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Clinical Trial Results:
A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

Summary
EudraCT number	2021-002147-29
Trial protocol	ES FR IT NL
Global end of trial date	28 May 2024

Results information
Results version number	v1(current)
This version publication date	06 Jun 2025
First version publication date	06 Jun 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BO43328

ISRCTN number

US NCT number

NCT05116202

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4058

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, genentech@druginfo.com

Scientific contact

Medical Communications, Hoffmann-La Roche, +41 616878333, genentech@druginfo.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 May 2024

Was the trial ended prematurely?

Yes

Main objective of the trial

This study evaluated the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2).

Protection of trial subjects

All study participants were required to read and sign an informed consent form (ICF).

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Feb 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 45

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Italy: 16

Country: Number of subjects enrolled

United States: 18

Worldwide total number of subjects

110

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study across 14 investigative sites in 5 countries: the United States, Italy, France, Spain, and Australia. A total of 110 participants with resectable Stage III melanoma and Stage IV melanoma took part in Cohort 1 and Cohort 2, respectively.

Screening details

A total of 6 treatment arms were planned in Cohort 1 and 102 participants were enrolled in only 4 arms. The study was closed before the Cohort 1 arms tobemstomig 600 milligrams (mg), and tobemstomig 600 mg + tiragolumab were opened. 8 participants were enrolled in 1 arm in Cohort 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Nivolumab + Ipilimumab (Control)

Arm description

Participants received nivolumab 3 milligrams/kilograms (mg/kg) intravenously (IV) and ipilimumab 1 mg/kg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13.

Arm type

Active comparator

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received nivolumab, 3 mg/kg, IV, on Day 1 of each 21 Day cycle.

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received ipilimumab, 1 mg/kg, IV, on Day 1 of each 21 Day cycle.

Cohort 1: Tobemstomig 2100 mg

Arm description

Participants received a fixed dose of tobemstomig 2100 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13.

Arm type

Experimental

Investigational medicinal product name

Tobemstomig

Investigational medicinal product code

RO7247669

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tobemstomig, 2100 mg, IV on Day 1 of each 21 Day cycle.

Cohort 1: Atezolizumab + Tiragolumab

Arm description

Participants received atezolizumab 1200 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13.

Arm type

Experimental

Investigational medicinal product name

Tiragolumab

Investigational medicinal product code

RO7092284

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tiragolumab, 600 mg, IV on Day 1 of each 21 Day cycle.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

RO5541267

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received atezolizumab, 1200 mg, IV on Day 1 of each 21 Day cycle.

Cohort 1: Tobemstomig + Tiragolumab

Arm description

Participants received tobemstomig 2100 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13.

Arm type

Experimental

Investigational medicinal product name

Tiragolumab

Investigational medicinal product code

RO7092284

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tiragolumab, 600 mg, IV on Day 1 of each 21 Day cycle.

Investigational medicinal product name

Tobemstomig

Investigational medicinal product code

RO7247669

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tobemstomig, 2100 mg, IV on Day 1 of each 21 Day cycle.

Cohort 2: Tobemstomig + Tiragolumab

Arm description

Participants received tobemstomig 2100 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Arm type

Experimental

Investigational medicinal product name

Tiragolumab

Investigational medicinal product code

RO7092284

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tiragolumab, 600 mg, IV on Day 1 of each 21 Day cycle.

Investigational medicinal product name

Tobemstomig

Investigational medicinal product code

RO7247669

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received tobemstomig, 2100 mg, IV on Day 1 of each 21 Day cycle.

