DRAFT — Proprietary Laboratory Analyses (PLA) Code Application
OncoPrecise GXP-47
Genome Dx Therapeutics Inc.
Prepared by:
Calderwood & Harkness LLP 1700 K Street NW, Suite 900 Washington, DC 20006
and
Carraway Regulatory Advisors, Inc. 233 South Wacker Drive, Suite 4100 Chicago, IL 60606
Prepared for:
Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130
Draft Date: March 22, 2024
Target Submission: AMA CPT Editorial Panel — September 2024 Meeting
Submission Deadline: June 28, 2024
Calderwood & Harkness Matter No.: 1043-00002
STATUS NOTATION: This draft application was prepared for review and comment. It was never submitted to the AMA CPT Editorial Panel due to termination of the engagement on June 3, 2024. This document remains the work product of Calderwood & Harkness LLP and Carraway Regulatory Advisors, Inc., and is subject to all applicable privileges and protections, including attorney-client privilege and work-product doctrine.
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Section 1: Application Cover Letter Summary
March 22, 2024
American Medical Association CPT Editorial Panel — PLA Code Application 330 N. Wabash Avenue, Suite 39300 Chicago, IL 60611-5885
Re: Proprietary Laboratory Analyses (PLA) Code Application — OncoPrecise GXP-47
Dear Members of the CPT Editorial Panel:
On behalf of Genome Dx Therapeutics Inc. ("GDT" or the "Applicant"), a Delaware corporation headquartered in San Diego, California, we respectfully submit this Proprietary Laboratory Analyses (PLA) code application to the American Medical Association ("AMA") CPT Editorial Panel pursuant to the PLA application process established by the AMA for the assignment of unique PLA codes to proprietary laboratory tests. This application is submitted in accordance with the guidelines and procedures set forth in the AMA's CPT® PLA Code Application Instructions and is intended for consideration at the September 2024 meeting of the CPT Editorial Panel.
The Applicant, Genome Dx Therapeutics Inc., is a clinical-stage molecular diagnostics company that develops and commercializes next-generation sequencing (NGS)-based genomic tests for oncology applications. GDT was incorporated in the State of Delaware on June 12, 2018, and maintains its principal offices and sole reference laboratory at 4720 Torrey Pines Road, Suite 300, San Diego, California 92130. GDT currently offers one commercially available product, OncoPrecise GXP-12, a 12-gene panel for early-stage breast cancer prognosis, which is reimbursed under Local Coverage Determination L38472 (effective August 15, 2021, issued by Cascade Fiscal Intermediaries, LLC).
The primary contact for this application is:
Theresa Nakamura General Counsel & Vice President of Regulatory Affairs Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Telephone: [TO BE CONFIRMED]
Email: [TO BE CONFIRMED]
Coding counsel and regulatory advisors assisting GDT in the preparation and submission of this application are:
Miriam Calloway, Partner Healthcare & Life Sciences Practice Calderwood & Harkness LLP 1700 K Street NW, Suite 900 Washington, DC 20006 Telephone: (202) 555-4700
Email: m.calloway@calderwoodharkness.com
Janet Carraway, CPC, CCS-P, Principal Carraway Regulatory Advisors, Inc. 233 South Wacker Drive, Suite 4100 Chicago, IL 60606 Telephone: (312) 555-8820
Email: jcarraway@carrawayra.com
By this application, GDT respectfully requests the assignment of a unique PLA code for OncoPrecise GXP-47, a proprietary 47-gene RNA expression panel test designed for use in patients with non-small-cell lung cancer (NSCLC). The test is performed exclusively at GDT's CLIA-certified, CAP-accredited reference laboratory located in San Diego, California (CLIA Certificate No. 05D2187432; CAP Accreditation No. 9074821). OncoPrecise GXP-47 analyzes the expression levels of 47 genes using a validated NGS platform and applies a proprietary, algorithm-derived Therapy Response Index (TRI) score to stratify patients by their predicted likelihood of response to immune checkpoint inhibitor therapy. The TRI score and associated clinical output are unique to GDT and are not captured by any existing Category I CPT code or previously assigned PLA code.
This application is accompanied by the supporting documentation set forth in Section 11 herein, including analytical validation data, laboratory certifications, test methodology descriptions, and a sample clinical report, among other materials. GDT is committed to providing any additional information or documentation that the CPT Editorial Panel may require in its review of this application.
We appreciate the Panel's consideration of this application and look forward to the opportunity to discuss it further.
Respectfully submitted,
GENOME DX THERAPEUTICS INC.
By: ________
Name: Dr. Anisha Raval
Title: Co-Founder & Chief Executive Officer
Date: ________
CALDERWOOD & HARKNESS LLP
By: ________
Name: Miriam Calloway
Title: Partner, Healthcare & Life Sciences Practice
Date: ________
Section 2: Proposed PLA Code Descriptor
2.1 Proposed Code Descriptor (Long)
In accordance with the AMA CPT Editorial Panel's formatting and editorial requirements for PLA code descriptors, GDT proposes the following long-form code descriptor for OncoPrecise GXP-47:
Proposed Long Descriptor:
"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."
