DRAFT — PRIVILEGED AND CONFIDENTIAL — NOT FOR SUBMISSION — PREPARED FOR INTERNAL REVIEW ONLY
MolDx Technical Assessment Dossier
OncoPrecise GXP-47
Submitted for Technical Assessment Review Under the Molecular Diagnostic Services (MolDx) Program
Version 1.0 — DRAFT
April 30, 2024
Prepared for Submission to:
Ridgeline Administrative Services, LLC 1600 Hampton Street, Suite 700 Columbia, SC 29201
Attention: Dr. Catherine Embry, PhD
MolDx Technical Assessment Director
Submitted on Behalf of:
Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130
Prepared by:
Calderwood & Harkness LLP Healthcare & Life Sciences Practice Group 1700 K Street NW, Suite 900 Washington, DC 20006
Engagement Team:
Miriam Calloway, Partner Joel Strauss, Partner Sean Morrissey, Senior Associate Christopher Aiken, Associate
Calderwood & Harkness Matter No.: 1043-00002
DRAFT — PRIVILEGED AND CONFIDENTIAL — NOT FOR SUBMISSION — PREPARED FOR INTERNAL REVIEW ONLY
This document has been prepared by Calderwood & Harkness LLP at the direction of Genome Dx Therapeutics Inc. for the sole purpose of internal review and preparation prior to formal submission to the MolDx program administered by Ridgeline Administrative Services, LLC. This document is protected by the attorney-client privilege and attorney work product doctrine. No portion of this document may be reproduced, distributed, or disclosed to any third party without the prior written consent of Genome Dx Therapeutics Inc. and Calderwood & Harkness LLP.
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EXECUTIVE SUMMARY
Genome Dx Therapeutics Inc. ("GDT" or the "Company") is a clinical-stage molecular diagnostics company specializing in the development and commercialization of next-generation sequencing ("NGS")-based genomic tests for oncology applications. GDT was founded in 2018 by Dr. Anisha Raval, PhD, and Dr. Marcus Yuen, MD, PhD, and is incorporated in the State of Delaware with its principal place of business and sole laboratory facility located at 4720 Torrey Pines Road, Suite 300, San Diego, California 92130. Since its founding, GDT has established itself as an innovative participant in the molecular diagnostics industry, with a focused research and development pipeline aimed at addressing critical unmet needs in precision oncology.
GDT operates a single Clinical Laboratory Improvement Amendments ("CLIA")-certified, College of American Pathologists ("CAP")-accredited reference laboratory at its San Diego headquarters. The laboratory holds CLIA Certificate No. 05D2187432 and CAP Accreditation No. 9074821. GDT's National Provider Identifier ("NPI") is 1902847365, and its Employer Identification Number ("EIN") is 83-2947156. The laboratory has maintained continuous CLIA certification and CAP accreditation since its initial certification in 2019, with no deficiency findings on its most recent biennial CAP inspection. GDT's intellectual property portfolio includes 14 issued United States patents and 7 pending United States patent applications related to the OncoPrecise genomic profiling platform, encompassing the gene panel composition, the bioinformatics pipeline, and the proprietary Therapy Response Index scoring algorithm.
This dossier is submitted in support of the technical assessment of OncoPrecise GXP-47, a 47-gene RNA expression panel performed on formalin-fixed, paraffin-embedded ("FFPE") tumor tissue obtained from patients with Stage IIIB or Stage IV non-small-cell lung cancer ("NSCLC"). The OncoPrecise GXP-47 assay produces a composite Therapy Response Index ("TRI") score on a scale of 0 to 100, which is designed to predict the likelihood of a patient's response to immune checkpoint inhibitor ("ICI") therapy. The TRI score stratifies patients into three clinically actionable categories: High Likelihood of Response (TRI ≥ 70), Intermediate (TRI 40–69), and Low Likelihood of Response (TRI < 40). The test is a laboratory-developed test ("LDT") performed exclusively at GDT's San Diego reference laboratory.
The clinical need for OncoPrecise GXP-47 is substantial. Advanced NSCLC remains the leading cause of cancer death in the United States, and while immune checkpoint inhibitor therapy — including pembrolizumab, nivolumab, and atezolizumab — has transformed the treatment landscape, response rates remain variable, ranging from approximately 20% to 45% depending on biomarker status, histologic subtype, and other clinical factors. Existing biomarkers for ICI response prediction, most notably programmed death-ligand 1 ("PD-L1") expression by immunohistochemistry ("IHC") and tumor mutational burden ("TMB"), are imperfect predictors with well-documented limitations. There is a significant and widely recognized unmet clinical need for a more accurate, integrative genomic tool to guide oncologist decision-making regarding the selection of first-line ICI therapy versus platinum-based chemotherapy in patients with advanced NSCLC. OncoPrecise GXP-47 is designed to address this critical gap.
The purpose of this dossier is to support the technical assessment of OncoPrecise GXP-47 by the MolDx program, administered by Ridgeline Administrative Services, LLC, as a prerequisite to a local coverage determination ("LCD") by Cascade Fiscal Intermediaries, LLC ("CFI"), the Medicare Administrative Contractor ("MAC") for Jurisdiction E, which includes the State of California. GDT has a demonstrated track record with the MolDx program and the CFI MAC: GDT's existing commercial product, OncoPrecise GXP-12 (a 12-gene RNA expression panel for early-stage breast cancer prognosis), received a favorable LCD (LCD L38472, effective August 15, 2021, issued by CFI) following successful MolDx technical assessment. GDT believes that the quality of its laboratory operations, the rigor of its validation methodology, and its history of successful engagement with the MolDx program provide a strong foundation for the assessment of OncoPrecise GXP-47.
GDT is pursuing a Proprietary Laboratory Analyses ("PLA") code for OncoPrecise GXP-47. The PLA code application has been prepared and is targeted for submission to the American Medical Association ("AMA") CPT Editorial Panel in advance of the September 2024 meeting, with a submission deadline of June 28, 2024. GDT's target Medicare reimbursement rate for OncoPrecise GXP-47 is $3,850 per test, a rate supported by crosswalk pricing analysis against comparable NGS-based oncology panels and justified by the proprietary nature of the TRI algorithm, the complexity of the 47-gene panel, and the predictive (rather than merely prognostic) clinical application of the test in the context of high-cost ICI therapy selection.
