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General |
Study Status |
Completed |
Application Number / Requirement Number |
P170019 S029/ PAS001 |
Date Original Protocol Accepted |
04/13/2022
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Date Current Protocol Accepted |
 
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Study Name |
MK-3475 MSI-H FMI F1CDx Post Approval Analysis
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Device Name |
FoundationOne CDx (F1CDx)
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General Study Protocol Parameters |
Study Design |
Retrospective Cohort Study
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Data Source |
Sponsor Registry
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Comparison Group |
Historical Control
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Analysis Type |
Descriptive
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Detailed Study Protocol Parameters |
Study Objectives |
The purpose of this study is to confirm in a post marketing setting the clinical effectiveness of the F1CDx as a companion diagnostic in identifying MSI-H solid tumor patients for treatment with pembrolizumab. While the clinical validity of the F1CDx for this intended use has been established in the sPMA (P170019/S029) by demonstrating a clinically meaningful response to pembrolizumab in MSI-H solid tumor patients identified by the F1CDx (ORR: 43.0%, 95% CI: [33.5, 52.9]), the intent of the proposed study is to show that the response rate to treatment with pembrolizumab seen in the additional F1CDx-positive participants included in this analysis are qualitatively similar to the previously established (P170019/S029) response rate. The primary objective of this study is to estimate the objective response rate (ORR) for pembrolizumab treatment among clinical study subjects whose archived solid tumor specimens are MSI-H as determined by retrospective testing with the F1CDx (CDx). Primary analysis will be based on subjects with complete CDx status, and sensitivity analysis will include subjects with and without CDx results. The missing CDx results will be imputed in the sensitivity analysis. The imputation model obtained using the sPMA primary efficacy population (KN164 + KN158 cohort K post amendment 7) will be applied. The key estimate of interest is the objective response rate (ORR): the proportion of subjects with best overall response being PR or CR among patients whose tumors are MSI-H by the CDx. Duration of response (DOR) will be reported as an additional endpoint.
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Study Population |
This study consists of 41 additional participants from KN158 Cohort K that were not included in PMA Supplement P170019/S029. Cohort K in KN-158 is an ongoing multicenter, global, open-label, single-arm cohort of pembrolizumab in participants with any advanced MSI-H/dMMR solid tumor (except CRC) that was incurable and for which prior standard first-line treatment had failed. MSI/MMR status was determined locally for enrollment eligibility determination. As this is a single-arm trial, there is no control arm and participants were not randomized. KN158 Cohort K enrolled a total of 355 participants with MSI-H/dMMR tumors; enrollment is complete. The 41 participants included in the proposed study have been enrolled and treated with pembrolizumab. Data from these participants was not included in the sPMA (P170019/S029) because they either did not have 26 weeks of follow-up (31 patients) by the data cut-off date of October 5, 2022 or samples (from 10 participants) were inadvertently not sent to FMI for MSI testing, despite being eligible for the efficacy population of the sPMA dataset. These 10 samples were subsequently sent to FMI for MSI testing. Thus, the total number of participants with F1CDx MSI testing results that will be included in the proposed study is 41 (16 patients with endometrial cancer, 14 with gastric cancer, 1 with anal cancer, 2 with breast cancer, 2 with cervical cancer, 4 with glioma, 1 with ovarian cancer and one with small intestine cancer). Among the 41 participants whose samples were tested by the CDx, 21 had F1CDx-positive status (10 with endometrial cancer, and 11 with gastric cancer), 10 had F1CDx-negative status (1 with cervical cancer, 5 with endometrial cancer, 3 with glioma and 1 with small intestine) and 10 had non-evaluable CDx status due to failing CDx QC metrics. It is anticipated that the primary population for efficacy analysis will be the 21 CDx positive patients, supplemented by a missing data sensitivity analysis imputing CDx status in the 10 non-evaluable patients via application of the same imputation model built for the sPMA.
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Sample Size |
A total of 41 patients (21 F1CDx-positive, 10 F1CDx-negative and 10 F1CDx-nonevaluable)
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Key Study Endpoints |
Primary Endpoints: Investigator-assessed Objective Response Rate (ORR) The primary efficacy endpoint is Objective Response Rate (ORR) by RECIST v1.1 as assessed by the investigator. Sensitivity Analysis A sensitivity analysis based on multiple imputation of CDx status to incorporate clinical outcome data for the 10 nonevaluable participants will also be performed. Secondary endpoints: ORR will also be assessed in subjects with observed CDx-negative and CDx-non-evaluable status. DOR may be descriptively analyzed given that responder sample size is not large enough per each CDx status (CDx-positive, CDx-negative, and CDx-non-evaluable).
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Follow-up Visits and Length of Follow-up |
26 weeks
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Interim or Final Data Summary |
Actual Number of Patients Enrolled |
Forty-one (41)
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Actual Number of Sites Enrolled |
20 sites across 9 countries
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Patient Follow-up Rate |
At least 26 weeks of follow up
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Final Safety Findings |
N/A
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Recommendations for Labeling Changes |
“An additional post approval study was conducted to evaluate the clinical effectiveness of F1CDx by retrospectively testing 41 patient samples from patients with non-CRC solid tumors with MSI-H/dMMR status as determined by CTAs enrolled and treated in Keynote 158 cohort K with KEYTRUDA. Of these 41 patient samples, 31 patients had F1CDx results that passed QC criteria, i.e., yielded evaluable/valid results with F1CDx. Of the 31 patients with F1CDx evaluable results, 21 were confirmed by F1CDx as MSI-H. The remaining 10 patients did not have MSI-H status confirmed by F1CDx; 8 patients had MSS status and 2 had MSI-cannot be determined status due to MSI scores being >0.0041 but <0.0124. The ORR in the 21 patients with confirmed MSI-H by F1CDx was 42.9%; 95% CI: 21.8, 66.0. The ORR in the 10 patients that did not have MSI-H status confirmed by F1CDx was 30%; 95% CI: 6.7, 65.2. The ORR in the F1CDx non-evaluable population was 10%; 95%CI (0.3, 44.5). The results of the post approval study further confirmed the clinical effectiveness for F1CDx to identify patients with solid tumors with MSI-H status that may benefit from KEYTRUDA therapy.”
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