This proposed descriptor is intended to comply with the PLA code descriptor format, which requires identification of the proprietary test name, the manufacturer/laboratory, the type of analysis performed, the clinical indication, the number and type of analytes, the specimen type, and the test output. Each element of the proposed descriptor is designed to enable accurate identification of OncoPrecise GXP-47 and to distinguish the test from other genomic profiling tests currently assigned PLA or CPT codes.
The descriptor identifies the proprietary test name ("OncoPrecise GXP-47"), the sole performing entity ("Genome Dx Therapeutics Inc."), the nature of the analysis ("genomic profiling"), the clinical application ("non-small-cell lung cancer"), the scope and modality of the panel ("47-gene RNA expression panel"), the required specimen type ("formalin-fixed paraffin-embedded tissue"), and the unique test output ("algorithm-derived Therapy Response Index (TRI) score"). GDT believes this descriptor accurately and completely describes the essential characteristics of the test and conforms to PLA editorial conventions.
2.2 Proposed Code Descriptor (Short/Abbreviated)
For purposes of Medicare fee schedule listings, claims adjudication systems, and other contexts requiring an abbreviated descriptor, GDT proposes the following short-form descriptor:
Proposed Short Descriptor:
"OncoPrecise GXP-47 (Genome Dx Therapeutics), NSCLC, 47-gene RNA panel, FFPE, TRI score"
This abbreviated descriptor retains all essential identifying elements of the long-form descriptor while conforming to character-length limitations typically applied to fee schedule and claims processing displays. The use of standard medical abbreviations (NSCLC, FFPE, TRI) is consistent with accepted conventions in the molecular diagnostics coding community and is expected to be readily understood by payers, coding professionals, and clinicians.
2.3 Rationale for PLA Code vs. Existing CPT Code
GDT has carefully analyzed the existing landscape of CPT Category I codes and previously assigned PLA codes to determine the most appropriate coding pathway for OncoPrecise GXP-47. Based on this analysis, GDT has concluded that the PLA pathway is the appropriate and preferred mechanism for obtaining a unique code for this test, for the following reasons:
No Existing Category I CPT Code Adequately Describes the Test. OncoPrecise GXP-47 does not fit within any existing Category I CPT code. The nearest existing CPT code is 81455 (Targeted genomic sequence analysis panel, solid organ neoplasm, DNA and RNA analysis when performed, 51 or greater genes), which describes a generic NGS panel for solid organ neoplasms analyzing 51 or more genes. However, OncoPrecise GXP-47 analyzes exactly 47 genes — fewer than the threshold required by CPT 81455 — and employs a proprietary algorithm that produces a composite score (the TRI score), which is not captured by the generic CPT code. CPT 81455 does not account for the proprietary algorithmic analysis that is the defining clinical feature of OncoPrecise GXP-47, nor does it identify the specific gene composition or the unique clinical output of the test. Reporting OncoPrecise GXP-47 under CPT 81455 would therefore be inaccurate and would not permit appropriate identification, tracking, or reimbursement of the test.
Other potentially relevant Category I CPT codes, including CPT 81445 (Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5–50 genes) and CPT 81450 (Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, 5–50 genes), are likewise inapplicable. CPT 81445 does not capture RNA expression analysis, and CPT 81450 is specific to hematolymphoid neoplasms rather than solid organ neoplasms such as NSCLC. No existing Category I code describes the combination of RNA-based expression analysis, the specific 47-gene panel composition, the proprietary TRI algorithm, and the unique clinical output that characterize OncoPrecise GXP-47.
The Test Meets All Criteria for PLA Code Assignment. The PLA code category was established by the AMA CPT Editorial Panel specifically to accommodate proprietary clinical laboratory tests that are performed by a single laboratory or manufacturer and that have unique characteristics not captured by existing CPT codes. OncoPrecise GXP-47 satisfies all of the criteria for PLA code assignment:
(a) The test is performed exclusively by a single laboratory — GDT's CLIA-certified, CAP-accredited reference laboratory located in San Diego, California. No other laboratory is authorized or equipped to perform OncoPrecise GXP-47.
(b) The test utilizes a proprietary methodology, including a 47-gene RNA expression panel and a proprietary algorithm (the TRI algorithm), both of which are developed, owned, and maintained exclusively by GDT.
(c) The test produces a unique reportable result — the Therapy Response Index (TRI) score — that is not generated by any other test and is not captured by any existing CPT or PLA code descriptor.
Coding Strategy Analysis. Calderwood & Harkness LLP conducted a comprehensive analysis of the PLA versus CPT coding pathways for OncoPrecise GXP-47, set forth in the Coding Strategy Memorandum dated March 11, 2024 (Calderwood & Harkness Matter No. 1043-00002). That memorandum analyzed the applicable AMA guidelines, the characteristics of the test, and the existing code landscape, and recommended the PLA route as the most appropriate, accurate, and strategically sound pathway for obtaining a unique code for OncoPrecise GXP-47. The conclusions of that memorandum are incorporated by reference herein and are available upon request by the CPT Editorial Panel.
For all of the foregoing reasons, GDT respectfully submits that assignment of a unique PLA code is the appropriate coding mechanism for OncoPrecise GXP-47.
