization until disease progression, up to 5.5 years.

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	Pharmacokinetics: Frequency of Anti-IMCgp100 Antibody Formation
Description	[Not Specified]
Time Frame	Approximately 5 assessments will be performed between first dose of IMCgp100 and end of treatment, assessed up to 5.5 years.

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Approximately 36 months.
Adverse Event Reporting Description	The Safety Analysis Set included all randomized participants who received at least 1 full or partial dose of tebentafusp or investigator's choice. Combining participants into a single group (Investigator's Choice) was pre-specified as part of the study design and data for each treatment in that arm were not analyzed separately. Adverse events were defined as events that were new or worsened during the on-treatment period.
Arm/Group Title	Tebentafusp		Investigator's Choice
Arm/Group Description	Tebentafusp administered at 20 mcg at Cycle 1 Day 1, 30 mcg at Cycle 1 Day 8, and 68 mcg at Cycle 1 Day 15 by IV infusion and weekly thereafter.		1 of 3 Investigator's Choice options: Systemic Dacarbazine, Ipilimumab or Pembrolizumab. Dacarbazine: administered at 1,000 mg/m2 of body surface area IV infusion every 3 weeks until disease progression or unacceptable toxicity; Ipilimumab: administered at 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 treatments; Pembrolizumab: administered at 2 mg/kg IV infusion up to a maximum of 200 mg administered Intravenously over 30 minutes every 3 weeks or 200 mg fixed dose administered intravenously every 3 weeks where approved locally until confirmed disease progression or unacceptable toxicity.
All-Cause Mortality
	Tebentafusp		Investigator's Choice
	Affected / at Risk (%)		Affected / at Risk (%)
Total	84/245 (34.29%)		57/111 (51.35%)
Serious Adverse Events
	Tebentafusp		Investigator's Choice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/245 (28.16%)		26/111 (23.42%)
Blood and lymphatic system disorders
Anemia * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Cardiac disorders
Left ventricular dysfunction * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Endocrine disorders
Hypopituitarism * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Eye disorders
Diplopia * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Periorbital edema * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Uveitis * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Gastrointestinal disorders
Abdominal pain * 1	2/245 (0.82%)	4	3/111 (2.70%)	3
Abdominal pain upper * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Colitis * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Diarrhea * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Enteritis * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Gastritis * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Nausea * 1	4/245 (1.63%)	6	1/111 (0.90%)	2
Vomiting * 1	2/245 (0.82%)	3	0/111 (0.00%)	0
General disorders
Asthenia * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Fatigue * 1	1/245 (0.41%)	3	0/111 (0.00%)	0
Gait disturbance * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
General physical health deterioration * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Pyrexia * 1	6/245 (2.45%)	6	2/111 (1.80%)	2
Hepatobiliary disorders
Biliary obstruction * 1	1/245 (0.41%)	3	0/111 (0.00%)	0
Hepatic failure * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Hepatic necrosis * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Hepatic pain * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Hepatomegaly * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Hepatotoxicity * 1	2/245 (0.82%)	18	0/111 (0.00%)	0
Hyperbilirubinemia * 1	2/245 (0.82%)	3	3/111 (2.70%)	5
Hypertransaminasemia * 1	1/245 (0.41%)	5	0/111 (0.00%)	0
Immune system disorders
Anaphylactic reaction * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Cytokine release syndrome * 1	24/245 (9.80%)	51	0/111 (0.00%)	0
Infections and infestations
Anorectal infection * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Appendicitis * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
