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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P170019 S043/ PAS001 |
| Date Original Protocol Accepted |
12/01/2023
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| Date Current Protocol Accepted |
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| Study Name |
RET Fusion Clinical Efficacy PAS for Selpercatinib
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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 |
No Control
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| Analysis Type |
Descriptive
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| Study Population |
Child: 2 yrs < 12 yrs,
Adolescent: 13-18 yrs,
Transit.Adolescent A (distinctively):18 yrs<22 yrs,
Transit.Adolescent B(as adults): 18 yrs < 22 yrs,
Adult: At least 22 yrs
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| Detailed Study Protocol Parameters |
| Study Objectives |
The purpose and objective of the PAS will be to confirm the clinical effectiveness of F1CDx as a CDx device for identification of patients with
solid tumors with RET fusions, who may benefit from treatment with selpercatinib, by evaluating the objective response rate (ORR) for tissue
agnostic patients from the LIBRETTO-001 clinical trial.
The RET fusion-positive (i.e., clinical trial assay positive (CTA+)) samples from LIBRETTO-001 clinical trail will be used (i.e., patients enrolled under
tissue agnostic). The clinical registrational samples from the LIBRETTO-001 clinical trial have already been evaluated by the CTA for enrollment
purposes. The qualifying RET fusions are summarized in QSR-BPM-062: RET biomarker definition to support the selpercatinib CDx claim in the US,
European Union (EU), and Japan using F1CDx.
Approximately 29 TA patients enrolled in LIBRETTO-001 with available FFPE for F1CDx testing will be evaluated in this study (Table 6.1 below).
TA patients were enrolled in LIBRETTO-001 as RET fusion positive by a local test result (i.e. CTA+) and retrospectively tested by F1CDx. Among
the up to approximately 29 CTA+ TA patient samples, approximately 15 were previously tested under the clinical bridging study for the US (QSRVAL-
RPT-410-02, evaluated under P170019/S043), approximately six were previously tested under the clinical bridging study for Japan (QSR-VALRPT-
425-02), and an estimated eight will be available from patients who were enrolled into LIBRETTO-001 until a later enrollment cutoff date (Q1
2024) and will be tested by F1CDx for the purposes of the PAS.
Approximately eight unique FFPE tissue samples will be prospectively obtained from TA patients enrolled in the LIBRETTO-001 trial and
processed in this study. Final numbers will be provided in the study report. The ORR will be calculated using Response Evaluation Criteria in Solid
Tumors Version 1.1 (RECIST 1.1), consistent with the LIBRETTO-001 clinical study protocol. The ORR will be defined as the observed proportion
of patients whose best overall response is confirmed complete response (CR) or partial response (PR), as determined by an independent review
committee (IRC) and by the treating Investigator, and will be accompanied by a two-sided 95% confidence interval (CI) when applicable. The ORR
will be calculated using a clinical cutoff date (for clinical outcomes) planned for Q2 2025 for all approximately 29 CTA-positive TA patients
with a valid F1CDx test result (F1CDx evaluable). The ORR will be reported for the following groups:
CTA + TA patients that are RET fusion positive as determined by CTA.
F1CDx + CTA + TA patients that are RET fusion positive by both CTA and by F1CDx.
F1CDx - CTA + TA patients that are RET fusion positive by CTA but RET fusion negative by F1CDx.
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| Study Population |
RET fusion positive tissue agnostic patients Samples meeting the pre-defined criteria specified below will be included.
Inclusion Criteria
. FFPE tissue samples (blocks or slides)
. DNA derived from FFPE samples
. Samples obtained in accordance with QA-028, POL-01008, and IRB-approved protocols
. Samples obtained in accordance with IRB#:120160955, Use of Leftover Nucleic Acid Samples
that are Not Individually Identifiable for Analytical Validation Studies (FMI)
. Sample that meet minimum criteria for F1CDx testing operational requirements.
. Samples from the LIBRETTO-001 clinical trial with proper informed consent
Exclusion Criteria
. Samples failing to meet any of the inclusion criteria. LIBRETTO-001 clinical trial samples that lack clear identification or labeling
Samples not obtained in accordance with QA-028 and POL-01008 or not receiving IRB approval. Samples not obtained in accordance with IRB#:
120160955, Use of Leftover Nucleic Acid Samples that are Not Individually Identifiable for Analytical Validation Studies (FMI)
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| Sample Size |
A total of up to approximately 29 TA patients enrolled in LIBRETTO-001, with available FFPE for F1CDx testing, will be evaluated in this study. TA
patients were enrolled in LIBRETTO-001 as RET fusion positive by a local test result (i.e., CTA positive) and retrospectively tested by F1CDx. Among
the up to approximately 29 CTA-positive TA patient samples, ~15 will be from the clinical bridging study for the US, ~6 will be from the clinical
bridging study for Japan, and an estimated ~8 will be available from patients who were enrolled into LIBRETTO- 001 until a later enrollment
cutoff date (Q1 2024) and tested by F1CDx for the purposes of this post approval study.