Section 3: Applicant Information
3.1 Applicant Entity
The following information is provided regarding the applicant entity:
Company Description. Genome Dx Therapeutics Inc. ("GDT") 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 co-founded in 2018 by Dr. Anisha Raval and Dr. Marcus Yuen with the mission of translating advances in genomic science into clinically actionable diagnostic tools that improve treatment selection and patient outcomes in cancer care. Since its founding, GDT has built a vertically integrated platform for the development, validation, and delivery of proprietary genomic assays, including a CLIA-certified, CAP-accredited reference laboratory at its San Diego headquarters, a bioinformatics and algorithm development group, and a growing clinical operations team.
Funding History. GDT has raised a total of approximately $187 million in equity financing across three institutional funding rounds:
• Series A (2018): Led by Pacific Rim Life Sciences Fund, LP
• Series B (2020): Led by HealthBridge Capital Partners, LLC
• Series C (March 28, 2022): $78 million round led by Pinnacle Health Ventures, L.P., with participation from existing investors
The proceeds of GDT's financing rounds have been directed principally toward the development of the OncoPrecise platform, the buildout and operation of GDT's San Diego reference laboratory, the conduct of clinical validation studies (including the CLARITY-LUNG trial described in Section 7 herein), and the commercialization of GDT's initial product, OncoPrecise GXP-12.
intellectual Property. GDT currently holds fourteen (14) issued United States patents and has seven (7) pending United States patent applications related to the OncoPrecise platform, including patents and applications directed to the gene panel compositions, the TRI algorithm methodology, RNA extraction and processing techniques, and bioinformatics analysis pipelines utilized in OncoPrecise GXP-47. A complete list of issued patents and pending applications is provided in Exhibits K and L, respectively, accompanying this application.
Existing Commercial Product. GDT currently offers one commercially available product: OncoPrecise GXP-12, a 12-gene expression panel for early-stage breast cancer prognosis. OncoPrecise GXP-12 is a laboratory-developed test performed exclusively at GDT's San Diego reference laboratory and is currently reimbursed by Medicare under Local Coverage Determination L38472, effective August 15, 2021, issued by Cascade Fiscal Intermediaries, LLC (the Medicare Administrative Contractor for Jurisdiction E, covering California). GDT's fiscal year 2023 revenue was approximately $6.2 million, derived exclusively from OncoPrecise GXP-12. The successful development, validation, commercialization, and reimbursement of OncoPrecise GXP-12 demonstrates GDT's operational capability and institutional experience in bringing proprietary genomic diagnostic tests to market through the applicable regulatory and reimbursement pathways.
OncoPrecise GXP-47 Pipeline Status. OncoPrecise GXP-47, the subject of this PLA code application, is the second product in GDT's OncoPrecise platform pipeline. As described in detail in Sections 5 through 8 of this application, OncoPrecise GXP-47 is a 47-gene RNA expression panel designed for use in non-small-cell lung cancer (NSCLC), with a proprietary algorithm-derived Therapy Response Index (TRI) score intended to guide oncologist decision-making regarding first-line immune checkpoint inhibitor therapy. The test has completed analytical validation and is currently undergoing clinical validation in the prospective, multi-site CLARITY-LUNG trial (NCT05891247).
3.2 Applicant Contact Information
Primary Contact:
Theresa Nakamura General Counsel & Vice President of Regulatory Affairs Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Telephone: [TO BE CONFIRMED PRIOR TO SUBMISSION]
Email: [TO BE CONFIRMED PRIOR TO SUBMISSION]
Ms. Nakamura serves as GDT's General Counsel and Vice President of Regulatory Affairs and is the designated primary contact for all correspondence related to this PLA code application. Ms. Nakamura is authorized to respond to inquiries from the AMA CPT Editorial Panel, to provide supplemental information and documentation, and to make representations on behalf of the Applicant in connection with this application.
Secondary Contact:
Kevin Driscoll Vice President of Market Access & Reimbursement Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Telephone: [TO BE CONFIRMED PRIOR TO SUBMISSION]
Email: [TO BE CONFIRMED PRIOR TO SUBMISSION]
Mr. Driscoll serves as GDT's Vice President of Market Access & Reimbursement and may be contacted as an alternative point of contact for matters related to reimbursement strategy, payer communications, and coverage pathway questions arising in connection with this application.
3.3 Legal and Coding Representatives
Outside Counsel:
Calderwood & Harkness LLP Contact: Miriam Calloway, Partner Healthcare & Life Sciences Practice 1700 K Street NW, Suite 900 Washington, DC 20006 Telephone: (202) 555-4700
Email: m.calloway@calderwoodharkness.com
Ms. Calloway is a partner in Calderwood & Harkness's Healthcare & Life Sciences Practice and serves as GDT's outside coding and reimbursement counsel in connection with the OncoPrecise GXP-47 PLA code application and related Medicare coverage strategy matters. Ms. Calloway has extensive experience advising molecular diagnostics companies on CPT and PLA coding applications, Medicare coverage determinations, and reimbursement rate-setting processes.
