International Society of Liquid Biopsy Annual Congress 2022

Specialty Pharmacist

Welldyne Specialty Pharmacy Service, Clinical Oncology

Lakeland, FL

The International Society of Liquid Biopsy (ISLB) held their 2022 Annual Congress on October 20th to 22nd in Miami, Florida. This hybrid event was the 4th annual meeting since ISLB was founded in 2017. ISLB aims to join healthcare professionals and world experts to expand the adoption of liquid biopsy as a clinical tool in oncology.

ISLB President, Dr. Christian Rolfo, Professor of Medicine at The Tisch Cancer Institute at Mount Sinai, greeted attendees and discussed ISLB activities including webinars, workshops, and “Critical Reviews in Oncology/Hematology” which is the official journal of ISLB. Dr. Rolfo also introduced clinical liquid biopsy application projects which will aid in establishing guidelines and in standardizing liquid biopsy labs around the world. He also announced the launch of “Certificate of Advanced Studies in Liquid Biopsy” as a new career development opportunity.

Presentations that may be of particular interest to HOPA members are highlighted below:

• How to Balance Next Generation Tumor Tissue Testing versus Liquid Biopsy Algorithms in the Clinic
  • Application of pathologist-initiated broad molecular reflex testing has brought remarkable value to Non-Small Cell Lung Cancer (NSCLC) diagnostics by providing complete results for treatment decision-making. Over 30% of US patients still start treatment without complete molecular results due to long test turnaround times and inadequate tissue samples.1 The speaker, Dr Leighl, addressed how integrating liquid biopsy into routine diagnostics will help more advanced NSCLC patients access optimal therapy. Conventionally, tissue genotyping is considered as standard of care and a plasma test is ordered if patients are unfit for an invasive biopsy or if tissue collection is inadequate for DNA sequencing (Sequential testing). Two approaches, “Concurrent Testing “ and “Plasma First Testing” were addressed to reduce time to treatment.2 “Concurrent Testing” is to send out both tissue and liquid samples for the complementary result as liquid biopsy overcomes tumor heterogeneity. “Plasma First Testing” is to order liquid biopsy test as part of the initial diagnostic workup while awaiting pathologic confirmation of advanced NSCLC. Dr Leighl reviewed several studies that investigated clinical utility of these two strategies: NILE and VALUE studies for Concurrent Testing and ACCELERATE and UK studies for Plasma First Testing. 3-6 The NILE study showed plasma testing is not inferior to tissue testing in identifying biomarkers with high concordance. Plasma testing resulted in complete genotyping more rapidly than tissue testing.3 The VALUE study demonstrated concurrent testing did not increase system costs from the Canadian public payer perspective and led to more patients receiving targeted therapy compared to the classic sequential approach.4 In the ACCELERATE and UK studies, "Plasma First testing” was performed while awaiting pathologic confirmation of advanced NSCLC. Thus, leading to faster time to results, shorter time to treatment, and more patients receiving targeted therapy.5-6 However, Dr Leighl noted the pitfall with plasma first testing approach is the cost for non-NSCLC patients (25% of the total patients were non-NSCLC in ACCELERATE study).

Dr Leighl touched on a few aspects of liquid biopsy in both the early-stage and the relapse setting. Targeted therapies such as EGFR TKIs and immunotherapies are being studied in early disease. In relapsed disease, tissue biopsy remains an issue because only 39% of patients with the first-line osimertinib resistance are able to complete a successful repeat biopsy and next-generation sequencing (NGS).7 Therefore, the liquid biopsy model will become increasingly important for treatment decisions in both disease settings.

Speaker: Natasha Leighl, MD, MMSc FRCPC, FASCO, Professor of Medicine, University of Toronto, Princess Margaret Cancer Centre, Toronto, Canada

• Dealing with Cost, Reimbursement and Co-pays in Liquid Biopsy
  • NGS testing can improve care and aid in clinical decision making. However, reimbursement remains a barrier to full adoption. A survey by Boston Healthcare Associates in 2018 showed reimbursement and cost are key concerns in launching NGS test products. Commercial coverage policies for circulating tumor DNA (ctDNA) testing change rapidly with positive movement, but primary commercial payors’ focus is skewed for lung cancer. The presenter shared an example with United Healthcare and Aetna’s ctDNA test coverage for NSCLC patients. Coverage is limited to no more than 50 genes for pathologically confirmed patients who are medically unfit for invasive biopsy or have insufficient tissue for molecular testing. Payors require analytical validity, clinical validity, and clinical utility in determining test coverage. Clinical utility is the biggest focus to ascertain risks and benefits in incorporating liquid biopsy into routine practice. In an effort to secure payor coverage, it is essential for test developers to create comprehensive technical assessments and invest in demonstrating clinical utility.

