Trial Outcomes & Findings for A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site (NCT NCT03498521)

Last Updated: 2025-11-19

Results Overview

This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

529 participants

Primary outcome timeframe

From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).

Results posted on

2025-11-19

Participant Flow

Participant milestones

Participant milestones
Measure	Molecularly-Guided Therapy (MGT) Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.	Category 2 Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Overall Study STARTED	326	110	93
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	326	110	93

Reasons for withdrawal

Reasons for withdrawal
Measure	Molecularly-Guided Therapy (MGT) Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.	Category 2 Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Overall Study Death	227	79	84
Overall Study Exclusion criteria	1	0	0
Overall Study Lost to Follow-up	4	3	3
Overall Study No profile due to technical failure	1	0	0
Overall Study Physician Decision	3	1	0
Overall Study Withdrawal by Subject	11	6	2
Overall Study Study terminated by sponsor	79	21	4

Baseline Characteristics

A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=326 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=110 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.	Category 2 n=93 Participants Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.	Total n=529 Participants Total of all reporting groups
Age, Continuous	60.5 Years STANDARD_DEVIATION 11.5 • n=39 Participants	61.1 Years STANDARD_DEVIATION 11.3 • n=29 Participants	59.2 Years STANDARD_DEVIATION 12.7 • n=60 Participants	60.42 Years STANDARD_DEVIATION 11.62 • n=185 Participants
Sex: Female, Male Female	161 Participants n=39 Participants	53 Participants n=29 Participants	44 Participants n=60 Participants	258 Participants n=185 Participants
Sex: Female, Male Male	165 Participants n=39 Participants	57 Participants n=29 Participants	49 Participants n=60 Participants	271 Participants n=185 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	4 Participants n=39 Participants	3 Participants n=29 Participants	1 Participants n=60 Participants	8 Participants n=185 Participants
Race/Ethnicity, Customized Asian	31 Participants n=39 Participants	12 Participants n=29 Participants	7 Participants n=60 Participants	50 Participants n=185 Participants
Race/Ethnicity, Customized Black or African American	5 Participants n=39 Participants	0 Participants n=29 Participants	0 Participants n=60 Participants	5 Participants n=185 Participants
Race/Ethnicity, Customized Unknown	21 Participants n=39 Participants	5 Participants n=29 Participants	6 Participants n=60 Participants	32 Participants n=185 Participants
Race/Ethnicity, Customized White	242 Participants n=39 Participants	81 Participants n=29 Participants	70 Participants n=60 Participants	393 Participants n=185 Participants
Race/Ethnicity, Customized Missing	1 Participants n=39 Participants	0 Participants n=29 Participants	0 Participants n=60 Participants	1 Participants n=185 Participants
Race/Ethnicity, Customized Hispanic or Latino	22 Participants n=39 Participants	9 Participants n=29 Participants	4 Participants n=60 Participants	35 Participants n=185 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	252 Participants n=39 Participants	85 Participants n=29 Participants	76 Participants n=60 Participants	413 Participants n=185 Participants
Race/Ethnicity, Customized Not Stated	31 Participants n=39 Participants	11 Participants n=29 Participants	7 Participants n=60 Participants	49 Participants n=185 Participants

PRIMARY outcome

Timeframe: From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).

Population: The intent-to-treat (ITT) population included all Category 1 randomized participants, whether or not the assigned study treatment was received. Endpoints for Category 2 were exploratory and were not included in this analysis.

Outcome measures

Outcome measures
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=326 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=110 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)	6.14 Months Interval 4.7 to 6.47	4.40 Months Interval 4.17 to 6.37

SECONDARY outcome

Timeframe: From randomization to death from any cause (approx. 4 years)

Population: The ITT population included all Category 1 randomized participants, whether or not the assigned study treatment was received. Endpoints for Category 2 were exploratory and were not included in this analysis.

Outcome measures

Outcome measures
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=326 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=110 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Overall Survival (OS)	15.18 Months Interval 13.9 to 18.43	12.78 Months Interval 9.86 to 15.38

SECONDARY outcome

Timeframe: Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)

Population: The ITT population included all Cat. 1 randomized participants, whether or not the assigned study treatment was received. Cat. 2 endpoints were exploratory and not analyzed. NA: Participants had no lesions to report at baseline NE: Post-baseline assessments reported not evaluable for any reason or if SD assessment was within 6 weeks of baseline Missing: No post-baseline assessments available