COVID-19 * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Erysipelas * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Pneumonia * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Pneumonia mycoplasmal * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Salmonella sepsis * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Injury, poisoning and procedural complications
Fall * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Procedural pain * 1	1/245 (0.41%)	1	1/111 (0.90%)	1
Investigations
Alanine aminotransferase increased * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Amylase increased * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Aspartate aminotransferase increased * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Blood creatinine increased * 1	2/245 (0.82%)	2	0/111 (0.00%)	0
Lipase increased * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Metabolism and nutrition disorders
Dehydration * 1	0/245 (0.00%)	0	2/111 (1.80%)	2
Hyperglycemia * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Tumor lysis syndrome * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Musculoskeletal and connective tissue disorders
Bone pain * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Pathological fracture * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Metastases to abdominal cavity * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Neoplasm progression * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Tumor pain * 1	2/245 (0.82%)	3	0/111 (0.00%)	0
Nervous system disorders
Brain edema * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Dizziness * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Intracranial mass * 1	0/245 (0.00%)	0	1/111 (0.90%)	2
Lethargy * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Motor dysfunction * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Presyncope * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Seizure * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Spinal cord compression * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Psychiatric disorders
Mental status changes * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Renal and urinary disorders
Acute kidney injury * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Renal failure * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Reproductive system and breast disorders
Scrotal inflammation * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Dyspnea * 1	2/245 (0.82%)	2	0/111 (0.00%)	0
Pleurisy * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Pneumonitis * 1	0/245 (0.00%)	0	1/111 (0.90%)	2
Pulmonary embolism * 1	1/245 (0.41%)	2	3/111 (2.70%)	4
Pulmonary edema * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Sleep apnea syndrome * 1	0/245 (0.00%)	0	1/111 (0.90%)	1
Skin and subcutaneous tissue disorders
Pruritus * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Rash * 1	6/245 (2.45%)	10	0/111 (0.00%)	0
Rash maculo-papular * 1	4/245 (1.63%)	13	0/111 (0.00%)	0
Rash papular * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Skin reaction * 1	1/245 (0.41%)	1	0/111 (0.00%)	0
Urticaria * 1	1/245 (0.41%)	2	0/111 (0.00%)	0
Vascular disorders
Hypotension * 1	5/245 (2.04%)	6	0/111 (0.00%)	0
1 Term from vocabulary, MedDRA 23.1; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Tebentafusp		Investigator's Choice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	245/245 (100.00%)		102/111 (91.89%)
Blood and lymphatic system disorders
Anemia * 1	25/245 (10.20%)	62	4/111 (3.60%)	4
Lymphopenia * 1	24/245 (9.80%)	51	3/111 (2.70%)	4
Thrombocytopenia * 1	5/245 (2.04%)	7	6/111 (5.41%)	10
Cardiac disorders
Tachycardia * 1	24/245 (9.80%)	45	3/111 (2.70%)	3
Endocrine disorders
Hyperthyroidism * 1	2/245 (0.82%)	2	13/111 (11.71%)	16
Hypothyroidism * 1	3/245 (1.22%)	3	12/111 (10.81%)	15
Eye disorders
Periorbital edema * 1	26/245 (10.61%)	51	1/111 (0.90%)	1
Gastrointestinal disorders
Abdominal pain * 1	59/245 (24.08%)	92	14/111 (12.61%)	21
Abdominal pain upper * 1	50/245 (20.41%)	79	14/111 (12.61%)	21
Constipation * 1	44/245 (17.96%)	65	13/111 (11.71%)	15
Diarrhea * 1	61/245 (24.90%)	120	22/111 (19.82%)	45
Dry mouth * 1	8/245 (3.27%)	9	6/111 (5.41%)	6
