臨床研究等提出・公開システム

A Phase 3 study of MK-4280A (coformulated favezelimab [MK-4280] plus pembrolizumab [MK-3475]) Versus Standard of Care in Previously Treated Metastatic PD-L1 positive Colorectal Cancer

MK-4280A Versus Standard of Care in Previously Treated Metastatic PD-L1 positive Colorectal Cancer

441

Favezelimab/Pembrolizumab group -Mean Age: 59.9 years -Sex: Female 37.6%, Male 62.4% -Ethnicity: Hispanic or Latino 8.6%, Not Hispanic or Latino 89.1%, Unknown or Not Reported 2.3% -Race: Asian 30.3%, Black or African American 2.3%, White 65.6%, Unknown or Not Reported 1.8% -Geographic Region: Asia Pacific 32.1%, Europe, the Middle East and Africa(EMEA)/Americas 67.9% -Presence of Liver Metastasis: Yes 77.8%, No 22.2% -Time from Initial Diagnosis of Metastatic Disease to Randomization: >=18 months 65.2%, <18 months 34.8% Standard of Care (Regorafenib or TAS-102) group -Mean Age: 57.6 years -Sex: Female 36.8%, Male 63.2% -Ethnicity: Hispanic or Latino 7.7%, Not Hispanic or Latino 89.1%, Unknown or Not Reported 3.2% -Race: Asian 29.5%, Black or African American 1.8%, White 66.8%, More Than One Race 0.9%, Unknown or Not Reported 0.9% -Geographic Region: Asia Pacific 31.8%, EMEA/Americas 68.2% -Presence of Liver Metastasis: Yes 78.6%, No 21.4% -Time from Initial Diagnosis of Metastatic Disease to Randomization: >=18 months 68.2%, <18 months 31.8% Total -Mean Age: 58.8 years -Sex: Female 37.2%, Male 62.8% -Ethnicity: Hispanic or Latino 8.2%, Not Hispanic or Latino 89.1%, Unknown or Not Reported 2.7% -Race: Asian 29.9%, Black or African American 2.0%, White 66.2%, More Than One Race 0.5%, Unknown or Not Reported 1.4% -Geographic Region: Asia Pacific 32.0%, EMEA/Americas 68.0% -Presence of Liver Metastasis: Yes 78.2%, No 21.8% -Time from Initial Diagnosis of Metastatic Disease to Randomization: >=18 months 66.7%, <18 months 33.3%

Favezelimab/Pembrolizumab group -Started: 221 participants -Treated: 221 participants -Completed: 0 participants -Not Completed: 221 participants (Death: 199 participants, Physician Decision: 4 participants, Sponsor Decision: 14 participants, Withdrawal by Subject: 4 participants) Standard of Care (Regorafenib or TAS-102) group -Started: 220 participants -Treated: 210 participants -Completed: 0 participants -Not Completed: 220 participants (Death: 196 participants, Physician Decision: 2 participants, Sponsor Decision: 11 participants, Withdrawal by Subject: 11 participants)

Percentage of participants with serious adverse events (SAEs) -Favezelimab/Pembrolizumab group: 33.94% (75/221 participants) -Standard of Care (Regorafenib or TAS-102) group: 26.67% (56/210 participants) SAEs with an incidence of >=1.0% -Favezelimab/Pembrolizumab group: Pyrexia (2.71%), Colitis (2.26%), Pneumonia (1.81%), Infusion related reaction (1.81%), Hyponatraemia (1.81%), Anaemia (1.36%), Adrenal insufficiency (1.36%), Sepsis (1.36%), Dehydration (1.36%) -Standard of Care (Regorafenib or TAS-102) group: Intestinal obstruction (1.43%), Pyrexia (1.43%), COVID-19 (1.43%), Urinary tract infection (1.43%), Pleural effusion (1.43%) Percentage of participants with non-serious adverse events with an incidence of >5% in one or more treatment groups -Favezelimab/Pembrolizumab group: 87.33% (193/221 participants) -Standard of Care (Regorafenib or TAS-102) group: 89.05% (187/210 participants) Non-serious adverse events with an incidence of >=15% -Favezelimab/Pembrolizumab group: Fatigue (23.98%), Decreased appetite (21.72%), Diarrhoea (16.29%), Hypothyroidism (15.84%), Nausea (15.84%) -Standard of Care (Regorafenib or TAS-102) group: Nausea (22.86%), Anaemia (22.86%), Palmar-plantar erythrodysaesthesia syndrome (21.43%), Fatigue (20.48%), Diarrhoea (20.00%), Neutropenia (16.67%), Neutrophil count decreased (15.24%)