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| Key Study Endpoints |
To evaluate the clinical effectiveness of selpercatinib for TA patients with RET fusions from LIBRETTO-001, the ORR will be calculated using
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), which is consistent with that in the LIBRETTO-001 clinical study protocol.
The ORR will be defined as the observed proportion of patients whose best overall response is confirmed complete response (CR) or partial response
(PR) as determined by independent review committee (IRC) and by the treating Investigator and will be accompanied by a two-sided 95%
confidence interval (CI) when applicable. The ORR will be calculated using a clinical cutoff date (for clinical outcomes) planned for Q2 2025 for all
approximately 29 CTA-positive TA patients with a valid F1CDx test result (F1CDx evaluable). The ORR will be reported for the following groups:
CTA + TA patients that are RET fusion positive as determined by CTA.
F1CDx + CTA + TA patients that are RET fusion positive by both CTA and by F1CDx.
F1CDx - CTA + TA patients that are RET fusion positive by CTA but RET fusion negative by F1CDx.
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| Follow-up Visits and Length of Follow-up |
For safety follow up: 28 days (+7 days) after final dose of study drug.
For long-term follow up: approximately every 3 month (-/+ 1 month) after that last dose of study drug.
Long term follow up will occur until the patient has withdrawn consent for further participation, is lost to follow up, has died, or the Sponsor makes a
decision to close the study.
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
A total of 34 valid F1CDx test results were obtained from 39 tissue-agnostic (TA) CTA-positive patients from the LIBRETTO-001 clinical trial, including 15 subjects from the US clinical bridging study, 6 subjects from the Japan clinical bridging study, and 18 newly enrolled post-approval study subjects, utilizing formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens. Five samples from the post-approval cohort failed DNA extraction QC, yielding 34 evaluable samples (87.2% evaluability rate).
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| Actual Number of Sites Enrolled |
N/A
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| Patient Follow-up Rate |
N/A
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| Final Safety Findings |
N/A
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| Final Effect Findings |
An additional post-approval study was conducted to evaluate the clinical effectiveness of F1CDx for RET fusion detection by testing 39 tissue-agnostic CTA-positive patients from the LIBRETTO-001 clinical trial, obtaining 34 valid F1CDx results (87.2% evaluability rate), including 15 subjects from the US F1CDx clinical bridging study previously reported in sPMA P170019/S043, 6 subjects from the Japan F1CDx clinical bridging study, and 18 newly enrolled subjects from the post-approval study for selpercatinib, utilizing formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from the LIBRETTO-001 clinical trial. The ORR in the F1CDx RET fusion positive and clinical trial assay (CTA) positive population (F1CDx+|CTA+) was 61.54% (16/26) [95% CI: 42.53%, 77.57%], which is similar to the ORR observed in the original sPMA dataset of 61.54% (8/13) [95% CI: 35.1%, 88.0%], and comparable to the ORR of the F1CDx-evaluable CTA-positive population (n=34) of 58.82% [95% CI: 42.22%, 73.63%]. The results of the post-approval study further confirmed the clinical effectiveness of F1CDx to identify patients with solid tumors with RET fusions that may benefit from RETEVMO (selpercatinib) therapy.
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| Study Strengths & Weaknesses |
The concordance analysis in the PAS results shows a positive percent agreement (PPA) for RET fusions of 76.5% (26/34), lower than the 86.7% (13/15) observed in the sPMA P170019/S043, with a discordance rate of 23.5% (8/34). Critically, 50% (4/8) of F1CDx-negative but CTA-positive patients responded to selpercatinib, including 100% response rates in neuroendocrine (1/1) and salivary (1/1) tumors. The discordances appear driven by technological differences between DNA-based F1CDx and RNA-based CTAs (~75% of discordant responders enrolled with RNA-based assays in sPMA analysis), F1CDx biomarker definition criteria (in-strand orientation, 3' RET positioning, breakpoint before kinase domain), contamination algorithm filtering, and technical factors (low tumor purity). Therefore, F1CDx as a DNA-based assay misses a significant number of patients (approximately 12% of evaluable patients, 4/34) who have RET fusions and may benefit from RETEVMO therapy, particularly in neuroendocrine and salivary gland tumors. A limitation to address this issue is already included in device labeling.
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| Recommendations for Labeling Changes |
A summary of the PAS study results should be added to the technical information document. The final text will be finalized during the review of the labeling PMA supplement that FMI should submit 30 days after the completion of the review of P170019/R073.
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