The evidence base supporting OncoPrecise GXP-47 encompasses the following key components:
• Analytical Validation: A comprehensive analytical validation study was completed on December 14, 2022, and published in the Journal of Molecular Oncology Diagnostics (Volume 18, Issue 4, pp. 412–429, December 2022). The study demonstrated that OncoPrecise GXP-47 meets or exceeds all pre-specified acceptance criteria for analytical sensitivity, specificity, accuracy, precision, reproducibility, reportable range, specimen stability, and interfering substance assessment.
• Clinical Validation: GDT has implemented a two-component clinical validation strategy comprising (a) retrospective cohort studies conducted during algorithm development and preliminary validation, and (b) a prospective, multi-site, blinded clinical validation study designated CLARITY-LUNG (Clinical Assessment of RNA-based Immunotherapy Treatment Yield in Lung Cancer Using NGS Genomics; ClinicalTrials.gov Identifier: NCT05891247). CLARITY-LUNG is currently enrolling, with 847 of 1,200 targeted patients enrolled as of May 2024 (70.58% of target enrollment). A pre-planned interim analysis at 50% enrollment (n = 600) was performed on March 29, 2024, yielding a positive predictive value ("PPV") of 0.68 and a negative predictive value ("NPV") of 0.71. While these interim results are encouraging in their directionality, they did not meet the pre-specified performance thresholds of PPV ≥ 0.75 and NPV ≥ 0.80. The Data Safety Monitoring Board ("DSMB"), chaired by Dr. Evelyn Matsuda, MD, PhD, met on April 5, 2024, and recommended continuation of enrollment, characterizing the interim results as "inconclusive and below pre-specified performance benchmarks." Final CLARITY-LUNG data are projected for Q2 2025.
• Health Economic Analysis: A health economics and outcomes research ("HEOR") analysis has been prepared by Larkfield Health Economics, LLC, under the direction of Dr. Nathan Ostroff, PhD, MS, Principal Consultant. The analysis includes a cost-effectiveness model and budget impact model from the Medicare payer perspective, demonstrating preliminary cost-effectiveness at the proposed $3,850 reimbursement rate.
This dossier is a draft prepared for GDT's internal review prior to formal submission to the MolDx program. The dossier will require substantial revision upon availability of final CLARITY-LUNG trial data before it is suitable for formal submission. The current draft is intended to allow GDT's leadership, scientific advisors, and legal counsel to review the completeness and organization of the submission, identify areas requiring additional data or analysis, and assess the strategic positioning of OncoPrecise GXP-47 for technical assessment and subsequent LCD review.
SECTION 1: TEST DESCRIPTION AND INTENDED USE
1.1 Test Name and Identifiers
The test that is the subject of this dossier is designated OncoPrecise GXP-47. The test has been developed, validated, and is performed exclusively by Genome Dx Therapeutics Inc. ("GDT"), a clinical-stage molecular diagnostics company headquartered in San Diego, California.
The proposed PLA code descriptor for OncoPrecise GXP-47 is as follows:
"OncoPrecise GXP-47 (Genome Dx Therapeutics Inc.), genomic profiling, non-small-cell lung cancer, 47-gene RNA expression panel, formalin-fixed paraffin-embedded tissue, algorithm-derived Therapy Response Index (TRI) score"
The proposed PLA code is 0XXXU (placeholder designation; the formal PLA code application has been prepared but has not yet been submitted to the AMA CPT Editorial Panel). GDT is targeting the September 2024 AMA CPT Editorial Panel meeting for PLA code consideration, with a submission deadline of June 28, 2024.
For reference purposes, the most relevant existing CPT code is CPT 81455 (Targeted genomic sequence analysis panel, solid organ neoplasm, DNA and/or RNA analysis, 51 or greater genes). However, CPT 81455 does not capture the proprietary nature of the TRI scoring algorithm or the specific clinical application of OncoPrecise GXP-47, which is the primary rationale for pursuing a dedicated PLA code.
The laboratory performing OncoPrecise GXP-47 is the GDT San Diego Reference Laboratory, located at 4720 Torrey Pines Road, Suite 300, San Diego, CA 92130. The laboratory's certifications and identifiers are as follows:
The GDT San Diego Reference Laboratory is the sole facility at which OncoPrecise GXP-47 is performed. GDT does not operate satellite laboratories or contract with third-party laboratories for the performance of any portion of the OncoPrecise GXP-47 assay. All pre-analytical, analytical, and post-analytical processes are conducted at the San Diego facility under the direct supervision of the Laboratory Director, Dr. Marcus Yuen, MD, PhD.
1.2 Technology Platform and Methodology
OncoPrecise GXP-47 is a next-generation sequencing ("NGS")-based assay that measures the expression levels of 47 genes from RNA extracted from formalin-fixed, paraffin-embedded ("FFPE") tumor tissue specimens. The assay is designed to be performed on FFPE NSCLC biopsy or surgical resection specimens obtained during standard clinical care.
Specimen Type and RNA Extraction. The assay accepts FFPE tumor tissue blocks or unstained tissue sections mounted on glass slides. RNA is extracted from FFPE tissue using a validated, automated extraction protocol optimized for the recovery of RNA from formalin-fixed specimens, which are known to present challenges related to RNA degradation and cross-linking. The extraction protocol has been validated to yield RNA of sufficient quantity and quality for downstream NGS analysis, as measured by fluorometric quantification and RNA quality assessment using the DV200 metric (the percentage of RNA fragments greater than 200 nucleotides in length).
Gene Panel Composition. The OncoPrecise GXP-47 panel comprises 47 genes selected on the basis of their established or emerging biological relevance to the molecular mechanisms underlying response to immune checkpoint inhibitor therapy in NSCLC. The gene selection was informed by a comprehensive literature review, pathway analysis, and machine learning-based feature selection applied to publicly available and proprietary gene expression datasets. The 47 genes span the following key biological pathways and functional categories:
(a) Tumor Microenvironment Immune Cell Infiltration: Genes encoding markers of T-cell activation, cytotoxic lymphocyte function, natural killer cell activity, macrophage polarization, and dendritic cell maturation, reflecting the composition and functional state of the immune infiltrate within the tumor microenvironment.
(b) PD-L1 signaling Pathway: Genes involved in the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis and related co-stimulatory and co-inhibitory receptor-ligand interactions, capturing the molecular context of the immune checkpoint targeted by ICI therapy.
(c) Tumor Mutational Burden Correlation: Genes whose expression levels have been shown to correlate with tumor mutational burden ("TMB") and neoantigen load, providing a transcriptomic proxy for the genomic features associated with ICI responsiveness.