Number of subjects in period 1	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab	Cohort 2: Tobemstomig + Tiragolumab
Started	22	40	20	20	8
Completed	0	0	0	0	0
Not completed	22	40	20	20	8
Consent withdrawn by subject	-	1	1	1	1
Death	1	1	2	1	5
Study Terminated by Sponsor	21	38	17	18	-
Lost to follow-up	-	-	-	-	2

Baseline characteristics

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Reporting group title

Cohort 1: Nivolumab + Ipilimumab (Control)

Reporting group description

Reporting group title

Cohort 1: Tobemstomig 2100 mg

Reporting group description

Reporting group title

Cohort 1: Atezolizumab + Tiragolumab

Reporting group description

Reporting group title

Cohort 1: Tobemstomig + Tiragolumab

Reporting group description

Reporting group title

Cohort 2: Tobemstomig + Tiragolumab

Reporting group description

Reporting group values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab	Cohort 2: Tobemstomig + Tiragolumab	Total
Number of subjects	22	40	20	20	8	110
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	55.05 ( 16.03 )	64.10 ( 10.97 )	58.90 ( 14.10 )	59.15 ( 10.69 )	52.63 ( 14.22 )	-
Sex: Female, Male
Units: participants
Female	11	9	8	6	3	37
Male	11	31	12	14	5	73
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	1	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	1	0	1
White	15	35	14	14	8	86
More than one race	0	0	0	0	0	0
Unknown or Not Reported	7	5	6	4	0	22
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	0	0	1
Not Hispanic or Latino	13	29	10	16	8	76
Unknown or Not Reported	8	11	10	4	0	33

End points

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Reporting group title

Cohort 1: Nivolumab + Ipilimumab (Control)

Reporting group description

Reporting group title

Cohort 1: Tobemstomig 2100 mg

Reporting group description

Reporting group title

Cohort 1: Atezolizumab + Tiragolumab

Reporting group description

Reporting group title

Cohort 1: Tobemstomig + Tiragolumab

Reporting group description

Reporting group title

Cohort 2: Tobemstomig + Tiragolumab

Reporting group description

Primary: Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review

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End point title

Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review ^[1]

End point description

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. Efficacy-evaluable population=all participants in Cohort 1 who received at least 1 dose of each drug for their assigned treatment regimen.

End point type

Primary

End point timeframe

Time of surgery (scheduled at Week 7)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: percentage of participants
number (confidence interval 95%)	77.3 (54.63 to 92.18)	80.0 (64.35 to 90.95)	45.0 (23.06 to 68.47)	60.0 (36.05 to 80.88)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Tobemstomig 2100 mg v Cohort 1: Nivolumab + Ipilimumab (Control)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

2.73

Confidence interval

level

95%

sides

2-sided

lower limit

-22.25

upper limit

27.7

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

-17.27

Confidence interval

level

95%

sides

2-sided

lower limit

-49.75

upper limit

15.21

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Atezolizumab + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

-32.27

Confidence interval

level

95%

sides

2-sided

lower limit

-65.01

upper limit

0.46

Primary: Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator

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End point title

Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator ^[2] ^[3]

End point description

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. Efficacy-evaluable population=all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.

End point type

Primary

End point timeframe

From randomization up to approximately 3.6 months

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis for this end point.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 36.94)

No statistical analyses for this end point

Secondary: pRR for Cohort 1 as Determined by Local Pathologic Assessment

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End point title

pRR for Cohort 1 as Determined by Local Pathologic Assessment ^[4]

End point description

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. Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.

End point type

Secondary

End point timeframe

Time of surgery (scheduled at Week 7)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: percentage of participants
number (confidence interval 95%)	81.8 (59.72 to 94.81)	75.0 (58.80 to 87.31)	50.0 (27.20 to 72.80)	60.0 (36.05 to 80.88)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig 2100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

-6.82

Confidence interval

level

95%

sides

2-sided

lower limit

-31.31

upper limit

17.68

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

-21.82

Confidence interval

level

95%

sides

2-sided

lower limit

-53.44

upper limit

9.8

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Atezolizumab + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in pRR

Point estimate

-31.82

Confidence interval

level

95%

sides

2-sided

lower limit

-63.79

upper limit

0.16

Secondary: Event-free Survival (EFS) for Cohort 1

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End point title

Event-free Survival (EFS) for Cohort 1 ^[5]

