Demonstrating the value of liquid biopsy for lung cancer in a public health care system.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3546-3546
Author(s):  
Rosalyn A. Juergens ◽  
Doreen Anuli Ezeife ◽  
Janessa J. Laskin ◽  
Jason Scott Agulnik ◽  
Desiree Hao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Liquid Biopsy ◽  
Checkpoint Inhibitors ◽  
Molecular Profiling ◽  
Public Health Care ◽  
Smoking History ◽  
Advanced Lung Cancer ◽  
First Line ◽  
Treatment Naïve

3546 Background: Given the challenges of molecular profiling in patients with advanced lung cancer, this prospective study examines clinical outcomes and utility of liquid biopsy in treatment naive stage IV lung adenocarcinoma patients (Cohort 1) and in the setting of resistance to targeted therapy (Cohort 2; not reported here). Methods: This study is being conducted at 6 Canadian centres (NCT03576937) using Guardant 360 (G360), a validated cell-free DNA next-generation sequencing assay that identifies variants in 74 cancer-associated genes, including fusions and copy number gain. Cohort 1 (N = 150) includes patients with treatment-naïve advanced non-squamous lung carcinoma, ≤10 pack-year smoking history, and measurable disease. Patients received standard of care tumour tissue (TT) molecular profiling ( EGFR, ALK +/- ROS1) and liquid biopsy (LB). The primary endpoint was response rate to first-line therapy (RECIST 1.1); secondary endpoints include incremental targetable alterations identified through G360 ( EGFR, ALK, BRAF, ERBB2, KRAS (G12C), NTRK, MET (amplification, exon 14 skipping), RET, ROS1), turn-around time (TAT) and successful molecular profiling rates. Results: To date, 84 eligible patients with clinical data have been accrued to Cohort 1. Median age is 64 (range 23-91), 64% are female, 85% never smokers, 96% have adenocarcinoma. Actionable targets have been identified in 55% of patients using G360 ( EGFR/ALK in 37%), 39% using standard TT profiling. Eight EGFR/ALK aberrations were identified in TT but not LB, while 6 were identified in LB but not TT. TT profiling for EGFR/ALK was unsuccessful in 8% of patients (insufficient tissue, failed biopsy). Fourteen patients (17%) had no ctDNA alterations detected by G360 (low disease burden vs. non-shedding). Of 75 patients receiving first-line treatment, 57% received targeted therapy, 28% chemotherapy combinations, 11% checkpoint inhibitors and 4% were observed. Treatment decisions were informed by G360 alone in 37% and by G360+TT results in 27% (by physician report). Among 46 evaluable patients, ORR was 54% (25/46). Using G360, ORR was 75% (15/20) in those with actionable alterations and 38.5% (10/26) in those without. Using TT, ORR was 67% (14/21) in those with actionable alterations and 44% (11/25) in those without. Mean TAT was 7.9 days (SD+/-1.7) for LB vs 19.9 days (SD+/- 9.8) for TT. Conclusions: Liquid biopsy using G360 identifies actionable targets beyond tissue profiling alone in newly diagnosed lung cancer patients, has faster TAT and yields similar outcomes with targeted and non-targeted therapy. Clinical trial information: NCT03576937 .

scholarly journals Clinical outcomes of patients with HER2-mutant advanced lung cancer: chemotherapies versusHER2-directed therapies

2020 ◽  
Vol 12 ◽  
pp. 175883592093609
Author(s):  
Jiebai Zhou ◽  
Ning Ding ◽  
Xiaobo Xu ◽  
Yong Zhang ◽  
Maosong Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Clinical Outcomes ◽  
Disease Diagnosis ◽  
Advanced Lung Cancer ◽  
Insertion Mutation ◽  
Targeted Agents ◽  
First Line ◽  
Line Therapy ◽  
Exon 20