Dyspepsia * 1	20/245 (8.16%)	28	5/111 (4.50%)	5
Nausea * 1	119/245 (48.57%)	288	28/111 (25.23%)	44
Vomiting * 1	73/245 (29.80%)	163	10/111 (9.01%)	19
General disorders
Asthenia * 1	38/245 (15.51%)	71	9/111 (8.11%)	11
Chills * 1	117/245 (47.76%)	378	4/111 (3.60%)	4
Face edema * 1	25/245 (10.20%)	39	2/111 (1.80%)	2
Fatigue * 1	124/245 (50.61%)	352	39/111 (35.14%)	53
Influenza like illness * 1	18/245 (7.35%)	75	2/111 (1.80%)	2
Edema peripheral * 1	66/245 (26.94%)	119	3/111 (2.70%)	3
Pyrexia * 1	186/245 (75.92%)	682	7/111 (6.31%)	11
Hepatobiliary disorders
Hepatic pain * 1	15/245 (6.12%)	41	4/111 (3.60%)	4
Hyperbilirubinemia * 1	26/245 (10.61%)	56	6/111 (5.41%)	6
Immune system disorders
Cytokine release syndrome * 1	34/245 (13.88%)	91	0/111 (0.00%)	0
Infections and infestations
Nasopharyngitis * 1	20/245 (8.16%)	24	1/111 (0.90%)	1
Urinary tract infection * 1	14/245 (5.71%)	19	5/111 (4.50%)	5
Investigations
Alanine aminotransferase increased * 1	50/245 (20.41%)	127	12/111 (10.81%)	19
Aspartate aminotransferase increased * 1	55/245 (22.45%)	134	11/111 (9.91%)	19
Blood alkaline phosphatase increased * 1	23/245 (9.39%)	60	3/111 (2.70%)	4
Blood creatinine increased * 1	13/245 (5.31%)	26	3/111 (2.70%)	3
Blood lactate dehydrogenase increased * 1	13/245 (5.31%)	20	3/111 (2.70%)	8
Lipase increased * 1	35/245 (14.29%)	73	7/111 (6.31%)	12
Weight decreased * 1	16/245 (6.53%)	16	7/111 (6.31%)	11
Metabolism and nutrition disorders
Decreased appetite * 1	45/245 (18.37%)	56	15/111 (13.51%)	17
Hypokalemia * 1	18/245 (7.35%)	24	3/111 (2.70%)	3
Hypomagnesemia * 1	19/245 (7.76%)	31	1/111 (0.90%)	1
Hypophosphatemia * 1	27/245 (11.02%)	52	2/111 (1.80%)	5
Musculoskeletal and connective tissue disorders
Arthralgia * 1	53/245 (21.63%)	97	18/111 (16.22%)	30
Back pain * 1	45/245 (18.37%)	56	9/111 (8.11%)	14
Muscle spasms * 1	14/245 (5.71%)	30	0/111 (0.00%)	0
Myalgia * 1	24/245 (9.80%)	40	7/111 (6.31%)	9
Pain in extremity * 1	24/245 (9.80%)	36	3/111 (2.70%)	3
Nervous system disorders
Dizziness * 1	26/245 (10.61%)	46	9/111 (8.11%)	12
Headache * 1	75/245 (30.61%)	135	11/111 (9.91%)	15
Parasthesia * 1	27/245 (11.02%)	53	1/111 (0.90%)	1
Psychiatric disorders
Anxiety * 1	13/245 (5.31%)	14	2/111 (1.80%)	2
Insomnia * 1	22/245 (8.98%)	24	6/111 (5.41%)	6
Respiratory, thoracic and mediastinal disorders
Cough * 1	44/245 (17.96%)	67	11/111 (9.91%)	12
Dyspnea * 1	31/245 (12.65%)	42	7/111 (6.31%)	7
Oropharyngeal pain * 1	16/245 (6.53%)	20	1/111 (0.90%)	1
Skin and subcutaneous tissue disorders
Alopecia * 1	21/245 (8.57%)	22	2/111 (1.80%)	2
Dry skin * 1	77/245 (31.43%)	106	4/111 (3.60%)	4
Erythema * 1	60/245 (24.49%)	120	1/111 (0.90%)	1
Hair color changes * 1	48/245 (19.59%)	62	0/111 (0.00%)	0
Night sweats * 1	13/245 (5.31%)	17	1/111 (0.90%)	1
Pruritus * 1	168/245 (68.57%)	536	26/111 (23.42%)	33
Rash * 1	132/245 (53.88%)	603	18/111 (16.22%)	25
Rash maculo-papular * 1	75/245 (30.61%)	343	9/111 (8.11%)	10
Skin exfoliation * 1	51/245 (20.82%)	80	2/111 (1.80%)	2
Skin hyperpigmentation * 1	19/245 (7.76%)	24	2/111 (1.80%)	2
Skin hypopigmentation * 1	22/245 (8.98%)	26	2/111 (1.80%)	2
Vitiligo * 1	40/245 (16.33%)	45	4/111 (3.60%)	5
Vascular disorders
Flushing * 1	25/245 (10.20%)	34	1/111 (0.90%)	2
Hypertension * 1	38/245 (15.51%)	91	8/111 (7.21%)	8
Hypotension * 1	91/245 (37.14%)	212	3/111 (2.70%)	4
1 Term from vocabulary, MedDRA 23.1; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Study Director
• Organization: Immunocore, Ltd
• Phone: 1-844-IMMUNO-1
• EMail: clinicaltrials@immunocore.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, Joshua AM, Sacco JJ, Shoushtari AN, Orloff M, Piulats JM, Milhem M, Salama AKS, Curti B, Demidov L, Gastaud L, Mauch C, Yushak M, Carvajal RD, Hamid O, Abdullah SE, Holland C, Goodall H, Piperno-Neumann S; IMCgp100-202 Investigators. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021 Sep 23;385(13):1196-1206. doi: 10.1056/NEJMoa2103485.

• Responsible Party: Immunocore Ltd
• ClinicalTrials.gov Identifier: NCT03070392
• Other Study ID Numbers: IMCgp100-202
• First Submitted: February 14, 2017
• First Posted: March 3, 2017
• Results First Submitted: August 17, 2021
• Results First Posted: September 14, 2021
• Last Update Posted: November 9, 2021