End point description

EFS=time from randomization to any of following events (whichever occurs first): documented disease progression (PD) that precludes surgery, as assessed by investigator per RECIST v1.1, local, regional/distant disease recurrence/death from any cause. PD=≤20% increase in smallest sum of diameter (SOD) of target lesions, taking as reference smallest SOD on study (including baseline). Local recurrence=tumor regrowth within 2cm of primary lesion’s tumor bed; regional recurrence=nodal/non-nodal tumor lesions >2cm from primary lesion but not beyond regional nodal basin; distant recurrence=non-local/non-regional recurrence. Participants without disease recurrence/PD/death at the time of analysis were censored at the time of last tumor assessment. Kaplan-Meier method was used to estimate the median EFS & 95% CI constructed using Brookmeyer & Crowley method. Efficacy-evaluable population was used. 99999=median & upper limit of the 95% CI was not estimable due to insufficient number of events.

End point type

Secondary

End point timeframe

From randomization to disease progression, disease recurrence or death or last tumor assessment (up to 22.5 months)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: months
median (confidence interval 95%)	19.55 (19.55 to 99999)	99999 (14.09 to 99999)	22.51 (6.08 to 99999)	99999 (6.51 to 99999)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig 2100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

10.42

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

6.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

53.7

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Atezolizumab + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

3.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

19.7

Secondary: Overall Survival (OS) for Cohort 1

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End point title

Overall Survival (OS) for Cohort 1 ^[6]

End point description

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. Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen. 9999 = The median and 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From randomization to death from any cause or last known to be alive (Up to 25 months)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: months
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig 2100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

12.39

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

18.58

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Atezolizumab + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

28.65

Secondary: Relapse-free Survival (RFS) for Cohort 1

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End point title

Relapse-free Survival (RFS) for Cohort 1 ^[7]

End point description

RFS was defined as the time from surgery to first documented recurrence of disease/death from any cause. Recurrent disease includes local, regional/distant recurrence. Local recurrence=tumor regrowth within 2cm of primary lesion’s tumor bed; regional recurrence = any nodal/non-nodal tumor lesions that are more than 2cm from primary lesion but are not beyond the regional nodal basin; distant recurrence = 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 median for RFS, and 95% CIs were constructed using Brookmeyer and Crowley method. Adjuvant evaluable population included participants in Cohort 1 who had completed surgery (CLND). 99999=The upper limit of the 95% CI was not estimable due to insufficient number of participants with events. 9999=The median and 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From surgery (scheduled at Week 7) to first documented disease recurrence or death or last tumor assessment (up to 20.9 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	38	18	19
Units: months
median (confidence interval 95%)	17.91 (17.91 to 99999)	17.08 (11.79 to 99999)	20.90 (4.40 to 99999)	9999 (9999 to 9999)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig 2100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

7.75

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

26.32

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Atezolizumab + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

12.62

Secondary: ORR for Cohort 1

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End point title

ORR for Cohort 1 ^[8]

End point description

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. Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.

End point type

Secondary

End point timeframe

Prior to surgery (up to Week 6)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: percentage of participants
number (confidence interval 95%)	59.1 (36.35 to 79.29)	37.5 (22.73 to 54.20)	35.0 (15.39 to 59.22)	60.0 (36.05 to 80.88)

Nivo + Ipi vs Tobe 2100 mg

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig 2100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in ORR

Point estimate

-21.59

Confidence interval

level

95%

sides

2-sided

lower limit

-50.55

upper limit

7.37

Nivo + Ipi vs Tobe + Tira

Comparison groups

Cohort 1: Nivolumab + Ipilimumab (Control) v Cohort 1: Tobemstomig + Tiragolumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in ORR

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

-33.58

upper limit

35.4

Nivo + Ipi vs Atezo + Tira

Comparison groups

Cohort 1: Atezolizumab + Tiragolumab v Cohort 1: Nivolumab + Ipilimumab (Control)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in ORR

Point estimate

-24.09

Confidence interval

level

95%

sides

2-sided

lower limit

-58.17

upper limit

9.99

Secondary: Number of Participants with Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1

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End point title

Number of Participants with Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 ^[9]

End point description

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.

