KEYTRUDA® for metastatic MSI-H/dMMR CRC, in the first-line setting1
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Explore KEYTRUDA® In the KEYNOTE-177 trial for patients with metastatic MSI-H/dMMR CRC
KEYNOTE-177: Active-controlled trial of KEYTRUDA® in the first-line setting for patients with metastatic MSI-H or dMMR colorectal cancer1
Trial overview1
- Randomized, multicenter, open-label, active-controlled trial
- Treatment arms were KEYTRUDA® vs chemotherapy#
- Encompassed 307 patients with previously untreated metastatic MSI-H or dMMR CRC
- MSI or MMR tumour status was determined locally using PCR or IHC, respectively
- Patients were randomized (1:1) to either treatment arm
- Patients with an autoimmune disease or a medical condition that required immunosuppression were excluded from the study
Treatment arms1
KEYTRUDA® 200 mg IV Q3W
Investigator’s choice of the following chemotherapy regimens IV Q2W
mFOLFOX6 or mFOLFOX6 in combination with either bevacizumab or cetuximab: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
or
FOLFIRI or FOLFIRI in combination with either bevacizumab or cetuximab: irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
- Treatment with KEYTRUDA® or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity.
- Patients treated with KEYTRUDA® without disease progression could be treated for up to 24 months or 35 administrations, whichever was longer.
- Treatment with KEYTRUDA® could be re-initiated for subsequent disease progression and administered for up to one additional year.
- Assessment of tumour status was performed every 9 weeks for the first 45 weeks and every 12 weeks thereafter.
- Patients randomized to chemotherapy were offered KEYTRUDA® at the time of disease progression.
Primary endpoints
- Progression-free survival, as assessed by BICR using RECIST 1.1
- Overall survival
Secondary endpoint
- Objective response rate, as assessed by BICR according to RECIST 1.1
BICR: blinded independent central review; CI: confidence interval; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; criteria in solid tumors; HR: hazard ratio; MSI-H: high microsatellite instability; ORR: objective response rate; Q3W: every 3 weeks; RECIST: response evaluation;
*Based on Cox regression model
†Based on log-rank test
*Assessed by BICR according to RECIST v1.1
#Investigator’s choice of chemotherapy regimen were mFOLFOX6 (oxaliplatin, leucovorin, and fluororacil), omFOLFOX6 in combination with either bevacizumab or cetuximab, FOLFIRI (irinotecan, leucovorin, and fluororacil) or FOLFIRI in combination with either bevacizumab or cetuximab.Progression-free Survival (Intent to Treat Population)1
40% reduction in the risk of progression or death with KEYTRUDA® vs Chemotherapy HR=0.60* (95% CI: 0.45, 0.80; p=0.0002†)
KEYTRUDA®
200 mg Q3W
n=153Chemotherapy
n=154
PFS154%
82/153 patients with event73%
113/154 patients with eventMedian PFS1(95% CI)16.5 months (5.4, 32.4)8.2 months (6.1, 10.2)Kaplan-Meier Curve for Progression-Free Survival in the KEYNOTE-177 trial (Intent to Treat Population)
Overall Survival (Primary Endpoint)
- The protocol-specified final analysis for OS was performed 12 months after PFS analysis with 62/140 patient events for KEYTRUDA® vs 78/140 events for chemotherapy
- There was no statistically significant difference between KEYTRUDA® and chemotherapy. The HR for OS was 0.74 (95% CI: 0.53, 1.03), with a p-value of 0.0359 (based on log-rank test compared to a significance level of 0.0246).
- mOS was not reached (95% CI: 49.2 months, NR) for KEYTRUDA® and was 36.7 months (95% CI: 27.6 months, NR) for chemotherapy.
- 60% of patients who had been randomized to receive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies including KEYTRUDA®.