Coding Consultant:
Carraway Regulatory Advisors, Inc. Contact: Janet Carraway, CPC, CCS-P, Principal 233 South Wacker Drive, Suite 4100 Chicago, IL 60606 Telephone: (312) 555-8820
Email: jcarraway@carrawayra.com
Ms. Carraway is a Certified Professional Coder (CPC) and Certified Coding Specialist — Physician-based (CCS-P) and serves as the principal of Carraway Regulatory Advisors, Inc. She has been retained by GDT to provide coding consultation services, including review of the proposed PLA code descriptor for conformity with AMA editorial conventions and formatting requirements, analysis of the existing code landscape, and assistance with the preparation of this application.
Section 4: Laboratory Information
4.1 Performing Laboratory
OncoPrecise GXP-47 is performed exclusively at a single laboratory location, which is owned and operated by Genome Dx Therapeutics Inc. The following information is provided regarding the performing laboratory:
GDT's San Diego Reference Laboratory has been continuously operational since March 15, 2019, and holds a valid Certificate of Accreditation under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. § 263a, authorizing the laboratory to perform high-complexity testing. The laboratory is additionally accredited by the College of American Pathologists (CAP), which serves as a deemed accrediting organization under CLIA. Copies of GDT's current CLIA certificate and CAP accreditation documentation are provided as Exhibits B and C, respectively, to this application.
The laboratory maintains full operational capabilities for specimen accessioning, RNA extraction, library preparation, next-generation sequencing, bioinformatics analysis, quality control, and clinical reporting. All steps of the OncoPrecise GXP-47 test procedure, from specimen receipt through report generation, are performed on-site at the San Diego Reference Laboratory by GDT personnel under the supervision of the laboratory's medical director and scientific leadership team.
Exclusive Performing Laboratory. OncoPrecise GXP-47 is performed exclusively at GDT's San Diego Reference Laboratory. No other laboratory — whether affiliated with GDT or operated by any third party — is authorized, licensed, or equipped to perform OncoPrecise GXP-47. The test relies on proprietary methodologies, algorithms, and bioinformatics pipelines that are maintained exclusively at the San Diego facility. GDT does not sublicense, distribute, or make available the OncoPrecise GXP-47 assay or the TRI algorithm to any external laboratory or entity.
4.2 Laboratory Director and Scientific Leadership
The laboratory's medical director and key members of its scientific leadership team are identified below:
Laboratory Medical Director / Chief Scientific Officer:
Dr. Marcus Yuen, MD, PhD Co-Founder & Chief Scientific Officer Genome Dx Therapeutics Inc.
Dr. Yuen received his MD and PhD degrees from the University of California, San Francisco (UCSF), where his doctoral research focused on molecular biomarkers of therapeutic response in thoracic malignancies. Dr. Yuen serves as both the Co-Founder and Chief Scientific Officer of GDT and as the Medical Director of GDT's San Diego Reference Laboratory. In his capacity as Medical Director, Dr. Yuen is responsible for the overall scientific and medical direction of the laboratory, oversight of test development and validation activities, quality management, and compliance with applicable CLIA and CAP requirements. Dr. Yuen's curriculum vitae is provided as Exhibit I to this application.
Chief Executive Officer:
Dr. Anisha Raval, PhD Co-Founder & Chief Executive Officer Genome Dx Therapeutics Inc.
Dr. Raval received her PhD in molecular biology from Stanford University, where her research focused on genomic approaches to cancer classification and therapeutic target identification. Dr. Raval serves as the Co-Founder and Chief Executive Officer of GDT and is responsible for overall corporate strategy, operations, and business development.
Section 5: Test Description — OncoPrecise GXP-47
5.1 Test Name and Overview
OncoPrecise GXP-47 is a proprietary, laboratory-developed test (LDT) that utilizes next-generation sequencing technology to perform RNA expression profiling across a panel of 47 carefully selected genes. The test is designed to generate a composite, algorithm-derived numerical score — the Therapy Response Index (TRI) — that provides clinically actionable information regarding a patient's predicted likelihood of response to immune checkpoint inhibitor (ICI) therapy in non-small-cell lung cancer (NSCLC).
The OncoPrecise GXP-47 assay represents the second product developed on GDT's OncoPrecise platform, building upon the technological infrastructure, bioinformatics capabilities, and operational expertise established through the development and commercialization of OncoPrecise GXP-12. While the two products share certain common platform elements (including core sequencing workflows and quality control systems), OncoPrecise GXP-47 incorporates a distinct gene panel, a novel proprietary algorithm, and a fundamentally different clinical application and intended use compared to OncoPrecise GXP-12.
5.2 Clinical Indications and Intended Use
Intended Clinical Use. OncoPrecise GXP-47 is intended to guide oncologist decision-making regarding the selection of first-line systemic therapy for patients with advanced non-small-cell lung cancer. Specifically, the test is designed to provide predictive information regarding whether a patient is likely to respond to first-line immune checkpoint inhibitor (ICI) therapy — including agents such as pembrolizumab (Keytruda®), nivolumab (Opdivo®), and atezolizumab (Tecentriq®) — versus conventional platinum-based chemotherapy. The test addresses a critical unmet need in the clinical management of advanced NSCLC, where existing biomarkers for predicting ICI response have demonstrated limited accuracy and clinical utility, as further described in Section 8 of this application.