End point type

Secondary

End point timeframe

From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 5.6 months)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: participants
AE, Any Grade	19	36	19	18
Worst Grade, Grade 1 AE	4	13	9	4
Worst Grade, Grade 2 AE	9	15	9	8
Worst Grade, Grade 3 AE	4	5	1	6
Worst Grade, Grade 4 AE	2	3	0	0
Worst Grade, Grade 5 AE	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1

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End point title

Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 ^[10]

End point description

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. Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment.

End point type

Secondary

End point timeframe

From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 5.6 months)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: participants	15	29	8	13

No statistical analyses for this end point

Secondary: Duration of Surgery Delay due to Treatment-related AEs

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End point title

Duration of Surgery Delay due to Treatment-related AEs ^[11]

End point description

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. Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment. Participants with a surgery delay of more than 2 weeks due to treatment-related AE were analyzed. 9999=Standard Deviation (SD) was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Time of surgery (scheduled at Week 7)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	3	1	0 ^[12]	1
Units: weeks
arithmetic mean (standard deviation)	17.0 ( 14.8 )	5.1 ( 9999 )	( )	3.0 ( 9999 )

Notes
[12] - No participants had a delay in surgery.

No statistical analyses for this end point

Secondary: Rate of Delayed Surgery due to Treatment-related AEs

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End point title

Rate of Delayed Surgery due to Treatment-related AEs ^[13]

End point description

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. Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment.

End point type

Secondary

End point timeframe

Time of surgery (scheduled at Week 7)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	40	20	20
Units: percentage of participants
number (not applicable)	13.6	5.0	0	5.0

No statistical analyses for this end point

Secondary: Surgical Complication Rates for Cohort 1

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End point title

Surgical Complication Rates for Cohort 1 ^[14]

End point description

Surgical complications were scored per Clavien-Dindo surgical classification. Complication rates for every grade were reported & scored for participants who underwent CLND. Surgical complications per Clavien-Dindo are classified as: Grade I=Any complication not needing pharmacological treatment/surgical, endoscopic &radiological interventions. Grade II=Complications requiring pharmacological treatment with drugs/blood transfusions &total parenteral nutrition. Grade III=Complications requiring surgical, endoscopic/radiological intervention with (Grade IIIb)/without (Grade IIIa) general anesthesia. Grade IV=Life-threatening complications requiring intensive care unit (ICU) management, can be single organ (Grade IVa)/multiorgan (Grade IVb) dysfunction. Grade V=Complications that might cause death of participant. Safety-evaluable population. Number analyzed=number of participants who underwent CLND. n=number of participants with surgical complication. TDV=Treatment discontinuation visit.

End point type

Secondary

End point timeframe

At treatment discontinuation visit (Week 13) and Surgery Follow-Up (6 months after surgery)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 1: Atezolizumab + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab
Number of subjects analysed	22	38	18	19
Units: percentage of participants
number (not applicable)
TDV: Grade 0 (n=22,38,18,19)	0	0	5.55	54.26
TDV: Grade I (n=22,38,18,19)	18.18	5.26	22.22	0
TDV: Grade II (n=22,38,18,19)	13.63	18.42	16.66	10.52
TDV: Grade IIIa (n=22,38,18,19)	0	7.89	0	54.26
TDV: Grade IIIb (n=22,38,18,19)	0	2.63	0	10.52
TDV: Grade IVa (n=22,38,18,19)	0	2.63	0	0
Follow-up Month 6: Grade 0 (n=22,37,17,17)	0	0	5.88	0
Follow-up Month 6: Grade I (n=22,37,17,17)	13.63	8.10	17.64	0
Follow-up Month 6: Grade II (n=22,37,17,17)	4.540	10.81	5.88	0
Follow-up Month 6: Grade IIIa (n=22,37,17,17)	0	13.51	5.88	0
Follow-up Month 6: Grade IIIb (n=22,37,17,17)	0	0	0	11.76
Follow-up Month 6: Grade IVa (n=22,37,17,17)	0	2.7	0	0

No statistical analyses for this end point

Secondary: Duration of Response (DOR) for Cohort 2

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End point title

Duration of Response (DOR) for Cohort 2 ^[15]

End point description

DOR=time from first occurrence of a documented objective response (OR) to PD/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. Efficacy-evaluable population.

