Trial Outcomes & Findings for Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status (NCT NCT03519412)

NCT ID: NCT03519412

Last Updated: 2026-03-03

Results Overview

Overall response rate (ORR) to pembrolizumab according to RECIST v1.1. An objective response is defined as either a CR or PR assessed by RECIST v1.1 at the discretion of the local investigator.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

107 participants

Primary outcome timeframe

Tumor assessments every 8-9 weeks from date of enrollment (in Trial Phase of the study) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months.

Results posted on

2026-03-03

Participant Flow

MMR-deficient (MMRd): 35 MMR-proficient (MMRp): 72 TMZ-treated MMR-proficient (MMRp): 22

TMZ-treated MMR-proficient (MMRp): subgroup of MMR-proficient (MMRp) patients primed with temozolomide achieving high-TMB and treated with pembrolizumab

Participant milestones

Participant milestones
Measure	MMR-proficient (MMRp) MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) orally until disease progression or unacceptable toxicity whichever comes first.	MMR-deficient (MMRd) Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first	TMZ-primed MMR-proficient (MMRp): 22 MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) orally with High Tumor Mutational Burden post-Temozolomide and treated with Pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.
Priming Phase - Temozolomide treatment STARTED	72	0	0
Priming Phase - Temozolomide treatment COMPLETED	72	0	0
Priming Phase - Temozolomide treatment NOT COMPLETED	0	0	0
Trial Phase - Pembrolizumab treatment STARTED	0	35	22
Trial Phase - Pembrolizumab treatment COMPLETED	0	35	22
Trial Phase - Pembrolizumab treatment NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MMR-proficient (MMRp) n=72 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population is selected for treatment with temozolomide (induction) orally until disease progression or unacceptable toxicity whichever comes first, followed by pembrolizumab IV if Tumor Mutational Burden post Temozolomide is \> 20 Muts/Mb	MMR-deficient (MMRd) n=35 Participants Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first	Total n=107 Participants Total of all reporting groups
Metastatic sites No liver involved	22 Participants n=72 Participants	14 Participants n=35 Participants	36 Participants n=107 Participants
Prior lines of therapy 1	6 number of previous line n=72 Participants	17 number of previous line n=35 Participants	23 number of previous line n=107 Participants
Age, Categorical <=18 years	0 Participants n=72 Participants	0 Participants n=35 Participants	0 Participants n=107 Participants
Age, Categorical Between 18 and 65 years	47 Participants n=72 Participants	23 Participants n=35 Participants	70 Participants n=107 Participants
Age, Categorical >=65 years	25 Participants n=72 Participants	12 Participants n=35 Participants	37 Participants n=107 Participants
Age, Continuous	61 year n=72 Participants	59 year n=35 Participants	61 year n=107 Participants
Sex: Female, Male Female	32 Participants n=72 Participants	21 Participants n=35 Participants	53 Participants n=107 Participants
Sex: Female, Male Male	40 Participants n=72 Participants	14 Participants n=35 Participants	54 Participants n=107 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Primary Tumor Colon	58 Participants n=72 Participants	32 Participants n=35 Participants	90 Participants n=107 Participants
Primary Tumor Rectum	14 Participants n=72 Participants	3 Participants n=35 Participants	17 Participants n=107 Participants
Metastatic sites Liver involved	50 Participants n=72 Participants	21 Participants n=35 Participants	71 Participants n=107 Participants
Prior lines of therapy 2	22 number of previous line n=72 Participants	12 number of previous line n=35 Participants	34 number of previous line n=107 Participants
Prior lines of therapy 3	26 number of previous line n=72 Participants	3 number of previous line n=35 Participants	29 number of previous line n=107 Participants
Prior lines of therapy >4	17 number of previous line n=72 Participants	3 number of previous line n=35 Participants	20 number of previous line n=107 Participants
Prior lines of therapy Missing	1 number of previous line n=72 Participants	0 number of previous line n=35 Participants	1 number of previous line n=107 Participants

PRIMARY outcome

Timeframe: Tumor assessments every 8-9 weeks from date of enrollment (in Trial Phase of the study) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months.

Overall response rate (ORR) to pembrolizumab according to RECIST v1.1. An objective response is defined as either a CR or PR assessed by RECIST v1.1 at the discretion of the local investigator.

Outcome measures

Outcome measures
Measure	TMZ-primed MMR-proficient (MMRp) n=22 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) with High Tumor Mutational Burden post Temozolomide followed by pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.	MMR-deficient (MMRd) Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Overall Response Rate (ORR)	0 % of participants Interval 0.0 to 0.0	—

SECONDARY outcome

Overall response rate (ORR) to pembrolizumab according to RECIST v1.1. An objective response is defined as either a CR or PR assessed by RECIST v1.1 criteria at the discretion of the local investigator.