(d) Interferon-Gamma Pathway Activation: Genes in the interferon-gamma (IFN-γ) signaling cascade, including downstream effectors and transcriptional targets, reflecting the T-cell-inflamed gene expression signature that has been associated with clinical benefit from ICI therapy across multiple tumor types.
(e) Immune Exclusion and Resistance Mechanisms: Genes associated with mechanisms of primary and adaptive immune resistance, including transforming growth factor-beta (TGF-β) signaling, Wnt/β-catenin pathway activation, and epithelial-mesenchymal transition (EMT), which may indicate reduced likelihood of ICI response.
A complete list of all 47 genes, including gene symbols, full gene names, and biological pathway annotations, is provided in Appendix A of this dossier.
Library Preparation and Sequencing. Following RNA extraction and quality assessment, targeted RNA sequencing libraries are prepared using a proprietary enrichment strategy that selectively captures and amplifies the transcripts of the 47 target genes along with a set of housekeeping reference genes used for normalization. Library preparation is performed using automated liquid handling instrumentation to minimize variability and maximize throughput. Prepared libraries are sequenced on an Marlowe Group NextSeq 550Dx instrument (or equivalent validated platform) using paired-end sequencing chemistry. Sequencing is performed to a target read depth sufficient to ensure reliable quantification of gene expression levels across the dynamic range of the assay, including for genes with low baseline expression.
Bioinformatics Pipeline. Raw sequencing data (FASTQ files) are processed through GDT's proprietary bioinformatics pipeline, which performs the following sequential steps: (i) quality filtering and adapter trimming; (ii) alignment of reads to the human reference transcriptome; (iii) quantification of mapped reads per gene; (iv) normalization of raw read counts using a multi-step normalization procedure that accounts for library size, GC content bias, and housekeeping gene expression levels; and (v) generation of normalized gene expression values for each of the 47 target genes. The bioinformatics pipeline has been fully validated and version-controlled, and is executed within a secure, HIPAA-compliant computational environment.
1.3 Therapy Response Index (TRI) Score — Algorithm Description
The normalized expression values for the 47 target genes serve as inputs to GDT's proprietary composite scoring algorithm, which produces the Therapy Response Index ("TRI") score. The TRI score is a continuous numerical value ranging from 0 to 100, with higher scores indicating a greater predicted likelihood of clinical response to immune checkpoint inhibitor therapy.
Algorithm Development. The TRI scoring algorithm was developed using a supervised machine learning approach applied to retrospective cohorts of patients with advanced NSCLC who received ICI therapy and for whom both gene expression profiling data and clinical outcome data (including progression-free survival and objective response rate) were available. The algorithm development process included the following stages:
(i) Feature Selection: Identification of the most informative gene expression features and their optimal weighting within the composite score, using regularized regression, random forest feature importance, and cross-validated performance assessment.
(ii) Model Training: Training of the scoring algorithm on a development cohort (N = 483 patients from three academic medical centers) with internal cross-validation to optimize model parameters and prevent overfitting.
(iii) Model Locking: The final TRI scoring algorithm was locked — that is, all model parameters, gene weights, and scoring thresholds were finalized and documented — prior to the initiation of the analytical validation study. No modifications to the algorithm have been made subsequent to the lock date, ensuring the integrity of independent analytical and clinical validation.
Patient Stratification Categories. The TRI score is reported alongside a patient stratification category based on pre-defined score thresholds:
The TRI score thresholds (40 and 70) were derived from the retrospective development cohort data and were selected to optimize the balance between sensitivity and specificity for identification of ICI responders and non-responders, respectively. These thresholds were locked as part of the algorithm lock prior to analytical validation.
Algorithmic Transparency. The precise mathematical formulation of the TRI scoring algorithm, including individual gene weights, interaction terms, and normalization coefficients, constitutes proprietary trade secret information of GDT. A high-level description of the algorithm structure and development methodology is provided in the published analytical validation study (see Section 2). GDT is prepared to provide additional algorithmic detail under appropriate confidentiality protections to MolDx reviewers upon request during the technical assessment process, consistent with the approach taken during the GXP-12 technical assessment.
1.4 Clinical Indications and Intended Use Population
OncoPrecise GXP-47 is intended for use as an aid to oncologist clinical decision-making regarding the selection of first-line therapy for patients with advanced non-small-cell lung cancer. Specifically, the test is designed to guide decisions on whether to initiate first-line immune checkpoint inhibitor therapy — including pembrolizumab (KEYTRUDA®, Calderon Corporation), nivolumab (OPDIVO®, Ostrander Group), and atezolizumab (TECENTRIQ®, Crowne Albany Partners LLC/Roche) — versus platinum-based chemotherapy in patients with Stage IIIB or Stage IV NSCLC.
The intended use population is defined as follows:
Target Population: Adult patients (≥ 18 years of age) with newly diagnosed, histologically or cytologically confirmed Stage IIIB or Stage IV non-small-cell lung cancer, regardless of PD-L1 expression status (including PD-L1 tumor proportion score < 1%, 1–49%, and ≥ 50%) and regardless of histologic subtype (including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and NSCLC not otherwise specified).
The test is designed to be ordered at the time of initial treatment planning, prior to the initiation of first-line systemic therapy, for patients who are being considered for ICI therapy based on standard clinical and pathological criteria.
Complementary Role. OncoPrecise GXP-47 is intended to complement, not replace, existing biomarkers used in the clinical assessment of ICI therapy candidacy. The test is designed to provide an integrative genomic response prediction that captures biological dimensions of ICI sensitivity and resistance not fully reflected by PD-L1 immunohistochemistry or tumor mutational burden testing alone. GDT recommends that the TRI score be interpreted in the context of the patient's complete clinical picture, including PD-L1 expression, TMB (if available), performance status, comorbidities, and patient preferences.
Populations Not Addressed. OncoPrecise GXP-47 has not been validated and is not intended for use in: (i) patients with small-cell lung cancer; (ii) patients with NSCLC harboring actionable driver mutations (e.g., EGFR, ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, RET, KRAS G12C) for whom targeted therapy is the standard first-line treatment; (iii) patients who have received prior systemic therapy for advanced NSCLC; or (iv) pediatric patients (< 18 years of age).
1.5 Ordering and Specimen Requirements
OncoPrecise GXP-47 is ordered by the patient's treating oncologist or other qualified healthcare provider. The test may be ordered through GDT's electronic test requisition portal, by facsimile, or via integration with participating electronic health record ("EHR") systems. Orders must include the patient's demographic information, clinical diagnosis (including NSCLC staging and histologic subtype), treating physician information, and insurance/payer information for billing purposes.