Target Patient Population. The target patient population for OncoPrecise GXP-47 comprises adult patients (age 18 years and older) with newly diagnosed Stage IIIB or Stage IV non-small-cell lung cancer who are candidates for first-line systemic therapy. The test is intended for use in the treatment-naïve setting, prior to the initiation of first-line therapy, to inform the therapeutic decision between ICI-based therapy and platinum-based chemotherapy. Patients who have previously received systemic therapy for NSCLC, or who have actionable driver mutations (e.g., EGFR, ALK, ROS1, BRAF V600E) for which targeted therapies are indicated, are outside the primary intended use population for OncoPrecise GXP-47.
TRI Score Interpretation and Clinical Response Categories. The Therapy Response Index (TRI) score generated by OncoPrecise GXP-47 is a continuous numerical score on a scale of 0 to 100. For clinical decision support purposes, the TRI score stratifies patients into three predefined clinical response categories:
Integration with Standard Clinical Assessment. The TRI score is intended to be used in conjunction with, and not as a replacement for, standard clinical and pathological assessment of patients with advanced NSCLC. The test is designed to supplement — not supplant — existing clinical decision-making tools, including but not limited to PD-L1 expression testing by immunohistochemistry (IHC), tumor mutational burden (TMB) analysis, assessment of actionable genomic alterations, radiographic staging, performance status evaluation, and other relevant clinical factors. The TRI score provides an additional, independent predictive data point that oncologists may consider alongside the totality of available clinical information when making first-line therapy selection decisions.
5.3 Specimen Type and Requirements
Specimen Type. OncoPrecise GXP-47 is performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue. FFPE tissue is the standard specimen format for histopathological evaluation of solid tumors and is widely available in clinical practice, ensuring broad accessibility of the test for eligible patients.
Specimen Source. Acceptable specimen sources include biopsy specimens and surgical resection specimens obtained from primary NSCLC tumors or from confirmed metastatic sites. Core needle biopsies, transbronchial biopsies, and surgical wedge resections are among the specimen types that may be submitted for testing, provided they meet the minimum tissue and quality requirements set forth below.
Minimum Tissue Requirements. The following minimum tissue and quality parameters must be met for a specimen to be accepted for OncoPrecise GXP-47 testing:
• Minimum tissue volume: [TO BE CONFIRMED — pending final confirmation with Dr. Yuen's laboratory operations team]
• Minimum number of FFPE tissue sections: [TO BE CONFIRMED]
• Minimum tumor cellularity: [TO BE CONFIRMED — estimated ≥ 20% tumor cellularity by pathologist assessment]
• Tissue fixation: Standard 10% neutral-buffered formalin fixation; fixation time of 6 to 72 hours recommended
• Tissue block age: FFPE blocks up to [TO BE CONFIRMED] years old may be accepted, subject to RNA quality assessment
Nucleic Acid Type Analyzed. The test analyzes RNA extracted from FFPE tumor tissue. DNA is not analyzed by the OncoPrecise GXP-47 assay.
Specimen Handling and Shipping Requirements. Specimen collection, handling, and shipping instructions are provided in GDT's Specimen Collection and Handling Guide, which is furnished to ordering physicians and pathology laboratories at the time of test ordering and is included as Exhibit F to this application. General requirements include:
• FFPE tissue blocks or unstained slides should be shipped at ambient temperature in accordance with applicable shipping regulations
• [TO BE CONFIRMED — additional cold chain or preservation requirements, if any]
• Specimens should be accompanied by a completed test requisition form and relevant pathology report confirming the diagnosis of NSCLC and estimated tumor cellularity
5.4 Test Methodology
The OncoPrecise GXP-47 test procedure consists of the following sequential analytical steps, all of which are performed at GDT's San Diego Reference Laboratory by trained laboratory personnel under the supervision of the laboratory medical director:
Step 1: RNA Extraction. Total RNA is extracted from FFPE tumor tissue using a validated RNA extraction protocol optimized for the recovery of high-quality RNA from formalin-fixed specimens. The extraction protocol has been developed and validated by GDT's laboratory team specifically for use with the OncoPrecise platform and employs commercially available reagents and extraction kits in conjunction with proprietary modifications to maximize RNA yield and integrity from FFPE tissue.
Step 2: Targeted RNA Sequencing. Following extraction and quality assessment of isolated RNA, targeted RNA sequencing is performed to measure the expression levels of the 47 genes comprising the OncoPrecise GXP-47 panel. Sequencing is performed using a validated next-generation sequencing (NGS) platform with targeted enrichment probes designed to capture and amplify the 47 gene targets of interest. The targeted sequencing approach enables deep coverage of the genes of interest while minimizing sequencing costs and turnaround time relative to whole-transcriptome approaches.
Step 3: Quality Control Assessment. Rigorous quality control (QC) metrics are applied at multiple stages of the analytical process to ensure the reliability and accuracy of results. QC parameters include, but are not limited to, RNA integrity assessment (RIN score or equivalent metric), library preparation quality metrics, sequencing depth (total read count), on-target mapping rate, and per-gene coverage uniformity. Specimens that fail to meet predefined QC thresholds are flagged for repeat analysis or are reported as quantity not sufficient (QNS) or quality not sufficient.
