Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC. METHODS: cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results. RESULTS: Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001). CONCLUSIONS: cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.

A pilot of Blood-First diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer.

INTRODUCTION: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic. METHODS: A pilot study assessing Guardant360™ cfDNA-NGS in patients with radiological-suspected advanced-stage lung cancer was performed at an academic cancer centre during COVID-19. Variants were tiered using AMP/ASCO/CAP guidelines and discussed at a tumour molecular board. The primary endpoint was the proportion of patients who commenced targeted treatment based on cfDNA-NGS results without tissue molecular results, predicted to be ≥ 10%. RESULTS: Between April 2020-May 2021, 51 patients were enrolled; 49 were evaluable. The median age was 71 years, 43% were never-smokers, 86% had stage IV disease. 80% of evaluable cfDNA-NGS were informative (tumour-derived cfDNA detected). cfDNA-NGS detected 30 (61%) AMP/ASCO/CAP tier 1 variants, including 20 additional tier 1 variants compared to tissue testing. Three patients with non-informative cfDNA-NGS had tier 1 variants identified on tissue testing. Eleven (22%; 95%CI 12%-27%) patients commenced targeted therapy based on cfDNA-NGS results without tissue molecular results, meeting the primary endpoint. Median time to results was shorter for cfDNA-NGS compared to standard-of-care tissue tests (9 versus 25 days, P < 0.0001). CONCLUSION: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making.

Safety monitoring of two and four-weekly adjuvant durvalumab for patients with stage III NSCLC: implications for the COVID-19 pandemic and beyond.

Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.

Systemic treatment of brain metastases in non-small cell lung cancer.

Brain metastases (BrMs) are associated with significant morbidity and are found in up to 50% of patients with advanced non-small cell lung cancer (NSCLC). Most of the literature focuses on symptomatic BrMs, with a lack of baseline brain imaging in asymptomatic patients. Unfortunately, much of the data on local treatments with or without systemic treatment is retrospective. Clinical trials of systemic treatments largely exclude patients with BrMs. Chemotherapy is an active treatment for BrM with response rates in the brain similar to other sites of disease. Targeted systemic treatments in patients with driver mutations (EGFR and ALK-MET to date) have impressive central nervous system (CNS) penetrance and response rates. Unfortunately, no prospective data can currently guide the timings or modality of local therapies with systemic treatments in these patients who have a high incidence of CNS disease, but retrospective data suggest that early local therapies may give better intracranial progression-free survival (ICPFS). Recent immunotherapy trials have included patients with BrMs. These patients have largely been pre-treated with local therapies and are asymptomatic. Thus, the current standard is becoming, early local therapies before or in conjunction with immunotherapy agents. The approach seems to be safe. Prospective studies are needed in NSCLC BrMs patients to make sure any benefit from local therapies on the ICPFS and quality of life is not overlooked. Here we report what we think are reasonable conclusions from the available data and make suggestions for future clinical trials in the management of NSCLC BrMs.