Specimen Requirements. The specimen requirements for OncoPrecise GXP-47 are as follows:
Specimen Shipping. Specimens should be shipped to the GDT San Diego Reference Laboratory at ambient temperature via standard overnight courier service using the specimen shipping kit provided by GDT at no charge to the ordering physician's office or pathology laboratory. The shipping kit includes pre-printed shipping labels, protective packaging, and a specimen requisition form. GDT provides a toll-free specimen logistics support line staffed during business hours to assist ordering providers with specimen preparation and shipment.
Turnaround Time. GDT's standard turnaround time for OncoPrecise GXP-47 results is 10 to 14 business days from the date of specimen receipt at the San Diego laboratory. Turnaround time is measured from the date the specimen is received and accessioned through the date the final test report is released to the ordering physician. GDT maintains a target of delivering results within 10 business days for at least 85% of all specimens processed.
1.6 Test Report Description
Upon completion of the assay, GDT generates and delivers a comprehensive test report to the ordering physician. The OncoPrecise GXP-47 test report includes the following components:
(a) Patient and Specimen Information: Patient demographics, specimen accession number, date of specimen receipt, specimen type, and tumor content assessment.
(b) Therapy Response Index (TRI) Score: The numerical TRI score on a scale of 0 to 100, displayed prominently on the first page of the report with a graphical indicator showing the score's position within the 0–100 scale.
(c) Patient Stratification Category: The categorical classification of the patient as "High Likelihood of Response" (TRI ≥ 70), "Intermediate" (TRI 40–69), or "Low Likelihood of Response" (TRI < 40), presented with an explanatory key describing the clinical interpretation of each category.
(d) Gene-Level Expression Data: A tabular summary of the normalized expression levels for each of the 47 genes in the panel, along with reference ranges derived from the analytical validation population, provided for informational purposes and to support potential research use.
(e) Interpretive Summary: A narrative summary written in plain clinical language for the treating oncologist, contextualizing the TRI score and stratification category within the current clinical evidence base and offering guidance on how the result may inform first-line therapy selection. The interpretive summary includes a statement that the TRI score should be integrated with other clinical and pathological factors in treatment planning.
(f) Methodology Statement: A brief description of the assay methodology, including the specimen type, the gene panel, the sequencing platform, and the bioinformatics and scoring algorithm, along with references to the published analytical validation study.
(g) Limitations: A statement of the known limitations of the test, including the populations in which the test has not been validated and a notation regarding the ongoing status of prospective clinical validation.
The test report is delivered electronically to the ordering physician via GDT's secure results portal and, where available, through direct integration with the physician's electronic health record system using HL7 FHIR-compatible interfaces. Paper copies of the report are available upon request. The report format has been designed in consultation with practicing oncologists and is intended to facilitate rapid interpretation and integration into clinical workflow.
A redacted, de-identified sample OncoPrecise GXP-47 test report is provided in Appendix B of this dossier.
SECTION 2: ANALYTICAL VALIDATION
2.1 Overview of Analytical Validation Study
The comprehensive analytical validation of OncoPrecise GXP-47 was completed on December 14, 2022, at GDT's San Diego Reference Laboratory (CLIA No. 05D2187432; CAP No. 9074821). The analytical validation study was designed in accordance with applicable guidance from the Clinical and Laboratory Standards Institute ("CLSI"), the College of American Pathologists ("CAP"), and the Centers for Medicare & Medicaid Services ("CMS") CLIA regulations, as well as recommendations from the Association for Molecular Pathology ("AMP") for the validation of NGS-based clinical assays.
The results of the analytical validation study were published in a peer-reviewed journal:
Yuen M, Raval A, Chen L, Pham TQ, Orozco-Vasquez JR, Delacroix S, Sundaram P. "Analytical Validation of OncoPrecise GXP-47: A 47-Gene RNA Expression Panel for Prediction of Immune Checkpoint Inhibitor Response in Non-Small-Cell Lung Cancer." Journal of Molecular Oncology Diagnostics. 2022;18(4):412–429.
A reprint of the published analytical validation study is provided in Appendix E of this dossier. The sections below summarize the key analytical validation parameters, study designs, and results. All validation experiments were conducted using the locked version of the TRI scoring algorithm (i.e., no algorithm modifications were made during or after analytical validation).
2.2 Analytical Sensitivity and Specificity
Limit of Detection (LOD) for RNA Input. The limit of detection for the OncoPrecise GXP-47 assay was established by testing serial dilutions of RNA extracted from FFPE NSCLC specimens across a range of input quantities. The study evaluated total RNA inputs ranging from 10 ng to 500 ng to determine the minimum RNA input at which the assay consistently generates reliable gene expression measurements and a reportable TRI score. The validated limit of detection was established at 50 ng of total RNA input, defined as the minimum RNA quantity at which ≥ 95% of target genes achieved a minimum read coverage threshold and the TRI score demonstrated acceptable reproducibility (coefficient of variation < 10%).
Minimum RNA Quality Metrics. RNA quality was assessed using the DV200 metric, which measures the fraction of RNA fragments greater than 200 nucleotides in length. The minimum acceptable DV200 value was established at ≥ 30%, below which RNA degradation was determined to compromise assay reliability. Specimens with DV200 values below 30% are rejected during pre-analytical quality assessment and are reported as "Quantity/Quality Not Sufficient" (QNS). During the analytical validation study, 94.2% of FFPE specimens evaluated met or exceeded the DV200 ≥ 30% threshold, demonstrating the assay's robustness with typical clinical FFPE specimens.
Analytical Sensitivity. Analytical sensitivity was assessed as the ability of the assay to detect and accurately quantify the expression levels of all 47 target genes across their expected range of expression in NSCLC tumor specimens. Using a panel of 120 FFPE NSCLC specimens representing diverse histologic subtypes and gene expression profiles, the assay achieved a target gene detection rate of 99.3% (i.e., 99.3% of all gene-specimen combinations yielded expression values above the lower limit of quantification). Genes with very low baseline expression in NSCLC tissue were specifically evaluated, and all 47 genes demonstrated detectable expression in ≥ 96% of specimens tested.