Background: Lung cancer is now the leading cause of cancer mortality worldwide for both men and women. In non-small cell lung cancer (NSCLC), matching a specifically targeted drug to the identified driver mutation in each patient resulted in dramatically improved therapeutic efficacy, often in conjunction with decreased toxicity. Mutations in HER2 have been identified as an oncogenic driver gene for NSCLC. This retrospective study was conducted to better understand the clinical outcomes of advanced lung cancer patients harboring HER2 mutations treated with chemotherapies and HER2-targeted agents, as well as the optimal clinical choice. Methods: Patients who were diagnosed with advanced lung cancer (stage IIIB/IV) and had undergone molecular testing at Zhongshan Hospital, Fudan University, Shanghai, China from April 2016 to December 2018 were reviewed. For patients that had HER2 mutant advanced lung cancer, we analyzed their clinical and molecular features and clinical outcomes, including overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR). Results: We identified 44 patients harboring HER2 mutations. Their median age was 56 years, with the majority being women ( n = 24), never smokers ( n = 32), and having the adenocarcinoma genotype ( n = 42). Amongst the HER2 mutations present, a 12 base pair in-frame insertion in exon 20 with p.771insAYVM was the most common subtype in patients with known detail variants of HER2 mutation (9/27). The median OS from the date of advanced disease diagnosis was 9.9 months with 24 deaths, and a median follow-up of 12.7 months for survivors. For patients with a known HER2 exon 20 insertion mutation, OS tended to be superior (though not statistically) in the first-line HER2-TKI group to that in the group receiving chemotherapy (10.8 versus 9.8 months, p = 0.40). However, patients that received first-line chemotherapy had a median PFS of 5.9 months, numerically longer than that of the HER2-TKI group (4.6 months, p = 0.63). Patients who received HER2-targeted therapy as first-line therapy had an improved OS (10.8 versus 10.1 months, p = 0.30) and PFS (4.6 versus 2.8 months, p = 0.36) relative to those who received HER2-targeted therapy as subsequent-line therapy, although they did not meet the threshold for statistical significance. Furthermore, patients with AYVM mutation were associated with poor clinical outcomes. Conclusion: Pemetrexed-based chemotherapy remains an important component of care for patients with HER2-mutant NSCLC. HER2-TKI given as an initial therapy may bring more clinical benefits than when given as a subsequent-line therapy. Refining the patient population based on patterns of HER2 variants may help improve the efficacy of anti- HER2 treatment in lung cancer. Developing highly effective and tolerable HER2-targeted agents is urgently needed for this population.

scholarly journals Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages

2020 ◽  
Vol 29 (155) ◽  
pp. 190052 ◽  
Author(s):  
Nicolas Guibert ◽  
Anne Pradines ◽  
Gilles Favre ◽  
Julien Mazieres
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Nonsmall Cell Lung Cancer ◽  
Response To Treatment ◽  
Genomic Alteration

Liquid biopsy refers to the analysis of any tumour-derived material circulating in the blood or any other body fluid. This concept is particularly relevant in lung cancer as the tumour is often difficult to reach and may need an invasive and potentially harmful procedure. Moreover, the multitude of anticancer drugs and their sequential use underline the importance of conducting an iterative assessment of tumour biology. Liquid biopsies can noninvasively detect any targetable genomic alteration and guide corresponding targeted therapy, in addition to monitoring response to treatment and exploring the genetic changes at resistance, overcoming spatial and temporal heterogeneity.In this article, we review the available data in the field, which suggest the potential of liquid biopsy in the area of lung cancer, with a particular focus on cell-free DNA and circulating tumour cells. We discuss their respective applications in patient selection and monitoring through targeted therapy, as well as immune checkpoint inhibitors. The current data and future applications of liquid biopsy in the early stage setting are also investigated.Liquid biopsy has the potential to help manage nonsmall cell lung cancer throughout all stages of lung cancer: screening, minimal residual disease detection to guide adjuvant treatment, early detection of relapse, systemic treatment initiation and monitoring of response (targeted or immune therapy), and resistance genotyping.

scholarly journals Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 111 (8) ◽  
pp. 772-781 ◽  
Author(s):  
Fabio Conforti ◽  
Laura Pala ◽  
Vincenzo Bagnardi ◽  
Giuseppe Viale ◽  
Tommaso De Pas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Advanced Lung Cancer ◽  
First Line ◽  
Randomized Controlled ◽  
Hazard Ratios ◽  
Meta Analyses ◽  
Cell Death Protein

Abstract Background We previously showed that therapy with anti–checkpoints T-lymphocyte-associated protein 4 (anti–CTLA-4) or antiprogrammed cell death protein 1 (anti–PD-1) agents was more effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1. Methods We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti–PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti–PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients’ sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women. Results Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti–PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval [CI] = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti–PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti–PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti–PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti–PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women. Conclusion Women with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.

scholarly journals The evolving immuno-oncology landscape in advanced lung cancer: first-line treatment of non-small cell lung cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591987036 ◽  
Author(s):  
Jia Li Low ◽  
Robert J. Walsh ◽  
Yvonne Ang ◽  
Gloria Chan ◽  
Ross A. Soo
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung ◽  
First Line