Step 4: Normalization and Expression Quantification. Raw sequencing data are processed through GDT's proprietary bioinformatics pipeline to normalize gene expression values across the 47 gene targets. Normalization procedures account for inter-sample variability in RNA input, sequencing depth, and other technical factors to ensure that expression values are comparable across specimens and across analytical runs. Following normalization, expression levels for each of the 47 genes are quantified and recorded.
Step 5: Application of Proprietary TRI Algorithm. The normalized expression values for all 47 genes are input into GDT's proprietary Therapy Response Index (TRI) algorithm, a multi-variable weighted computational model that integrates the expression data to generate a single composite numerical score on a continuous scale of 0 to 100. The TRI algorithm applies proprietary gene-specific weights, interaction terms, and threshold parameters that have been developed and validated through extensive training on retrospective cohort data, as described in Section 5.6 below. The algorithm is executed computationally at GDT's San Diego Reference Laboratory using validated software systems.
Step 6: Classification into Response Category. Based on the TRI score generated in Step 5, the result is classified into one of three predefined clinical response categories: High Likelihood of Response (TRI ≥ 70), Intermediate Likelihood of Response (TRI 40–69), or Low Likelihood of Response (TRI < 40). The classification thresholds have been established based on the algorithm development and validation process and are fixed within the assay protocol.
Step 7: Generation of Clinical Report. A comprehensive clinical report is generated for each patient specimen tested. The report includes the patient's TRI score, the assigned response category classification, and interpretive guidance to assist the ordering oncologist in understanding and applying the test results in the context of clinical decision-making. The report also includes relevant quality control metrics, specimen information, and appropriate disclaimers and limitations of the test. A sample clinical report (with all patient identifiers redacted) is provided as Exhibit G to this application.
Turnaround Time. The estimated turnaround time for OncoPrecise GXP-47, from receipt of a compliant specimen at GDT's San Diego Reference Laboratory through issuance of the clinical report, is approximately 7 to 10 business days. [TO BE CONFIRMED — final turnaround time to be validated prior to submission.]
5.5 Gene Panel Composition
The OncoPrecise GXP-47 gene panel comprises 47 genes that have been selected based on their biological relevance to the mechanisms of immune checkpoint inhibitor response and resistance in non-small-cell lung cancer. The gene panel was assembled through a rigorous, data-driven gene selection process that integrated published literature on ICI pharmacology and tumor immunology, GDT's internal research findings, and bioinformatics analyses of publicly available gene expression data sets from NSCLC cohorts treated with ICI therapy.
The 47 genes span the following functional categories:
• Immune Activation Markers: Genes encoding key mediators of T-cell activation, cytotoxic effector function, and adaptive immune response within the tumor microenvironment.
• Tumor Microenvironment Genes: Genes reflecting the composition and functional state of the tumor immune microenvironment, including markers of immune cell infiltration, stromal composition, and immunosuppressive signaling.
• Checkpoint Pathway Genes: Genes directly involved in immune checkpoint signaling pathways targeted by ICI therapies, including PD-1/PD-L1, CTLA-4, and related co-inhibitory receptor-ligand systems.
• Antigen Presentation Genes: Genes involved in major histocompatibility complex (MHC)-mediated antigen processing and presentation, which are critical determinants of tumor immunogenicity and ICI responsiveness.
• Cell Proliferation and signaling Genes: Genes involved in tumor cell proliferation, survival signaling, and oncogenic pathway activation, which may influence the balance between immune-mediated tumor control and immune evasion.
Full Gene List. A complete table listing all 47 genes included in the OncoPrecise GXP-47 panel, including official gene symbols, full gene names, and assigned functional category classifications, is provided as Exhibit E to this application. [NOTE: The final gene list is pending confirmation with Dr. Yuen's laboratory team — see Appendix, Open Item 1.]
Proprietary Nature of Gene Selection. The specific composition of the 47-gene panel, including the selection of individual genes and their assignment to functional categories, represents proprietary intellectual property of Genome Dx Therapeutics Inc. The gene panel composition and the rationale for the inclusion of each gene are the result of GDT's extensive research and development efforts and are protected by GDT's issued and pending U.S. patents. While the identities of the 47 genes will be disclosed in connection with this application and in published validation studies, the algorithmic weighting applied to each gene in the TRI algorithm (as described in Section 5.6) constitutes a trade secret of GDT and will not be publicly disclosed.
5.6 Proprietary TRI Algorithm
The Therapy Response Index (TRI) algorithm is a proprietary, multi-variable weighted computational algorithm developed and validated by Genome Dx Therapeutics Inc. The TRI algorithm is the core intellectual property element that distinguishes OncoPrecise GXP-47 from generic NGS-based gene expression assays and is the principal basis for the unique clinical utility of the test.
Algorithm Input. The TRI algorithm receives as input the normalized RNA expression values for all 47 genes in the OncoPrecise GXP-47 panel, as quantified through the analytical process described in Section 5.4, Steps 1 through 4.
Algorithm Output. The TRI algorithm produces a single composite numerical score on a continuous scale of 0 to 100, where higher scores indicate a greater predicted likelihood of response to immune checkpoint inhibitor therapy and lower scores indicate a lower predicted likelihood of response.