Analytical Specificity. Analytical specificity was evaluated by assessing the proportion of sequencing reads that mapped to intended target gene sequences versus off-target genomic regions. The assay demonstrated an on-target read rate of 92.7% across all validation specimens, with off-target reads distributed across genomic regions unrelated to the 47-gene panel and housekeeping reference genes. No evidence of systematic off-target amplification or cross-hybridization was observed. In silico analysis confirmed that the primer and probe sequences used in library preparation are specific to the intended target transcripts, with no predicted cross-reactivity with homologous gene family members or pseudogene sequences that could confound expression quantification.
2.3 Accuracy. The accuracy of the OncoPrecise GXP-47 assay was assessed by comparing NGS-based gene expression measurements against an orthogonal reference method. Specifically, a subset of 15 genes from the 47-gene panel was selected for orthogonal validation using quantitative reverse transcription polymerase chain reaction ("RT-qPCR") performed on the same RNA extracts used for NGS analysis. These 15 genes were selected to span the range of expression levels observed across the panel, including genes with high, moderate, and low expression levels.
A total of 60 FFPE NSCLC specimens were analyzed by both NGS (OncoPrecise GXP-47 assay) and RT-qPCR for the 15 selected genes, yielding 900 paired gene expression measurements. Concordance between the two methods was assessed by Ostrander Corporation coefficient and Bland-Altman analysis.
The overall Ostrander Corporation coefficient between NGS-derived normalized expression values and RT-qPCR-derived relative expression values was r = 0.94 (95% CI: 0.92–0.96), indicating excellent agreement between the two methods. Bland-Altman analysis demonstrated a mean bias of −0.12 log2 expression units (95% limits of agreement: −0.78 to 0.54 log2 expression units), which was within the pre-specified acceptance criterion of ±1.0 log2 expression units. No systematic bias was observed across the range of expression levels or across the 15 evaluated genes.
These results confirm that the NGS-based gene expression measurements produced by OncoPrecise GXP-47 are accurate and concordant with an established orthogonal methodology, supporting the reliability of the gene expression data that serve as inputs to the TRI scoring algorithm.
2.4 Precision and Reproducibility
A comprehensive precision and reproducibility study was conducted in accordance with CLSI EP05-A3 guidelines, evaluating multiple sources of variability in the OncoPrecise GXP-47 assay. The study utilized a panel of 10 FFPE NSCLC specimens representing the full range of TRI scores (including specimens in each of the three stratification categories: High, Intermediate, and Low Likelihood of Response).
Within-Run Precision (Intra-Assay). Within-run precision was assessed by processing five replicates of each of the 10 specimens within a single analytical run. The mean coefficient of variation ("CV") for individual gene expression values across intra-assay replicates was 4.2% (range: 1.8%–7.6% across the 47 genes). The mean CV for the TRI score across intra-assay replicates was 2.8% (range: 1.4%–4.5% across the 10 specimens).
Between-Run Precision (Inter-Assay). Between-run precision was assessed by processing three replicates of each of the 10 specimens across five independent analytical runs conducted on five separate days over a three-week period. The mean CV for the TRI score across inter-assay replicates was 4.1% (range: 2.1%–6.3% across the 10 specimens).
Between-Operator Precision. Between-operator precision was assessed by having three independently trained laboratory operators process two replicates each of the 10 specimens (total of six replicates per specimen across three operators). The mean CV for the TRI score across operators was 3.7% (range: 1.9%–5.8% across the 10 specimens). No statistically significant operator-dependent bias was observed (p > 0.05 by one-way ANOVA for all 10 specimens).
Between-Lot Precision (Reagent Lot-to-Lot Variability). Between-lot precision was evaluated by processing three replicates of each of the 10 specimens using three different production lots of the library preparation reagent kit. The mean CV for the TRI score across reagent lots was 3.9% (range: 2.0%–6.1% across the 10 specimens). No systematic lot-dependent bias was observed.
TRI Score Reproducibility. Across all precision experiments (combined intra-assay, inter-assay, inter-operator, and inter-lot data), the overall CV for the TRI score was 4.3%, well within the pre-specified acceptance criterion of ≤ 10%.
Concordance of TRI Category Assignment. The concordance of TRI stratification category assignment (High/Intermediate/Low) across all replicates was evaluated. Overall category concordance across all precision experiments was 97.8% (i.e., 97.8% of all replicates for a given specimen were assigned to the same TRI category as the specimen's consensus classification). Discordant category assignments were observed exclusively for specimens with TRI scores near the category boundaries (i.e., TRI scores close to 40 or 70), consistent with expected random variability in the vicinity of classification thresholds. The pre-specified acceptance criterion for category concordance was ≥ 95%, which was met.
2.5 Reportable Range
The reportable range of the OncoPrecise GXP-47 assay was evaluated by demonstrating that the assay generates valid TRI scores across the full theoretical range of 0 to 100. The analytical validation cohort of 120 FFPE NSCLC specimens yielded TRI scores ranging from 7 to 96, effectively spanning the clinically relevant range. The distribution of TRI scores across the validation cohort was approximately normally distributed (Shapiro-Wilk p = 0.12), with the following distribution across stratification categories:
The representation of all three categories in the validation cohort, with meaningful numbers of specimens in each category, confirms the assay's ability to generate reportable results across the full TRI score range and supports the clinical interpretability of results in all three stratification categories.
2.6 Specimen Stability and Pre-Analytical Variables
Specimen stability and the impact of pre-analytical variables on assay performance were systematically evaluated to establish the conditions under which OncoPrecise GXP-47 produces reliable results.
FFPE Block Age. The effect of FFPE block age on assay performance was assessed using specimens ranging from less than 1 year to 10 years from the date of initial formalin fixation and paraffin embedding. Paired analysis of matched specimens at varying time points confirmed that the assay produces concordant TRI scores and category assignments for FFPE blocks up to 10 years of age, provided that the specimen meets the minimum RNA quality threshold (DV200 ≥ 30%). Beyond 10 years, specimen failure rates (i.e., QNS due to insufficient RNA quality) increased significantly, and TRI score reproducibility degraded. Accordingly, the validated maximum FFPE block age for OncoPrecise GXP-47 is 10 years from initial fixation.
Fixation Time. The effect of formalin fixation time on assay performance was evaluated across fixation durations ranging from 2 hours to 96 hours. Specimens fixed for 6 to 72 hours in 10% neutral buffered formalin demonstrated consistent RNA quality and concordant TRI scores. Specimens with fixation times less than 6 hours or greater than 72 hours showed increased variability in gene expression measurements and TRI scores. The recommended fixation time range of 6 to 72 hours was established based on these data; specimens with fixation times outside this range may be tested but are flagged for review and accompanied by a qualifying statement in the test report.