Objective Response Rate (Secondary Endpoint)
44% Objective response rate with KEYTRUDA® vs 33% with Chemotherapy1
KEYTRUDA®
200 mg Q3W
n=153Chemotherapy
n=154
Objective response rate44%
(35.8, 52.0)33%
(25.8, 41.1)Complete response rate11%4%Partial response rate33%29%BICR: blinded independent central review; CI: confidence interval; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; criteria in solid tumors; HR: hazard ratio; MSI-H: high microsatellite instability; ORR: objective response rate; Q3W: every 3 weeks; RECIST: response evaluation;
*Based on Cox regression model
†Based on log-rank test
*Assessed by BICR according to RECIST v1.1
#Investigator’s choice of chemotherapy regimen were mFOLFOX6 (oxaliplatin, leucovorin, and fluororacil), omFOLFOX6 in combination with either bevacizumab or cetuximab, FOLFIRI (irinotecan, leucovorin, and fluororacil) or FOLFIRI in combination with either bevacizumab or cetuximab.KEYTRUDA® demonstrated safety profile in patients with metastatic MSI-H/dMMR colorectal cancer vs chemotherapy.
The most common grades 3-5 treatment-related adverse events for patient treated with KEYTRUDA® were:
Adverse ReactionKEYTRUDA®
200 mg every 3 weeks
(n=153) (%)Chemotherapy
(n=143)(%)Diarrhea2.09.8Fatigue2.09.1Alanine aminotransferase increased2.00.7Colitis2.00- 22.2% of patients had ≥ Grade 3 treatment-related adverse events.
- Treatment-related adverse events leading to discontinuation of KEYTRUDA® occurred in 9.8% of patients.
- The most common treatment-related adverse events leading to discontinuation (occurring in more than 1 patient) were: alanine aminotransferase increased (n=2), autoimmune colitis (n=2), colitis (n=2), and hepatitis (n=2).
- The median time to discontinuation for treatment-related adverse events was 6.3 months.
Treatment-related adverse events, any grades (reported in ≥10% of patients) were:1
Adverse ReactionKEYTRUDA®
200 mg every 3 weeks
(n=153)(%)Chemotherapy
(n=143)(%)Diarrhea24.8052.40Fatigue20.9044.10Decreased appetite17.8034.30Pruritus13.704.90Nausea12.4055.20Aspartate aminotransferase increased11.104.90Rash11.107.70Arthralgia10.501.40Hypothyroidism10.500Asthenia7.2017.50Anemia5.9011.90Stomatitis5.2030.10Alopecia3.3019.60Vomiting3.3028Dizziness2.6010.50Mucosal inflammation2.6017.50For the complete list of treatment-related adverse events, please consult the Product Monograph.
BICR: blinded independent central review; CI: confidence interval; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; criteria in solid tumors; HR: hazard ratio; MSI-H: high microsatellite instability; ORR: objective response rate; Q3W: every 3 weeks; RECIST: response evaluation;
*Based on Cox regression model
†Based on log-rank test
*Assessed by BICR according to RECIST v1.1
#Investigator’s choice of chemotherapy regimen were mFOLFOX6 (oxaliplatin, leucovorin, and fluororacil), omFOLFOX6 in combination with either bevacizumab or cetuximab, FOLFIRI (irinotecan, leucovorin, and fluororacil) or FOLFIRI in combination with either bevacizumab or cetuximab.