End point type

Secondary

End point timeframe

Time from the first occurrence of a documented OR to PD or death from any cause (up to 3.6 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	0 ^[16]
Units: months
median (confidence interval 95%)	( to )

Notes
[16] - DOR was only evaluated in participants who achieved an OR (CR or PR).

No statistical analyses for this end point

Secondary: OS Rates at Specific Timepoints for Cohort 2

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End point title

OS Rates at Specific Timepoints for Cohort 2 ^[17]

End point description

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. Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen. 'n' for each timepoint are unique number of participants out of all the assessed participants who remain at risk for an OS event at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Months 3, 6 and 12

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: percentage of participants
number (confidence interval 95%)
3 months (n=7)	100.0 (100.0 to 100.0)
6 months (n=4)	71.43 (37.96 to 100.0)
12 months (n=2)	47.62 (3.47 to 91.77)

No statistical analyses for this end point

Secondary: OS for Cohort 2

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End point title

OS for Cohort 2 ^[18]

End point description

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. Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen. 99999 = The upper limit of the 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From randomization/enrollment to death from any cause or last known to be alive (Up to 24.2 months)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: months
median (confidence interval 95%)	8.94 (4.17 to 99999)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) for Cohort 2

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End point title

Progression-Free Survival (PFS) for Cohort 2 ^[19]

End point description

PFS after randomization/enrollment was defined as the time from randomization/enrollment to the first occurrence of PD 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 PD 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. Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.

End point type

Secondary

End point timeframe

From randomization/enrollment to first documented disease progression or death or last tumor assessment (up to 3.6 months)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: months
median (confidence interval 95%)	2.07 (1.68 to 2.37)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) for Cohort 2

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End point title

Disease Control Rate (DCR) for Cohort 2 ^[20]

End point description

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. Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.

End point type

Secondary

End point timeframe

From randomization up to 3.6 months

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: percentage of participants
number (confidence interval 95%)	0 (0.00 to 36.94)

No statistical analyses for this end point

Secondary: Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2

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End point title

Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 ^[21]

End point description

AE=untoward medical occurrence in participant administered a drug, regardless of causal attribution.AE can be any unfavorable & unintended sign (abnormal laboratory), symptom/disease temporally associated with use of drug, whether/not considered related to drug. Severity of AEs 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/limiting age-appropriate instrumental activities of daily living; Grade 3: Severe/medically significant,but not immediately life-threatening:hospitalization/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 AE. Safety-evaluable population. AEs were reported until 30 days after final dose/until initiation of new systemic anti-cancer therapy (whichever occurs first).

End point type

Secondary

End point timeframe

From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 10 months)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this end point.

End point values	Cohort 2: Tobemstomig + Tiragolumab
Number of subjects analysed	8
Units: participants
AE, Any Grade	7
Worst Grade, Grade 1 AE	0
Worst Grade, Grade 2 AE	6
Worst Grade, Grade 3 AE	1
Worst Grade, Grade 4 AE	0
Worst Grade, Grade 5 AE	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs: From initiation of study treatment up to 135 days after final dose (Cohort 1: Up to 5.6 months; Cohort 2: 10 months); All-cause Mortality: Randomization up to end of long-term follow-up (Cohort 1: Up to approximately 25 months; Cohort 2: 24.2 months)

Adverse event reporting additional description

Safety evaluable population included all randomized participants who received at least one dose of the study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Cohort 1: Nivolumab + Ipilimumab (Control)

Reporting group description

Participants received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13.