Primary Outcome Efficacy Overall Survival (OS) -Analysis population: all randomized participants -Favezelimab/Pembrolizumab group: Median 7.3 months [95% confidence interval (CI):5.8 to 8.8] -Standard of Care (Regorafenib or TAS-102) group: Median 8.5 months (95% CI: 7.5 to 9.9) -Hazard ratio (HR): 0.98 (95% CI: 0.80 to 1.20), P-Value: 0.4183 [Stratified by geographic region (Asia Pacific; EMEA/Americas), presence of liver metastasis (Yes/No) and time from initial diagnosis of metastatic disease to randomization (>=18 months, <18 months)] Secondary Outcome Efficacy Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) -Analysis population: all randomized participants -Favezelimab/Pembrolizumab group: Median 2.1 months (95% CI: 2.1 to 2.1) -Standard of Care (Regorafenib or TAS-102) group: Median 2.6 months (95% CI: 2.2 to 3.3) -HR: 1.34 (95% CI: 1.09 to 1.64), P-Value: 0.9967 [Stratified by geographic region (Asia Pacific; EMEA/Americas), presence of liver metastasis (Yes/No) and time from initial diagnosis of metastatic disease to randomization (>=18 months, <18 months)] Objective Response Rate (ORR) per RECIST 1.1 as assessed by BICR -Analysis population: all randomized participants -Favezelimab/Pembrolizumab group: 6.8% (95% CI: 3.8 to 10.9) -Standard of Care (Regorafenib or TAS-102) group: 0.9% (95% CI: 0.1 to 3.2) -Difference in percentage: 5.9% (95% CI: 2.5 to 10.1), P-Value: 0.0007 Duration of Response (DOR) per RECIST 1.1 as assessed by BICR -Analysis population: all randomized participants who experienced a confirmed Complete Response (CR) or Partial Response (PR) -Favezelimab/Pembrolizumab group: Median Not available (NA) (95% CI: 5.7 to NA) -Standard of Care (Regorafenib or TAS-102) group: Median NA (95% CI: NA to NA) Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) and Quality of Life (QoL) (Item 30) Combined Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had at least one EORTC QLQ-C30 assessment data available -Favezelimab/Pembrolizumab group: Least Squares Mean -7.11 (95% CI: -9.95 to -4.26) -Standard of Care (Regorafenib or TAS-102) group: Least Squares Mean -4.03 (95% CI: -7.05 to -1.00) -Difference in Least Squares Means: -3.08 (95% CI: -7.09 to 0.93), P-Value: 0.1318 Change From Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had at least one EORTC QLQ-C30 assessment data available -Favezelimab/Pembrolizumab group: Least Squares Mean -7.13 (95% CI: -9.86 to -4.40) -Standard of Care (Regorafenib or TAS-102) group: Least Squares Mean -6.17 (95% CI: -9.08 to -3.27) -Difference in Least Squares Means: -0.95 (95% CI: -4.93 to 3.02), P-Value: 0.6370 Change From Baseline in EORTC QLQ-C30 Appetite Loss (Item 13) Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had at least one EORTC QLQ-C30 assessment data available -Favezelimab/Pembrolizumab group: Least Squares Mean 8.04 (95% CI: 3.93 to 12.15) -Standard of Care (Regorafenib or TAS-102) group: Least Squares Mean 4.18 (95% CI: -0.16 to 8.53) -Difference in Least Squares Means: 3.86 (95% CI: -1.85 to 9.57), P-Value: 0.1846 Change From Baseline in EORTC Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had at least one EORTC QLQ-CR29 assessment data available -Favezelimab/Pembrolizumab group: Least Squares Mean 4.33 (95% CI: 0.37 to 8.30) -Standard of Care (Regorafenib or TAS-102) group: Least Squares Mean 3.77 (95% CI: -0.44 to 7.98) -Difference in Least Squares Means: 0.56 (95% CI: -4.96 to 6.08), P-Value: 0.8410 Time to Deterioration (TTD) in EORTC QLQ-C30 Global Health Status (Item 29) and QoL (Item 30) Combined Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had EORTC QLQ-C30 assessment data available at baseline -Favezelimab/Pembrolizumab group: Median NA (95% CI: NA to NA) -Standard of Care (Regorafenib or TAS-102) group: Median NA (95% CI: 14.4 to NA) -HR: 1.00 (95% CI: 0.64 to 1.58), P-Value: 0.5094 TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Combined Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had EORTC QLQ-C30 assessment data available at baseline -Favezelimab/Pembrolizumab group: Median NA (95% CI: 9.1 to NA) -Standard of Care (Regorafenib or TAS-102) group: Median 20.3 months (95% CI: 10.9 to NA) -HR: 1.51 (95% CI: 0.98 to 2.33), P-Value: 0.9704 TTD in EORTC QLQ-C30 Appetite Loss (Item 13) Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had EORTC QLQ-C30 assessment data available at baseline -Favezelimab/Pembrolizumab group: Median NA (95% CI: NA to NA) -Standard of Care (Regorafenib or TAS-102) group: Median NA (95% CI: NA to NA) -HR: 1.82 (95% CI: 1.11 to 2.98), P-Value: 0.9905 TTD in EORTC QLQ-CR29 Bloating (Item 37) Score -Analysis population: all randomized participants who have received at least one dose of the study intervention and had EORTC QLQ-CR29 assessment data available at baseline -Favezelimab/Pembrolizumab group: Median NA (95% CI: 17.4 to NA) -Standard of Care (Regorafenib or TAS-102) group: Median NA (95% CI: NA to NA) -HR: 1.86 (95% CI: 1.06 to 3.26), P-Value: 0.9853 Safety Number of participants who experienced at least one adverse event (AE) -Analysis population: all randomized participants who received at least one dose of study intervention -Favezelimab/Pembrolizumab group: 92.8% (205/221 participants) -Standard of Care (Regorafenib or TAS-102) group: 94.8% (199/210 participants) Number of participants who discontinued study treatment due to an AE -Analysis population: all randomized participants who received at least one dose of study intervention -Favezelimab/Pembrolizumab group: 9.5% (21/221 participants) -Standard of Care (Regorafenib or TAS-102) group: 9.0% (19/210 participants)