Algorithm Development. The TRI algorithm was developed using machine learning and statistical modeling techniques applied to training data sets derived from retrospective cohorts of NSCLC patients who received ICI therapy and for whom both gene expression data and clinical outcome data (including treatment response and progression-free survival) were available. The algorithm development process involved iterative feature selection, model training, cross-validation, and hyperparameter optimization to identify the optimal gene weights, interaction terms, and model structure for maximizing predictive performance. The specific details of the algorithm architecture, gene weights, and model parameters are proprietary to GDT and are not disclosed in this application.
intellectual Property Protection. The TRI algorithm is protected by multiple issued and pending United States patents held by GDT. As of the date of this application, GDT holds fourteen (14) issued U.S. patents and seven (7) pending U.S. patent applications related to the OncoPrecise platform, a substantial portion of which are directed specifically to the TRI algorithm methodology, gene weighting systems, and composite scoring approaches. Complete lists of issued patents and pending applications are provided as Exhibits K and L, respectively.
Section 6: Analytical Validation Summary
6.1 Analytical Validation Study
The analytical performance characteristics of OncoPrecise GXP-47 have been established through a comprehensive analytical validation study conducted at GDT's San Diego Reference Laboratory (CLIA No. 05D2187432). The analytical validation study was completed on December 14, 2022, and the results were subsequently published in a peer-reviewed scientific journal.
Publication: The analytical validation study was published in the Journal of Molecular Oncology Diagnostics, Volume 18, Issue 4, pages 412–429, December 2022. The full publication is provided as Exhibit A to this application.
The analytical validation study was designed and conducted in accordance with applicable CLIA regulations, CAP requirements, and recognized best practices for the validation of NGS-based laboratory-developed tests, including guidance from the Association for Molecular Pathology (AMP) and the College of American Pathologists. The study was performed entirely at GDT's San Diego Reference Laboratory using the same instrumentation, reagents, protocols, and bioinformatics pipelines that are employed in the routine clinical performance of the test.
6.2 Analytical Performance Characteristics
The analytical validation study evaluated the following performance characteristics of OncoPrecise GXP-47:
Accuracy. The accuracy of the OncoPrecise GXP-47 assay was assessed by comparing gene expression measurements and TRI scores generated by the assay to reference standard measurements. [PLACEHOLDER — specific performance data to be extracted from the published analytical validation manuscript and inserted prior to final submission.]
Precision (Reproducibility and Repeatability). The precision of the assay was evaluated through within-run repeatability studies (intra-assay precision), between-run reproducibility studies (inter-assay precision), and inter-operator reproducibility assessments. [PLACEHOLDER — specific coefficient of variation (CV) data and concordance metrics to be inserted from published study.]
Analytical Sensitivity. The analytical sensitivity (lower limit of detection) of the assay was evaluated to determine the minimum RNA input quantity and minimum gene expression level at which the assay produces reliable and reproducible results. [PLACEHOLDER — specific sensitivity data to be inserted.]
Analytical Specificity. The analytical specificity of the assay was assessed to confirm that the targeted enrichment and sequencing approach accurately measures expression of the intended 47 gene targets without significant cross-reactivity, off-target amplification, or interference from non-target sequences. [PLACEHOLDER — specific specificity data to be inserted.]
Reportable Range. The reportable range of the TRI score generated by OncoPrecise GXP-47 is 0 to 100 on a continuous numerical scale. The analytical validation study confirmed that the assay produces reliable and reproducible TRI scores across the full reportable range.
Interfering Substances Evaluation. The potential effects of common interfering substances on assay performance were evaluated, including but not limited to hemoglobin, melanin, formalin fixation artifacts, and necrotic tissue. [PLACEHOLDER — specific interfering substances data to be inserted.]
Specimen Stability Studies. The stability of FFPE tissue specimens under various storage and shipping conditions was evaluated to establish acceptable specimen handling parameters. [PLACEHOLDER — specific stability data to be inserted.]
The full analytical validation data, including all performance metrics, statistical analyses, and experimental protocols, are presented in the published manuscript provided as Exhibit A and are available in raw data form upon request.
Section 7: Clinical Validation Summary
7.1 CLARITY-LUNG Trial Overview
The clinical validity of OncoPrecise GXP-47 is being evaluated through a prospective, multi-site clinical validation study designated CLARITY-LUNG (Clinical Assessment of RNA-Integrated Therapy Yield in Lung Cancer). The CLARITY-LUNG trial is designed to establish the clinical performance of the TRI score as a predictor of patient response to immune checkpoint inhibitor therapy in the first-line treatment setting for advanced NSCLC.
Study Design. The CLARITY-LUNG trial is a prospective, multi-site, blinded clinical validation study conducted at 14 clinical sites across the United States. The study enrolls adult patients with newly diagnosed Stage IIIB or Stage IV NSCLC who are candidates for first-line systemic therapy. FFPE tumor tissue specimens from enrolled patients are submitted to GDT's San Diego Reference Laboratory for OncoPrecise GXP-47 testing. TRI scores are generated in a blinded manner and are not disclosed to treating oncologists or patients during the treatment period. Patient outcomes, including treatment selection, tumor response, and progression-free survival, are captured through prospective clinical follow-up. The primary analysis evaluates the association between the TRI score and 12-month progression-free survival in patients who receive ICI-based therapy, with the pre-specified performance thresholds of PPV ≥ 0.75 and NPV ≥ 0.80.