Outcome measures

Outcome measures
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=326 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=110 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Objective Response Rate (ORR) Complete response (CR)	4.9 Percentage of participants Interval 2.83 to 7.85	3.6 Percentage of participants Interval 1.0 to 9.05
Objective Response Rate (ORR) Partial response (PR)	12.9 Percentage of participants Interval 9.45 to 17.01	4.5 Percentage of participants Interval 1.49 to 10.29
Objective Response Rate (ORR) Stable disease (SD)	44.5 Percentage of participants Interval 39.0 to 50.06	49.1 Percentage of participants Interval 39.43 to 58.8
Objective Response Rate (ORR) Non-CR/Non-PD	7.1 Percentage of participants Interval 4.52 to 10.4	6.4 Percentage of participants Interval 2.6 to 12.67
Objective Response Rate (ORR) Not Applicable (NA)	2.5 Percentage of participants Interval 1.07 to 4.78	2.7 Percentage of participants Interval 0.57 to 7.76
Objective Response Rate (ORR) Progressive disease (PD)	17.8 Percentage of participants Interval 13.8 to 22.38	21.8 Percentage of participants Interval 14.51 to 30.7
Objective Response Rate (ORR) Not evaluable participants	0.6 Percentage of participants Interval 0.07 to 2.2	0 Percentage of participants Interval 0.0 to 3.3
Objective Response Rate (ORR) Missing participants	9.8 Percentage of participants Interval 6.81 to 13.57	11.8 Percentage of participants Interval 6.45 to 19.36

SECONDARY outcome

Timeframe: From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 4 years)

Outcome measures

Outcome measures
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=58 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=9 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Duration of Response (DOR)	16.39 Months Interval 8.08 to Value is NA due to insufficient no. of participants with the event.	NA Months Interval 4.14 to Value is NA due to insufficient no. of participants with the event.

SECONDARY outcome

Timeframe: From randomization to death from any cause, through the end of study (approximately 4 years)

Outcome measures

Outcome measures
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=326 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=110 Participants Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
Disease Control Rate (DCR)	64.7 Percentage of responders Interval 59.27 to 69.91	60.0 Percentage of responders Interval 50.22 to 69.22

Adverse Events

Molecularly-Guided Therapy (MGT) Category 1

Serious events: 119 serious events

Other events: 279 other events

Deaths: 227 deaths

Chemotherapy Category 1

Serious events: 15 serious events

Other events: 81 other events

Deaths: 79 deaths

Category 2

Serious events: 39 serious events

Other events: 73 other events

Deaths: 84 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Molecularly-Guided Therapy (MGT) Category 1 n=312 participants at risk Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.	Chemotherapy Category 1 n=102 participants at risk Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.	Category 2 n=93 participants at risk Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.
General disorders Pain	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
General disorders Pyrexia	2.2% 7/312 • Number of events 8 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Anal abscess	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations COVID-19	2.2% 7/312 • Number of events 7 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Peritonitis	0.32% 1/312 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Pneumonia	1.9% 6/312 • Number of events 6 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Sepsis	0.96% 3/312 • Number of events 3 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	4.3% 4/93 • Number of events 4 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Urinary tract infection	1.9% 6/312 • Number of events 6 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Urosepsis	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Encephalitis	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Investigations Liver function test abnormal	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Investigations Neutrophil count decreased	0.64% 2/312 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Nervous system disorders Seizure	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Atrial fibrillation	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	3.2% 3/93 • Number of events 3 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Cardiac Arrest	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Cardiac failure chronic	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Gastrointestinal disorders Ascites	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Wound infection	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Renal and urinary disorders Hydronephrosis	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Renal and urinary disorders Renal failure	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Anaemia	1.3% 4/312 • Number of events 4 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	5.4% 5/93 • Number of events 5 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Febrile neutropenia	0.96% 3/312 • Number of events 3 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
General disorders Death	0.96% 3/312 • Number of events 3 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
General disorders General physical health deterioration	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
General disorders Oedema peripheral	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Injury, poisoning and procedural complications Hip fracture	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Nervous system disorders Cerebral haemorrhage	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 4 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Infections and infestations Infection	0.96% 3/312 • Number of events 3 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	1.1% 1/93 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Nervous system disorders Ischaemic stroke	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	2.2% 2/93 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Agranulocytosis	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Autoimmune haemolytic anaemia	0.64% 2/312 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Bone marrow failure	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Neutropenia	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Pancytopenia	1.3% 4/312 • Number of events 4 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.64% 2/312 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Blood and lymphatic system disorders Thrombotic microangiopathy	0.00% 0/312 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.98% 1/102 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Acute myocardial infarction	0.32% 1/312 • Number of events 1 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.
Cardiac disorders Cardiac failure	0.64% 2/312 • Number of events 2 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/102 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.	0.00% 0/93 • Approximately 4.5 years The all-cause mortality table contains all participants. The safety evaluable (SE) population (used to report serious and other AE) included all participants who received at least one dose of any component of study drug.