Another barrier to access is the patient copay. It is challenging to correctly set an expectation for out-of-pocket costs since ctDNA copays are highly variable. The ‘No Surprises Act’ came into effect in 2022 to protect people from unexpected medical bills. All options need to be considered to maximize reimbursement and minimize patient cost. A possible alternative is to use compliant billing. For example, genes in the NGS test must be reviewed since different ctDNA CPT codes based on the number of genes are associated with various reimbursement rates. Molecular “NOC” (Not Otherwise Classified) code is often used, but test price and reimbursement are variable and high denial risk exists.

Speaker: Sarah Clancey Overton, Director of Reimbursement at PierianDx, CA, USA

• Liquid Biopsy: Regulatory Challenges and Opportunities from a Global Perspective
  • With the increasing number of clinical trials to validate ctDNA as endpoint in the perioperative setting of early-stage cancer, the FDA issued “Guidance of ctDNA use for Early-Stage Solid Tumor Drug Development” in March 2022 to provide perspectives on trial design, validation of ctDNA endpoints, and assay standardization.8 A major focus of the FDA guidance is on trial designs for ctDNA Molecular Residual Disease (MRD) after curative intent therapy. Dr. Vellanki discussed three trial designs: stratification, enrichment, and adaptive enrichment. One approach is to stratify patients by ctDNA status after surgery or neoadjuvant therapy to receive adjuvant standard of care treatment with or without investigational therapy (Stratification trial design). Enrichment trial design is another approach to enrich for a high-risk population by enrolling only ctDNA-positive patients. Thus, helping lead trials to completion in a shorter time than with a conventional design. Another variation is to close the ctDNA-negative arm at the interim analysis (Adaptive Enrichment trial design). Trials must correlate ctDNA-MRD status with long term outcomes such as disease-free survival and overall survival to validate ctDNA clearance as early endpoint.

To support its use as a response biomarker, ctDNA tests must be standardized within a trial to accurately interpret results and harmonize across trials. Assay analytical validation must be established for assay cutoffs, ctDNA positivity determination, high sensitivity/negative predictive values for de-escalation studies, and high specificity/positive predictive values for escalation studies. The FDA guidance also addresses sampling considerations including standardized protocols for sample collection, storage, processing, and handling. Clinical trials should pre-specify the timing of ctDNA testing considering differences in ctDNA shedding based on histology, grade, stage, and tumor burden.

Speaker: Paz Vellanki, MD, PhD, Medical Oncologist, U.S. Food and Drug Administration

• Redefining ctDNA Endpoints in Perioperative Clinical Trials
  • Dr Leighl addressed challenges in validating ctDNA MRD clearance as an endpoint in clinical trials for early-stage NSCLC. She discussed how liquid biopsy can be used to provide better biomarkers as an endpoint in perioperative clinical trials. Impower010 led to approval of atezolizumab as adjuvant therapy for resected NSCLC with stage IB-IIIA. In this trial, ctDNA was prognostic, but disappointingly it did not help to select therapy even with a sensitive tumor-informed assay (Limit of Detection, LOD 0.01%).9 Dr Leighl emphasized the need for greater sensitivity in MRD assay for solid tumors. CheckMate816 and NADIM II studies demonstrated that perioperative therapy improved pathologic complete response (pCR) in resectable stage III NSCLC. Both studies provided evidence that pCR is a promising surrogate endpoint and CheckMate816 suggested ctDNA clearance was associated with pCR.10-11 Dr Leighl suggested ctDNA clearance may be incorporated as a part of a composite endpoint in conjunction with pCR rather than a standalone endpoint.

Speaker: Natasha Leighl, MD, MMSc FRCPC, FASCO, Professor of Medicine, University of Toronto, Princess Margaret Cancer Centre, Toronto, Canada