Principal Investigator. The CLARITY-LUNG trial is led by Dr. Priya Sundaram, GDT's Vice President of Clinical Development, who serves as the study's overall Principal Investigator. Dr. Sundaram's curriculum vitae is provided as Exhibit J to this application.
Data Safety Monitoring Board. An independent Data Safety Monitoring Board (DSMB) has been established to oversee the conduct of the CLARITY-LUNG trial and to review interim safety and efficacy data. The DSMB is chaired by Dr. Evelyn Matsuda, MD, PhD, a medical oncologist and clinical trialist at the Carrington Cancer Institute in Houston, Texas. The DSMB charter is available upon request.
Enrollment and Timeline. Enrollment in the CLARITY-LUNG trial commenced on January 18, 2023, with a target enrollment of 1,200 patients. The final data readout was originally projected for the fourth quarter of 2024.
7.2 Status of Clinical Validation at Time of Application Drafting
As of the drafting date of this application (March 22, 2024), the CLARITY-LUNG trial is ongoing and enrollment is progressing toward the 1,200-patient target. The CLARITY-LUNG interim analysis had not yet been released as of the date of this draft. It is noted for the record that interim analysis results were subsequently released on March 29, 2024, one week after the preparation of this draft application.
GDT intends to update the clinical validation data presented in this section prior to the final submission of this PLA code application to the AMA CPT Editorial Panel. The final application is expected to incorporate the most current enrollment data, interim analysis results (if available and appropriate for disclosure), and any updated projections for the final data readout.
Prior Retrospective Evidence. In addition to the prospective CLARITY-LUNG trial, the clinical validity of the OncoPrecise GXP-47 gene panel and TRI algorithm is supported by prior retrospective studies analyzing the association between the 47-gene expression profile and ICI treatment outcomes in historical NSCLC cohorts. [PLACEHOLDER — summary of retrospective evidence to be inserted, including key findings from prior publications and internal analyses.]
7.3 Supporting Clinical Evidence
A comprehensive bibliography of peer-reviewed publications supporting the clinical validity and biological plausibility of the OncoPrecise GXP-47 test has been compiled in support of GDT's MolDx technical assessment dossier. This bibliography includes 43 peer-reviewed publications spanning the following topics:
• Immune checkpoint inhibitor pharmacology and mechanisms of action in NSCLC
• Gene expression profiling as a predictive biomarker for ICI response
• Tumor microenvironment characterization and its relationship to immunotherapy outcomes
• Biological roles and clinical significance of the individual genes comprising the OncoPrecise GXP-47 panel
• RNA expression profiling methodologies in FFPE tissue
• Clinical validation frameworks for molecular diagnostic tests in oncology
The full bibliography is included in the MolDx technical assessment dossier (Version 1.0, delivered April 30, 2024) and is available upon request. A summary of the most pertinent retrospective and preliminary evidence supporting the biological plausibility and potential clinical utility of the 47-gene expression panel and TRI algorithm in predicting ICI response in NSCLC is provided in the dossier and may be furnished to the CPT Editorial Panel as a supplement to this application if requested.
Section 8: Clinical Utility
8.1 Unmet Clinical Need
The management of advanced non-small-cell lung cancer has been transformed in recent years by the introduction of immune checkpoint inhibitor (ICI) therapies, which have demonstrated significant improvements in overall survival for a subset of patients. However, a major and persistent challenge in the clinical management of advanced NSCLC is the limited ability of current standard-of-care biomarkers to accurately predict which patients will respond to ICI therapy and which patients will not.
The two most widely used biomarkers for predicting ICI response in NSCLC are PD-L1 expression as measured by immunohistochemistry (IHC) and tumor mutational burden (TMB). While both biomarkers have demonstrated some correlation with ICI treatment outcomes, their predictive accuracy is limited. PD-L1 expression is subject to significant inter-assay variability, temporal heterogeneity, and intra-tumoral heterogeneity, and many patients with low or negative PD-L1 expression nonetheless respond to ICI therapy, while a substantial proportion of PD-L1-high patients fail to respond. Similarly, TMB analysis, while informative in certain contexts, has demonstrated inconsistent predictive performance across studies and patient populations, and its clinical utility as a standalone predictive biomarker remains the subject of ongoing debate.
As a consequence of these limitations, a significant proportion of NSCLC patients currently receive ICI therapy but do not respond, exposing them to the potential toxicity and adverse effects of immunotherapy — including immune-related adverse events (irAEs) such as pneumonitis, colitis, hepatitis, and endocrinopathies — without deriving meaningful clinical benefit. Conversely, patients who would respond to ICI therapy may not receive it if their PD-L1 or TMB results are equivocal or below decision thresholds. There is a clear and widely recognized unmet clinical need for improved predictive tools that can more accurately identify patients who are most likely to benefit from ICI therapy and those who are unlikely to respond, thereby enabling more precise and individualized first-line therapy selection.
8.2 Expected Clinical Utility of OncoPrecise GXP-47