Efficacy Favezelimab + pembrolizumab did not demonstrate a statistically significant improvement in OS when compared with standard of care in the patients with treatment refractory programmed cell death ligand 1 positive (Combined Positive Score >=1) microsatellite stable metastatic colorectal cancer. Safety The safety profile of favezelimab + pembrolizumab is manageable and is generally consistent with the established safety profile of pembrolizumab monotherapy. No new safety risks were identified.

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210482

Shimoyama Ryo

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

msdjrct@msd.com

inquiry mailbox MSDJRCT

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

+81-3-6272-1957

msdjrct@msd.com

Complete

Dec. 10, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

-Has a histologically confirmed colorectal adenocarcinoma that is metastatic and unresectable.
-Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by the local site investigator.
-Has been previously treated for the disease and radiographically progressed on or after or could not tolerate standard treatment.
-Submits an archival (<= 5 years) or newly obtained tumor tissue sample or newly obtained tumor tissue sample that has not been previously irradiated.
-Has an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1 within 10 days prior to first dose of study intervention.
-Has a life expectancy of at least 3 months, based on the investigator assessment.
-Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption.
-Has adequate organ function.

-Has previously been found to have deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumor status.
-Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease.
-Has a history of acute or chronic pancreatitis.
-Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
-Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
-Has urine protein greater than or equal to 1g/24h.
-A woman of childbearing potential who has a positive urine/serum pregnancy test within 24/72 hours prior to the first dose of study intervention.
-Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2), anti-lymphocyte activation gene 3 (LAG-3) antibody, with a tyrosine kinase inhibitor (TKI; eg, lenvatinib) other than rapidly accelerated fibrosarcoma (RAF) inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40, cluster of differentiation [CD] 137).
-Has previously received regorafenib or TAS-102.
-Has received prior systemic anticancer therapy including investigational agents within 28 days before randomization.
-Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<=2 weeks of radiotherapy) to non-CNS disease.
-Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
-Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
-Has severe hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its excipients.
-Has an active autoimmune disease that has required systemic treatment in past 2 years.
-Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
-Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections, etc.).
-Has a known history of human immunodeficiency virus (HIV) infection.
-Has a known history of Hepatitis B or known active Hepatitis C virus infection.
-Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
-Has had an allogenic tissue/solid organ transplant.

Both

Previously treated metastatic PD-L1 positive colorectal cancer

-MK-4280A (coformulated favezelimab 800 mg/pembrolizumab 200 mg), every 3 weeks (Q3W), intravenously (IV) infusion, for up to 35 infusions.

-Regorafenib
160 mg, 4-week cycle (daily, Days 1-21, no dose Days 22-28), Oral

-TAS-102
35 mg/m2, 4-week cycle (twice daily, Days 1-5 and Days 8-12, no dose Days 6, 7 and 13-28), Oral

Overall survival (OS)

-Progression free survival (PFS)
-Objective response rate (ORR)
-Duration of response (DOR)
-Safety and tolerability
-Change from baseline in global health status/Quality of Life (QoL), physical functioning, appetite loss and bloating
-Time to deterioration in global health status/QoL, physical functioning, appetite loss and bloating

+81-48-722-1111

Nov. 04, 2021

Australia/China/South Korea/Taiwan/Malaysia/Czech Republic/France/Germany/Israel/Italy/Norway/Russia/Spain/South Africa/Turkey/UK/Ukraine/Chile/Canada/USA