Fixative Type. The assay was validated using specimens fixed in 10% neutral buffered formalin (the standard fixative used in most clinical pathology laboratories). A limited evaluation of specimens fixed in other common fixatives (Bouin's solution, zinc formalin) was conducted. Zinc formalin-fixed specimens demonstrated performance comparable to neutral buffered formalin-fixed specimens. Bouin's-fixed specimens showed elevated failure rates due to RNA quality degradation and are not recommended for OncoPrecise GXP-47 testing.
Minimum and Maximum Tumor Content. The effect of tumor cellularity on assay performance was evaluated by testing specimens with tumor nuclei percentages ranging from 5% to 95%. The minimum validated tumor content is ≥ 20% tumor nuclei, as assessed by pathologist review of a hematoxylin and eosin (H&E)-stained reference slide. Below 20% tumor content, TRI scores showed increased variability and reduced correlation with higher-purity matched specimens, indicating dilution of the tumor-derived gene expression signal by surrounding normal tissue. All clinical specimens submitted for OncoPrecise GXP-47 testing undergo tumor content assessment by a GDT pathologist prior to RNA extraction; specimens with < 20% tumor nuclei are rejected as QNS.
Shipping Condition Impact. Shipping stability was evaluated by subjecting FFPE tissue blocks and unstained slides to simulated shipping conditions, including ambient temperature exposure for up to 72 hours, temperature cycling (between 4°C and 40°C over 48 hours), and physical handling conditions typical of overnight courier transport. No significant impact on RNA quality, gene expression measurements, or TRI scores was observed under any tested shipping condition, confirming that FFPE specimens are stable during standard overnight courier shipment at ambient temperature.
2.7 Interfering Substances
The impact of potential interfering substances and tissue characteristics on OncoPrecise GXP-47 assay performance was assessed.
Necrotic Tissue. Specimens containing varying proportions of necrotic tissue (ranging from 0% to 60% of the tissue section area) were evaluated. Necrosis levels up to 30% of the tissue area did not significantly affect RNA quality, gene expression measurements, or TRI scores. At necrosis levels exceeding 30%, RNA quality degradation was observed, and TRI score variability increased. Specimens with > 30% necrosis are flagged during pre-analytical pathologist review, and macrodissection to enrich for viable tumor tissue is performed when feasible.
Blood Contamination. The effect of blood contamination (hemoglobin) on assay performance was evaluated by spiking RNA extracts with varying concentrations of hemoglobin. Hemoglobin concentrations up to 10 μg/mL did not significantly affect gene expression measurements or TRI scores. At higher concentrations, sequencing library quality was reduced, and affected samples were identified during automated library quality assessment and flagged for repeat extraction or rejection.
Decalcification. FFPE specimens that had undergone decalcification treatment (a common procedure for bone or calcified tissue specimens) were evaluated. Specimens treated with EDTA-based decalcification agents showed no significant impact on assay performance. Specimens treated with strong acid-based decalcification agents (hydrochloric acid) demonstrated significantly degraded RNA quality and elevated failure rates. Acid-decalcified specimens are not recommended for OncoPrecise GXP-47 testing and are flagged for rejection during pre-analytical review.
2.8 Summary of Analytical Validation Conclusions
The comprehensive analytical validation of OncoPrecise GXP-47, completed on December 14, 2022, and published in the Journal of Molecular Oncology Diagnostics (2022;18(4):412–429), demonstrated that the assay meets or exceeds all pre-specified acceptance criteria across the full spectrum of analytical performance parameters. The key conclusions of the analytical validation study are summarized below:
(a) The assay demonstrates excellent analytical sensitivity, with reliable detection and quantification of all 47 target genes from clinically relevant FFPE NSCLC specimens at a validated limit of detection of 50 ng total RNA input.
(b) Analytical specificity is high, with an on-target read rate of 92.7% and no evidence of systematic off-target amplification or cross-reactivity.
(c) Accuracy is confirmed by strong concordance between NGS-based gene expression measurements and orthogonal RT-qPCR measurements (r = 0.94).
(d) The assay demonstrates robust precision and reproducibility, with an overall TRI score coefficient of variation of 4.3% and a TRI category concordance rate of 97.8% across all precision experiments.
(e) The full reportable range of TRI scores (0–100) is demonstrated across the validation specimen cohort.
(f) Specimen stability and pre-analytical variable tolerances are well-characterized, with validated performance for FFPE blocks up to 10 years of age, fixation times of 6–72 hours, and tumor content ≥ 20%.
(g) Potential interfering substances have been evaluated, and appropriate pre-analytical safeguards are in place to identify and manage specimens that may be affected.
In summary, OncoPrecise GXP-47 has demonstrated robust and clinically suitable analytical performance characteristics. The analytical validation data provide a strong foundation for clinical validation and clinical application of the assay.
SECTION 3: CLINICAL VALIDATION
3.1 Overview of Clinical Validation Strategy
GDT has implemented a two-component clinical validation strategy for OncoPrecise GXP-47, comprising (a) retrospective cohort studies conducted during assay development and preliminary clinical validation, and (b) a prospective, multi-site, blinded clinical validation study designated CLARITY-LUNG. This two-component approach was designed to generate a comprehensive body of clinical evidence supporting the predictive performance of the TRI score and its clinical validity for use in guiding ICI therapy decisions in advanced NSCLC.
The overarching objective of clinical validation is to demonstrate that the TRI score produced by OncoPrecise GXP-47 has clinically meaningful positive predictive value ("PPV") and negative predictive value ("NPV") for 12-month progression-free survival ("PFS") in patients with Stage IIIB/IV NSCLC treated with first-line immune checkpoint inhibitor therapy. Specifically, clinical validation seeks to establish that patients classified as "High Likelihood of Response" (TRI ≥ 70) experience significantly higher rates of 12-month PFS on ICI therapy than patients classified as "Low Likelihood of Response" (TRI < 40), and that the TRI score adds predictive information beyond that provided by existing biomarkers (PD-L1 IHC, TMB).
3.2 Prior Retrospective Studies
During the development of the TRI scoring algorithm and prior to the initiation of the prospective CLARITY-LUNG trial, GDT conducted a series of retrospective cohort studies to establish the preliminary clinical validity of the 47-gene expression panel and the TRI score.