Outcome measures

Outcome measures
Measure	TMZ-primed MMR-proficient (MMRp) n=35 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) with High Tumor Mutational Burden post Temozolomide followed by pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.	MMR-deficient (MMRd) Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Overall Response Rate (ORR)	54.3 % of participants Interval 32.7 to 84.8	—

SECONDARY outcome

Timeframe: From the date of treatment initiation with pembrolizumab to the date of first documented progression or date of death from any cause, whichever came first, up to maximum 72 months.

Progression Free Survival (PFS) in pembrolizumab treated patients. PFS was estimated using the Kaplan-Meier method. Patient without disease progression were censored at the last follow-up visit available.

Outcome measures

Outcome measures
Measure	TMZ-primed MMR-proficient (MMRp) n=22 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) with High Tumor Mutational Burden post Temozolomide followed by pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.	MMR-deficient (MMRd) n=35 Participants Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Progression Free Survival (PFS)	3.3 Months Interval 2.2 to 6.4	49.7 Months Interval 3.5 to Insufficient number of participants with events based on Kaplan-Meier Estimates

SECONDARY outcome

Timeframe: Every 8-12 weeks from date of treatment initiation with pembrolizumab to the date of death due to any cause (up to maximum 72 months). A participant who has not died will be censored at last known date alive.

Overall Survival (OS) in pembrolizumab treated patients. OS was estimated using the Kaplan-Meier method. Patient without disease progression were censored at the last survival follow-up available.

Outcome measures

Outcome measures
Measure	TMZ-primed MMR-proficient (MMRp) n=22 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) with High Tumor Mutational Burden post Temozolomide followed by pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.	MMR-deficient (MMRd) n=35 Participants Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Overall Survival (OS)	5.6 Months Interval 2.9 to Insufficient number of participants with events based on Kaplan-Meier Estimates	NA Months Interval 15.4 to Insufficient number of participants with events based on Kaplan-Meier Estimates

SECONDARY outcome

Timeframe: From the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment.

Population: The Safety Evaluable (SE) population defined as all treated patients within ARETHUSA trial (i.e. eligible as decided at the time of registration that receives at least 1 dose of any study treatment temozolomide or Pembrolizumab).

Safety and Tolerability according to CTCAE version 4.03

Outcome measures

Outcome measures
Measure	TMZ-primed MMR-proficient (MMRp) n=66 Participants MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) with High Tumor Mutational Burden post Temozolomide followed by pembrolizumab IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first.	MMR-deficient (MMRd) n=57 Participants Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Safety and Tolerability All treatment-related Adverse Event (AE), any grade	42 Number or patients	15 Number or patients
Safety and Tolerability All treatment-related Adverse Event (AE), grade ≥ 3	8 Number or patients	5 Number or patients

Adverse Events

MMR-proficient (MMRp)

Serious events: 14 serious events

Other events: 30 other events

Deaths: 6 deaths

MMR-deficient (MMRd)/TMZ-primed TMB-high MMR-proficient (MMRp)

Serious events: 20 serious events

Other events: 14 other events

Deaths: 13 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	MMR-proficient (MMRp) n=66 participants at risk MGMT-IHC-negative, MGMT promoter methylation-positive patient population treated with temozolomide (induction) until disease progression or unacceptable toxicity, whichever comes first.	MMR-deficient (MMRd)/TMZ-primed TMB-high MMR-proficient (MMRp) n=57 participants at risk MMRd and TMB-high TMZ-primed MMRp patients treated with pembrolizumab until tumor progression or discontinuation for toxicity.
Blood and lymphatic system disorders Anaemia	3.0% 2/66 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.	14.0% 8/57 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.
Blood and lymphatic system disorders Thrombocytopenia	9.1% 6/66 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.	0.00% 0/57 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.
Gastrointestinal disorders Nausea	27.3% 18/66 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.	5.3% 3/57 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.
Blood and lymphatic system disorders Neutropenia	9.1% 6/66 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.	0.00% 0/57 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.
General disorders Asthenia	4.5% 3/66 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.	5.3% 3/57 • All-Cause Mortality monitored/assessed up to 72 months. Adverse Events monitored/assessed from the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment. Toxicity were assessed using NCI CTCAE Version 4.03. All adverse events (AEs) occurring after the last administration of study treatment were recorded on the eCRF. The investigator decided if those events are drug related (not related, not likely, possibly, probably, certainly) and this decision was recorded on the forms for all AEs. AEs could be assessed directly by the Investigator during a clinical visit or based on laboratory/instrumental examinations or could be referred by the patients.

Additional Information

Luca Lazzari

IFOM ETS - The AIRC Institute of Molecular Oncology

Phone: +39 02 57430 3799

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place