Lung cancer is the most common cancer and leading cause of cancer death. While targeted therapies have redefined treatment options for non-small cell lung carcinoma (NSCLC) with genetic aberrations such as epidermal growth factor and anaplastic lymphoma kinase, many patients do not harbour these oncogenic drivers. Cancer immunology has enabled the development of immune modulators that has dramatically altered the therapeutic landscape of advanced NSCLC. The success of immune-checkpoint inhibitors in pretreated NSCLC has led to the conduct of multiple studies exploring their role in the first-line setting. This article provides an overview of the evolving landscape of immune-checkpoint inhibitors with a focus on the programmed cell-death 1 (PD-1; pembrolizumab, nivolumab) and programmed cell-death ligand 1 (PD-L1; atezolizumab, durvalumab, avelumab) immune-checkpoint inhibitors as single agent or in combination with either chemotherapy or with another immune-checkpoint inhibitor in the treatment of NSCLC, the challenges faced, as well as future perspectives.

scholarly journals Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1794
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Francesco Grossi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Circulating Biomarkers ◽  
Small Cell Lung ◽  
Nsclc Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.

scholarly journals Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

2021 ◽  
Vol 9 (1) ◽  
pp. e001933
Author(s):  
Sophie M Poznanski ◽  
Tyrah M Ritchie ◽  
Isabella Y Fan ◽  
Abdullah El-Sayes ◽  
Ana L Portillo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Combined Treatment ◽  
Death Receptor ◽  
High Rate ◽  
Advanced Lung Cancer ◽  
Pd1 Blockade

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

scholarly journals Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhenyu Ding ◽  
Qing Li ◽  
Rui Zhang ◽  
Li Xie ◽  
Yang Shu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dendritic Cell ◽  
Cancer Treatment ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Therapeutic Modality ◽  
Advanced Lung Cancer ◽  
Cell Vaccine ◽  
Lung Cancer Treatment ◽  
Dc Vaccine

AbstractNeoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3–14 doses/person). In total, 12–30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1–2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

scholarly journals Astragalus Polysaccharide Injection (PG2) Normalizes the Neutrophil-to-Lymphocyte Ratio in Patients with Advanced Lung Cancer Receiving Immunotherapy

2021 ◽  
Vol 20 ◽  
pp. 153473542199525
Author(s):  
Shih Ming Tsao ◽  
Tz Chin Wu ◽  
JiZhen Chen ◽  
Feichi Chang ◽  
Thomos Tsao
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Survival Data ◽  
Treatment Initiation ◽  
Checkpoint Inhibitors ◽  
Neutrophil To Lymphocyte Ratio ◽  
Advanced Lung Cancer ◽  
Control Group ◽  
Lymphocyte Ratio ◽  
Astragalus Polysaccharide

Objectives: The neutrophil-to-lymphocyte ratio (NLR) is a prognostic marker in patients with cancer receiving immunotherapy. Recent studies have shown that a high NLR was associated with a poor response and decreased survival. However, there is no intervention to reverse abnormally high NLR and improve clinical outcomes. Astragalus polysaccharide injection (PG2) is an immunomodulatory therapy for cancer-related fatigue. This study aimed to examine whether PG2 might normalize the NLR and affect the overall survival of patients with lung cancer treated with immunotherapy. Materials and Methods: We retrospectively examined the medical records of patients with lung cancer treated with immune checkpoint inhibitors (ICIs) between October 1, 2015 and November 30, 2019. All patients received ICI combination chemotherapies, and some similarly received PG2 (Control vs PG2). The NLR was assessed before treatment and 6 weeks after ICI initiation, and the survival data was collected at least 4 years after treatment initiation for the first enrolled patient. Results: Fifty-three patients were included. Six weeks after ICI initiation, 91.3% of the patients in the PG2 group exhibited a predefined “Decrease or no change” in the NLR, which was 28% higher than that in the Control group (63.3%) ( P = .028). The NLR significantly decreased by 31.60% from baseline in the PG2 group ( P = .012), whereas it increased by 5.80% in the Control group ( P = .572). Six weeks after ICI treatment initiation, both groups had a median NLR of 3.73, and the overall survival was also similar (PG2 vs Control, 26.1 months vs 25.4 months, respectively); however, the PG2 group had a higher median baseline NLR than the Control group (PG2 vs Control, 4.51 vs 2.81, respectively). Conclusion: This study demonstrated that PG2 could normalize the NLR in patients with lung cancer receiving ICI combination treatments.

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