• ISLB Research Award Lecture: Enhanced Detection of Minimal Residual Disease by Targeted Sequencing of Phased Variants in Circulating Tumor DNA
  • Dr. Diehn presented a new ctDNA MRD assay that he and his team recently developed at Stanford University. MRD is a key prognostic marker for tumor recurrence, but the existing ctDNA MRD assays have insufficient analytic sensitivity with LOD of 0.01% for detecting the majority of MRD shortly after treatment of solid tumors. This suboptimal sensitivity is derived from background error rate. The first generation ctDNA MRD assays quantify ctDNA by sequencing “Single Nucleotide Variants” (SNV) of mutation and overcoming the background error rate with this method has been challenging. Dr. Diehn and his team successfully increased assay sensitivity to 0.0001% by sequencing ”Phased Variants” (PV) where multiple mutations occur on the same strand of DNA instead of SNV which contains only one mutation. This technique, Phased variant Enrichment and Detection Sequencing (PhasED-Seq), reduces the background error rate by increasing the number of concordant mutation events from one to two or more. Dr. Diehn’s team found the presence of the phased mutations in diverse cancer types and applied PhasED-Seq to lung and breast cancer for MRD detection improvement.12 This finding shows the broad application potential to detect more MRD-positive patients for adjuvant therapy escalation trials and to minimize false negatives for de-escalation trials.

Speaker: Maximilian Diehn, MD, PhD, Professor of Radiation Oncology, Division Chief of Radiation and Cancer Biology at Stanford University, CA

Liquid biopsy plays an important role in the development of therapeutics and diagnostics across the cancer care continuum from early screening and diagnosis to measuring MRD after surgery to monitoring patients with metastatic disease and determining mechanism of resistance. ctDNA analysis brought a significant advance to the liquid biopsy arena. The ctDNA plasma test is used in various cancer types to detect biomarkers for guideline-recommended targeted therapy and it is being tested in prospective studies in stage II and III colorectal cancer. However, questions remain regarding which technologies provide the best specificity and sensitivity. In the future, liquid biopsy can be refined by moving beyond ctDNA to integrate different types of liquid biopsies including epigenetics, fragmentomics, and T-cell receptors to identify histologic transformation at disease relapse, carcinoma of unknown primary, and resistance mechanisms to immunotherapy.

Recommended Reading/References:

1. Hess LM, Krein PM, Haldane D, Han, Y, et al. Biomarker testing for patients with advanced/metastatic non-squamous NSCLC in the United States of America 2015-2021. JTO Clinical and Research Reports. 2022 June 01;3(6):100336
2. Rolfo C, Mack P, Scagliotti GV, Aggarwal C, et al. Liquid biopsy for advanced NSCLS: a consensus statement from the international association for the study of lung cancer. Journal of Thoracic Oncology. 2021 October;16(10):1647-1662.
3. Leighl N, Page RD, Raymond VM, Daniel DB, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic NSCLC. Clinical Cancer Research. 2019 August 01;25(15): 4691-4700.
4. Ezeife DA, Spackman E, Juergens RA, Laskin JJ, et al. The economic value of liquid biopsy for genomic profiling in advanced non-small cell lung cancer. Therapeutic Advances in Medical Oncology. 2022;14. Doi.org/10.1177/17588359221112696
5. Garcia-Pardo M, Czarnecka K, Law JH, Salvarrey AM, et al. Plasma first: Accelerating lung cancer diagnosis through liquid biopsy. Journal of Clinical Oncology. 2022;40(Suppl16), ASCO 2022 Abstract 3039.
6. Cui W, Milner-Watts C, McVeigh TP, Minchom A, et al. A pilot of blood-first diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer. Lung Cancer. 2022 Jan 20;165:34-42.
7. Piotrowska Z, Agn YK, Pang SH, Kim S, et al. A multicentre, molecular profiling study of patients with EGFR-mutated advanced NSCLC treated with first-line osimertinib. ESMO 2022 September 11: LBA53-ELIOS
8. U.S. Food and Drug Administration. Use of Circulating Tumor DNA for Early-Stage Solid Tumor Drug Development. Guidance for Industry (Draft Guidance). 2022 May. https://www.fda.gov/media/158072/download
9. Felip E, Srivastava M, Rect M, Zhou C et al. ctDNA status in patients with resected NSCLC who received adjuvant chemotherapy followed by Atezolizumab or best supportive care. Immuno-Oncology and Technology. 2022 December 1; Volume 16, Supplement 1, 100106. DOI:https://doi.org/10.1016/j.iotech.2022.100106
10. Forde PM, Spicer J, Lu S, Provencio M, et al. Neoadjuvant Nivolumab plus chemotherapy in resectable lung cancer. New England Journal of Medicine. 2022;386:1973-85.
11. Romero A, Serna R, Nadal E, Provencio M, et al. Pre-treatment ctDNA levels significantly predicts of OS and PFS in NADIM II trial. Journal of Thoracic Oncology. 2022 September:17(9):S63. Presented at IASLC-WCLC 2022 June 24; Abstract PL03.12.
12. Kurtz DM, Soo J, Keh LCT, Alig S et al. Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nature Biotechnology. 2021 December;39(12):1537-1547.