Development Cohort. The TRI algorithm was trained on a development cohort of 483 patients with Stage IIIB/IV NSCLC treated with first-line ICI therapy (pembrolizumab, nivolumab, or atezolizumab) at three academic medical centers between 2017 and 2021. Archival FFPE tumor tissue specimens from these patients were retrieved and tested with OncoPrecise GXP-47, and clinical outcome data (progression-free survival, overall survival, best objective response by RECIST v1.1 criteria) were retrospectively collected from medical records. This cohort was used for algorithm training and internal cross-validation, as described in Section 1.3.
Independent Retrospective Validation Cohort. Following algorithm lock, a separate, independent retrospective validation cohort of 217 patients from two additional academic medical centers was assembled. These patients met the same clinical criteria as the development cohort (Stage IIIB/IV NSCLC, first-line ICI therapy) and had not been included in algorithm development. FFPE specimens were tested with the locked version of OncoPrecise GXP-47, and clinical outcomes were retrospectively ascertained. The key results from this independent retrospective validation were as follows:
These retrospective results provided preliminary evidence supporting the predictive performance of the TRI score and informed the design of the prospective CLARITY-LUNG trial, including the pre-specified performance thresholds (PPV ≥ 0.75, NPV ≥ 0.80).
Limitations of Retrospective Studies. The following limitations of the retrospective validation data are acknowledged:
(i) Retrospective Design: The retrospective nature of the studies introduces potential for selection bias, as the patient populations may not be fully representative of the broader population of patients with advanced NSCLC who would be tested with OncoPrecise GXP-47 in clinical practice.
(ii) Non-Blinded Assessments: Clinical outcome assessments (including imaging-based determination of disease progression) were performed as part of standard clinical care and were not subject to blinded central review by independent radiologists.
(iii) Academic Medical Center Populations: The retrospective cohorts were drawn from academic medical centers, which may have patient populations, treatment patterns, and outcome distributions that differ from community oncology settings.
(iv) Limited Diversity: The racial and ethnic diversity of the retrospective cohorts may not fully reflect the demographic composition of the Medicare-eligible advanced NSCLC population.
These limitations underscore the critical importance of the prospective CLARITY-LUNG trial, which was specifically designed to address these gaps and generate the level of clinical validation evidence required by the MolDx program.
3.3 The CLARITY-LUNG Trial — Prospective Clinical Validation Study
3.3.1 Study Design. The CLARITY-LUNG trial (Clinical Assessment of RNA-based Immunotherapy Treatment Yield in Lung Cancer Using NGS Genomics) is a prospective, multi-site, blinded clinical validation study designed to definitively establish the clinical validity of the OncoPrecise GXP-47 TRI score for predicting response to first-line ICI therapy in patients with Stage IIIB/IV NSCLC.
The trial is registered on ClinicalTrials.gov under identifier NCT05891247 and is being conducted at 14 clinical sites across the United States, including a mix of academic medical centers and community oncology practices to ensure broad generalizability of results. The study is classified as a prospective observational study, as the TRI score results are not used to guide treatment decisions during the study; rather, treatment is selected by the treating oncologist based on standard-of-care clinical criteria, and TRI scores are generated and analyzed in a blinded fashion after treatment assignment.
Key Study Design Elements:
• Study Type: Prospective, multi-site, blinded observational clinical validation study
• Blinding: TRI scores are generated after specimen collection but are not disclosed to treating physicians, patients, or outcome assessors during the study. Scores are analyzed only by the study biostatistics team and the Data Safety Monitoring Board (DSMB).
• Treatment Assignment: Patients receive standard-of-care first-line therapy as determined by their treating oncologist. The study does not dictate or influence treatment selection.
• Study Duration: Enrollment phase plus 12-month follow-up from last patient enrolled.
Principal Investigator: Dr. Priya Sundaram, MD, Vice President of Clinical Development, Genome Dx Therapeutics Inc. Dr. Sundaram oversees the clinical operations, site management, and data collection for the CLARITY-LUNG trial.
Data Safety Monitoring Board (DSMB): An independent DSMB has been established for the CLARITY-LUNG trial to provide ongoing oversight of study conduct, patient safety, and data integrity. The DSMB Chair is Dr. Evelyn Matsuda, MD, PhD, a thoracic oncologist and clinical trial methodologist at the Carrington Cancer Institute in Houston, Texas. The DSMB includes three additional independent members with expertise in thoracic oncology, biostatistics, and molecular diagnostics, none of whom have financial or professional relationships with GDT. The DSMB charter specifies pre-planned interim analyses and stopping rules for safety and futility.
A condensed CLARITY-LUNG trial protocol summary, including study design, enrollment criteria, endpoints, and statistical analysis plan, is provided in Appendix C of this dossier.
3.3.2 Patient Population and Enrollment. Enrollment Target. The CLARITY-LUNG trial was designed with a target enrollment of 1,200 patients with newly diagnosed Stage IIIB or Stage IV NSCLC. The sample size was calculated to provide 80% statistical power to demonstrate a PPV of ≥ 0.75 and an NPV of ≥ 0.80 for the TRI score in predicting 12-month progression-free survival on ICI therapy, assuming an ICI treatment rate of approximately 60% in the enrolled population and accounting for expected rates of specimen failure, protocol deviations, and loss to follow-up.
Enrollment Timeline. Enrollment began on January 18, 2023, and is ongoing. As of May 2024, 847 patients have been enrolled across the 14 study sites, representing 70.58% of the target enrollment (847 ÷ 1,200 = 70.58%). Enrollment pace has been generally consistent with projections, with minor fluctuations attributable to site activation timing and seasonal variability.
Key Inclusion Criteria:
(i) Adults ≥ 18 years of age.
(ii) Histologically or cytologically confirmed Stage IIIB or Stage IV NSCLC (per AJCC 8th edition staging criteria).
(iii) Newly diagnosed; no prior systemic therapy for advanced NSCLC.
(iv) FFPE tumor tissue specimen available from biopsy or surgical resection performed within 60 days of enrollment.
(v) Planned initiation of first-line systemic therapy (ICI therapy, platinum-based chemotherapy, or combination ICI/chemotherapy) within 30 days of enrollment.
(vi) ECOG performance status 0–2.
(vii) Adequate organ function as defined by protocol-specified laboratory values.
(viii) Ability to provide written informed consent.
Key Exclusion Criteria:
(i) Known actionable driver mutations (EGFR, ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, RET, KRAS G12C) for which targeted therapy is the standard first-line treatment.
(ii) Prior systemic therapy for advanced NSCLC (prior adjuvant chemotherapy for earlier-stage disease is permitted if completed > 12 months before enrollment).