Reporting group title

Cohort 1: Tobemstomig 2100 mg

Reporting group description

Reporting group title

Cohort 2: Tobemstomig + Tiragolumab

Reporting group description

Reporting group title

Cohort 1: Tobemstomig + Tiragolumab

Reporting group description

Reporting group title

Cohort 1: Atezolizumab + Tiragolumab

Reporting group description

Serious adverse events	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 2: Tobemstomig + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab	Cohort 1: Atezolizumab + Tiragolumab
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 22 (18.18%)	9 / 40 (22.50%)	1 / 8 (12.50%)	6 / 20 (30.00%)	3 / 20 (15.00%)
number of deaths (all causes)	1	1	5	1	2
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Troponin increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Heart rate irregular
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphatic fistula
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Ventricular fibrillation
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Scar excision
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Immune-mediated hepatitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated lung disease
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myositis
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Catheter site infection
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected seroma
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperlipasaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1: Nivolumab + Ipilimumab (Control)	Cohort 1: Tobemstomig 2100 mg	Cohort 2: Tobemstomig + Tiragolumab	Cohort 1: Tobemstomig + Tiragolumab	Cohort 1: Atezolizumab + Tiragolumab
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 22 (81.82%)	34 / 40 (85.00%)	7 / 8 (87.50%)	18 / 20 (90.00%)	18 / 20 (90.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	3	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Lymphoedema
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 22 (9.09%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	4 / 20 (20.00%)
occurrences all number	2	2	0	1	4
Chest pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	1	0	0
Hyperthermia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Fatigue
subjects affected / exposed	7 / 22 (31.82%)	15 / 40 (37.50%)	4 / 8 (50.00%)	6 / 20 (30.00%)	3 / 20 (15.00%)
occurrences all number	7	15	4	6	4
Extravasation
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Chills
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	4 / 20 (20.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	4	0
Influenza like illness
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	1 / 8 (12.50%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	1	1	1	1	1
Pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	2	0
Peripheral swelling
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Pyrexia
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	2 / 8 (25.00%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	1	0	4	1	2
Xerosis
subjects affected / exposed	2 / 22 (9.09%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 22 (0.00%)	2 / 40 (5.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	2	0	1
Immune system disorders
Contrast media allergy
subjects affected / exposed	2 / 22 (9.09%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 22 (9.09%)	2 / 40 (5.00%)	2 / 8 (25.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	2	2	2	2	0
Dyspnoea
subjects affected / exposed	2 / 22 (9.09%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	0	0	0
Haemoptysis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	2	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	1
Pleural effusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Insomnia
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	1	0	0	2
Sleep disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 22 (13.64%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	3	2	0	1	0
Amylase increased
subjects affected / exposed	0 / 22 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	3	0	1	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 22 (4.55%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	2	0	1	0
Blood creatinine increased
subjects affected / exposed	1 / 22 (4.55%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	2	0	0	0
International normalised ratio decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Lipase increased
subjects affected / exposed	2 / 22 (9.09%)	3 / 40 (7.50%)	1 / 8 (12.50%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	2	4	1	1	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	1	0	0
Serum ferritin decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Troponin increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Injury, poisoning and procedural complications
Procedural nausea
subjects affected / exposed	0 / 22 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	0	1
Post procedural constipation
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	1
Joint injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Infusion related reaction
subjects affected / exposed	2 / 22 (9.09%)	6 / 40 (15.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	2	8	0	1	0