KEYTRUDA® for metastatic MSI-H/dMMR CRC, in the second-line setting1
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Explore KEYTRUDA® In KEYNOTE-164 trial for patients with metastatic MSI-H/dMMR CRC
KEYNOTE-164: A single-arm open-label trial of KEYTRUDA® in patients with advanced MSI-H or dMMR colorectal cancer (CRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1
Trial overview1
- Nonrandomized, single-arm multicenter, open-label phase II trial
- Patients received KEYTRUDA® 200 mg every 3 weeks until unacceptable toxicity or disease progression
- Encompassed 61 patients with metastatic MSI-H or dMMR CRC
- Patients with an autoimmune disease or a medical condition that required immunosuppression were excluded from the study
- Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed
- Patients without disease progression were treated for up to 24 months
- Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to one additional year
- Assessment of tumour status in the KEYNOTE-164 trial was performed every 9 weeks
Treatment arm1
KEYTRUDA® 200 mg IV Q3W
Major Efficacy Outcomes*1
- Overall response rate, assessed by BICR using RECIST 1.1
- Duration of response, assessed by BICR using RECIST 1.1
Secondary Outcomes
- Time to response
BICR: blinded independent central review; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; DOR: duration of response; ORR: objective response rate; MSI-H: high microsatellite instability; Q3W: every 3 weeks; RECIST: response evaluation criteria in solid tumors
* Assessed by BICR using RECIST 1.1
‡ Based on Kaplan-Meier estimates; include 14 patients with response of 6 months or longer
† The safety profile information refers to a combination of data of both KEYNOTE-164 and KEYNOTE-158.Objective Response Rate
28% Objective response rate with KEYTRUDA® (95% CI: (17.1, 40.8)) for patients with MSI-H or dMMR CRC (n=61)
- Complete Response : 0%
- Partial Response : 28%
Duration of Response
82%‡ with Duration of Response ≥ 6 months with KEYTRUDA® for patients with MSI-H or dMMR CRC previously treated with either ≥1 prior line or with 2 or more prior lines of therapy1‡
KEYTRUDA®200 mg Q3W (n=61)Duration of Response* (median in months [range])Time to Response (secondary endpoint), median in months [range]82% with DOR ≥ 6 months (NR [2.9+, 12.5+])4.0 months [1.8, 10.4]BICR: blinded independent central review; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; DOR: duration of response; ORR: objective response rate; MSI-H: high microsatellite instability; Q3W: every 3 weeks; RECIST: response evaluation criteria in solid tumors
* Assessed by BICR using RECIST 1.1
‡ Based on Kaplan-Meier estimates; include 14 patients with response of 6 months or longer
† The safety profile information refers to a combination of data of both KEYNOTE-164 and KEYNOTE-158.KEYTRUDA® demonstrated safety profile in previously-treated patients with metastatic MSI-H/dMMR colorectal cancer.1†
The most common grades 3-5 treatment-related adverse events were†1:
Adverse ReactionKEYTRUDA® 200mg Q3W
(n=155) (%)
Pancreatitis1.9Blood alkaline phosphatase increased1.9Gamma-glutamyltransferase increased1.9- Fourteen percent of patients had ≥ Grade 3 adverse events
- Treatment-related adverse events leading to discontinuation of KEYTRUDA® occurred in 4.5% of patients with MSI-H cancer
- The most common treatment-related adverse events leading to study drug discontinuation (occurring in 2 or more patients) were: pneumonitis (n=2, 1.3%); and blood alkaline phosphatase increased (n=2, 1.3%)
- The median time to discontinuation for treatment-related adverse events was 0.7 months
Treatment-related adverse events, any grades (reported in ≥10% of patients) were:1†
Adverse ReactionKEYTRUDA® 200mg Q3W
(n=155) (%)
Diarrhea11Nausea11Fatigue11Pruritus11.6For the complete list of treatment-related adverse events, please consult the Product Monograph.
BICR: blinded independent central review; CRC: colorectal cancer; dMMR: mismatch-repair deficiency; DOR: duration of response; ORR: objective response rate; MSI-H: high microsatellite instability; Q3W: every 3 weeks; RECIST: response evaluation criteria in solid tumors
* Assessed by BICR using RECIST 1.1
‡ Based on Kaplan-Meier estimates; include 14 patients with response of 6 months or longer
† The safety profile information refers to a combination of data of both KEYNOTE-164 and KEYNOTE-158.
References:
- 1. KEYTRUDA® Product Monograph. Merck Canada Inc. April 19, 2023.
- 2. Mayo Clinic. Microsatellite Instability, Tumor. Available at: https://www.mayocliniclabs.com/test-catalog/Overview/609364. Accessed February 14, 2022.
- 3. College of American Pathologists. POET Report: Prognostic Uses of MSI Testing. Available at: https://webapps.cap.org/apps/docs/committees/technology/microsatellite_testing.pdf. Accessed February 14, 2022.
- 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V1.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed April 11, 2022.
- 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V1.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed April 11, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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