(iii) Active autoimmune disease requiring systemic immunosuppressive therapy.
(iv) Concurrent participation in an interventional clinical trial involving an investigational therapeutic agent.
(v) Insufficient FFPE tumor tissue for OncoPrecise GXP-47 testing (as determined by GDT pathologist review).
The enrolled patient population includes patients across all PD-L1 expression levels (including PD-L1 < 1%, 1–49%, and ≥ 50%) and all NSCLC histologic subtypes (adenocarcinoma, squamous cell carcinoma, and other subtypes), consistent with the intended use population for OncoPrecise GXP-47.
3.3.3 Study Endpoints. Primary Endpoint. The primary endpoint of the CLARITY-LUNG trial is the positive predictive value (PPV) and negative predictive value (NPV) of the OncoPrecise GXP-47 TRI score for 12-month progression-free survival (PFS) in patients treated with first-line ICI therapy (including ICI monotherapy and ICI/chemotherapy combination regimens). Progression-free survival is assessed by blinded central radiology review using RECIST v1.1 criteria, with PFS defined as the time from the date of first-line therapy initiation to the date of documented disease progression or death from any cause.
The pre-specified performance thresholds for the primary endpoint are:
• PPV ≥ 0.75: Among patients with TRI ≥ 70 ("High Likelihood of Response") who are treated with ICI therapy, at least 75% are expected to be alive and progression-free at 12 months.
• NPV ≥ 0.80: Among patients with TRI < 40 ("Low Likelihood of Response") who are treated with ICI therapy, at least 80% are expected to have experienced disease progression or death within 12 months.
These thresholds were established based on the retrospective validation data, clinical expert input, and benchmark performance levels of comparable genomic predictive tests that have received Medicare coverage through the MolDx program.
Secondary Endpoints. The following secondary endpoints are pre-specified in the CLARITY-LUNG protocol:
(a) Correlation of TRI score with overall survival ("OS") at 12 and 24 months.
(b) Concordance of TRI score with PD-L1 expression level (tumor proportion score by IHC) and with tumor mutational burden (TMB), including analysis of the incremental predictive value of TRI score beyond PD-L1 and TMB.
(c) Subgroup analyses of TRI score predictive performance by histologic subtype (adenocarcinoma vs. squamous cell carcinoma), PD-L1 expression level (< 1%, 1–49%, ≥ 50%), ICI agent (pembrolizumab, nivolumab, atezolizumab), and treatment regimen (ICI monotherapy vs. ICI/chemotherapy combination).
(d) TRI score performance in the Intermediate category (TRI 40–69), including comparison of 12-month PFS rates between patients in the Intermediate category treated with ICI therapy versus platinum-based chemotherapy.
(e) Specimen evaluability rate (proportion of enrolled patients with successful OncoPrecise GXP-47 testing).
3.3.4 Interim Analysis Results (March 29, 2024). A pre-planned interim analysis of the CLARITY-LUNG trial was conducted at the point of 50% enrollment (n = 600 enrolled patients). The interim analysis was performed on March 29, 2024, by the study biostatistics team (ClinStat Analytics, Inc., a contract research organization independent of GDT). The interim analysis evaluated the primary endpoint (PPV and NPV of TRI score for 12-month PFS on ICI therapy) in the subset of enrolled patients who had completed at least 12 months of follow-up or who had experienced a PFS event (disease progression or death) prior to 12 months.
Interim Analysis Population. Of the 600 patients enrolled at the time of the interim analysis, 478 were evaluable for the primary endpoint analysis (i.e., had successful OncoPrecise GXP-47 testing, had initiated first-line ICI therapy, and had either completed 12-month follow-up or experienced a PFS event). The evaluable population was distributed across TRI categories as follows: High (TRI ≥ 70), n = 141; Intermediate (TRI 40–69), n = 198; Low (TRI < 40), n = 139.
Interim Analysis Results — Primary Endpoint:
The interim PPV of 0.68 indicates that among patients classified as "High Likelihood of Response" (TRI ≥ 70) who received first-line ICI therapy, 68% were alive and progression-free at 12 months. The interim NPV of 0.71 indicates that among patients classified as "Low Likelihood of Response" (TRI < 40) who received ICI therapy, 71% experienced disease progression or death within 12 months. While both metrics demonstrate directionality consistent with the intended predictive performance of the TRI score, neither metric met the pre-specified performance threshold at the interim analysis.
Discussion of Interim Results. The interim results should be interpreted within the following important contextual considerations:
(i) Interim Data Limitations: The interim analysis was conducted on a subset of the planned enrollment (50%) and represents a limited follow-up period. Many patients in the interim analysis cohort had only recently reached the 12-month follow-up milestone, and late progressions or censoring events may not yet be fully captured.
(ii) Maturation of Follow-Up Data: As the trial continues and follow-up matures, additional PFS events will accrue, and the precision of the PPV and NPV estimates is expected to improve. It is well-established in oncology clinical trials that predictive performance metrics can shift between interim and final analyses as event rates stabilize.
(iii) Enrollment Composition: The interim analysis population may not be fully representative of the final enrolled population with respect to clinical characteristics, site distribution, and treatment patterns. As enrollment continues and additional sites reach full enrollment, the composition of the evaluable population will evolve.
(iv) Comparability to Existing Tests: The interim PPV of 0.68 and NPV of 0.71, while below the pre-specified thresholds, are within the range of performance reported for other NGS-based predictive tests in oncology at comparable stages of validation. Several currently covered molecular diagnostics achieved coverage with PPV and NPV values in the 0.65–0.80 range in their pivotal validation studies.
DSMB Review. The DSMB convened on April 5, 2024, to review the interim analysis results. After deliberation, the DSMB issued the following recommendation:
"The DSMB has reviewed the pre-planned interim analysis data from the CLARITY-LUNG trial. The interim results for the primary endpoint (PPV = 0.68; NPV = 0.71) are inconclusive and below the pre-specified performance benchmarks (PPV ≥ 0.75; NPV ≥ 0.80). However, the results do not meet the pre-specified criteria for early futility stopping, and the directional trend of the data is consistent with the predicted performance of the TRI score. The DSMB recommends that enrollment continue toward the full 1,200-patient target and that the final analysis be conducted as planned upon completion of enrollment and 12-month follow-up for all enrolled patients."
GDT has accepted the DSMB's recommendation and is continuing enrollment in CLARITY-LUNG as planned.