Procedural pain
subjects affected / exposed	2 / 22 (9.09%)	8 / 40 (20.00%)	0 / 8 (0.00%)	3 / 20 (15.00%)	4 / 20 (20.00%)
occurrences all number	2	8	0	3	4
Seroma
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	1	0
Skin laceration
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 22 (9.09%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	2	1	0	1	1
Dysgeusia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Headache
subjects affected / exposed	2 / 22 (9.09%)	1 / 40 (2.50%)	2 / 8 (25.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	2	1	2	2	0
Hypoaesthesia
subjects affected / exposed	2 / 22 (9.09%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	0	0	0
Lethargy
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Paraesthesia
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0
Sensory disturbance
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Anaemia
subjects affected / exposed	1 / 22 (4.55%)	2 / 40 (5.00%)	2 / 8 (25.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	2	3	0	0
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Eyelid ptosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Dry eye
subjects affected / exposed	0 / 22 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	0
Gastrointestinal disorders
Gastrointestinal pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Nausea
subjects affected / exposed	4 / 22 (18.18%)	1 / 40 (2.50%)	1 / 8 (12.50%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	4	1	1	3	1
Vomiting
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0
Dry mouth
subjects affected / exposed	2 / 22 (9.09%)	3 / 40 (7.50%)	0 / 8 (0.00%)	4 / 20 (20.00%)	1 / 20 (5.00%)
occurrences all number	2	3	0	4	1
Diarrhoea
subjects affected / exposed	2 / 22 (9.09%)	3 / 40 (7.50%)	3 / 8 (37.50%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	2	3	3	5	1
Constipation
subjects affected / exposed	2 / 22 (9.09%)	3 / 40 (7.50%)	1 / 8 (12.50%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences all number	2	3	1	2	1
Abdominal tenderness
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Abdominal pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	2 / 8 (25.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	3	0	0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	2 / 22 (9.09%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	2	0	0	1
Hypertransaminasaemia
subjects affected / exposed	1 / 22 (4.55%)	2 / 40 (5.00%)	0 / 8 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	1	2	0	2	0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	1 / 22 (4.55%)	3 / 40 (7.50%)	0 / 8 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)
occurrences all number	1	3	0	2	2
Dry skin
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	1 / 8 (12.50%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	1	1	2	0
Eczema
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	1
Hyperhidrosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0
Lichenoid keratosis
subjects affected / exposed	2 / 22 (9.09%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	3	4	0	1	0
Pruritus
subjects affected / exposed	8 / 22 (36.36%)	6 / 40 (15.00%)	2 / 8 (25.00%)	5 / 20 (25.00%)	2 / 20 (10.00%)
occurrences all number	8	6	3	5	2
Psoriasis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Rash
subjects affected / exposed	6 / 22 (27.27%)	7 / 40 (17.50%)	2 / 8 (25.00%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	7	8	2	3	1
Rash erythematous
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	1
Renal and urinary disorders
Renal impairment
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Endocrine disorders
Thyroiditis
subjects affected / exposed	1 / 22 (4.55%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	2	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 22 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	3	0	1	1
Hypophysitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Hyperthyroidism
subjects affected / exposed	4 / 22 (18.18%)	7 / 40 (17.50%)	1 / 8 (12.50%)	6 / 20 (30.00%)	3 / 20 (15.00%)
occurrences all number	4	7	1	6	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 22 (13.64%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	3	3	0	1	2
Joint stiffness
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Muscle spasms
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	2	0
Myalgia
subjects affected / exposed	1 / 22 (4.55%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	1	1	0	1	2
Myositis
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 22 (0.00%)	1 / 40 (2.50%)	1 / 8 (12.50%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	2	1	2	0
Groin pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Infections and infestations
COVID-19
subjects affected / exposed	1 / 22 (4.55%)	0 / 40 (0.00%)	2 / 8 (25.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	2	1	0
Cystitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Device related infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Pharyngitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 22 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	1	1
Hyperamylasaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0
Hyperkalaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

24 Feb 2022

The following changes were made as per amendment 2: - It was clarified that the biopsy to be collected on Day 1 of Cycle 2 in Cohort 1 can be done up to 24 hours prior to drug administration - The eligibility requirement for aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) was updated to clarify that the listed exceptions are specific to participants in Cohort 2 - An eligibility criterion was revised to clarify that in Cohort 2, only participants with histologically confirmed Stage IV (metastatic) cutaneous melanoma will be enrolled - Language was updated to clarify that for participants enrolled in Cohort 1, pathological tumor assessment is only performed after 6 weeks of treatment with completion lymph node dissection and radiographic tumor assessment is only required to be performed according to RECIST v1.1 at baseline and at Week 6. - Text was added to clarify that adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate (ESR) will be assessed at screening and pre-surgery only for participants enrolled in Cohort 1 - It was clarified that the pregnancy test performed at Week 13 is part of the treatment completion/discontinuation visit and not considered to be part of the follow-up period. - Timepoint for collection of blood and plasma samples for biomarker assessments during follow-up in Cohort 2 of the RO7247669 + tiragolumab arm was removed

13 Dec 2022

The following changes were made as per amendment 3: - The adverse event management guidelines were updated to align with the Atezolizumab Investigator’s Brochure, Version 19 and addendums. - The term, survival follow-up, was replaced with the term long-term follow up, for clarity . - Text was revised to specify that on-treatment tissue samples will be collected up to 72 hours prior to study drug administration on Day 1 of Cycle 2. - Text was added to clarify that participants with missing or no pathological response evaluation will be classified as non-responders. - The follow-up visit at 6 months was renamed Surgery Follow-Up and text was updated to clarify that this visit will occur 6 months after surgery for participants who proceed to surgery. - Text was added to clarify when a participant will return to the clinic for a treatment completion/discontinuation visit, which depends on whether or not the participant proceeds to surgery. - Text was revised to clarify that the Wald method with continuity correction will be used to calculate the difference in pathologic response rate and objective response rate

08 May 2023

The following changes were made as per amendment 4: - The RO7247669 600 mg treatment arm was for Cohort 1 to evaluate the efficacy, safety, and pharmacokinetics of a lower dose of RO7247669 based on merging data. - The RO7247669 600 mg+tiragolumab treatment arm was added for Cohort 1 to evaluate the efficacy, safety, and pharmacokinetics of a lower dose of RO7247669 in combination with tiragolumab based on emerging data. - The sample sizes was updated to 195-290 participants in Cohort 1 and 8-46 participants in Cohort 2 to reflect the number of participants currently enrolled (as of 20 March 2023) in the trial and the addition of the two new treatment arms. - Text was added to clarify that for most arms, approximately 20 participants will be enrolled during the preliminary phase. Approximately 40 participants will be enrolled in the RO7247669 600 mg and RO7247669 600 mg+tiragolumab arms during the preliminary phase to ensure a more precise benefit-risk assessment in arms with the lower dose of RO7247669. - Text was modified to clarify that participants who do not proceed to complete lymph node dissection will be classified as non-responders. - Throughout the protocol, the dose of RO7247669 was updated to indicate the use of either 2100 or 600 mg.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review

Primary: Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review

Primary: Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator

Primary: Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator

Secondary: pRR for Cohort 1 as Determined by Local Pathologic Assessment

Secondary: pRR for Cohort 1 as Determined by Local Pathologic Assessment

Secondary: Event-free Survival (EFS) for Cohort 1

Secondary: Event-free Survival (EFS) for Cohort 1

Secondary: Overall Survival (OS) for Cohort 1

Secondary: Overall Survival (OS) for Cohort 1

Secondary: Relapse-free Survival (RFS) for Cohort 1

Secondary: Relapse-free Survival (RFS) for Cohort 1

Secondary: ORR for Cohort 1

Secondary: ORR for Cohort 1

Secondary: Number of Participants with Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1

Secondary: Number of Participants with Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1

Secondary: Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1

Secondary: Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1

Secondary: Duration of Surgery Delay due to Treatment-related AEs

Secondary: Duration of Surgery Delay due to Treatment-related AEs

Secondary: Rate of Delayed Surgery due to Treatment-related AEs

Secondary: Rate of Delayed Surgery due to Treatment-related AEs

Secondary: Surgical Complication Rates for Cohort 1

Secondary: Surgical Complication Rates for Cohort 1

Secondary: Duration of Response (DOR) for Cohort 2

Secondary: Duration of Response (DOR) for Cohort 2

Secondary: OS Rates at Specific Timepoints for Cohort 2

Secondary: OS Rates at Specific Timepoints for Cohort 2

Secondary: OS for Cohort 2

Secondary: OS for Cohort 2

Secondary: Progression-Free Survival (PFS) for Cohort 2

Secondary: Progression-Free Survival (PFS) for Cohort 2

Secondary: Disease Control Rate (DCR) for Cohort 2

Secondary: Disease Control Rate (DCR) for Cohort 2

Secondary: Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2

Secondary: Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)