Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9097-9097
Author(s):  
Takaya Ikeda ◽  
Hajime Oi ◽  
Kiyotaka Yoh ◽  
Shingo Matsumoto ◽  
Terufumi Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell ◽  
Clinical Utility ◽  
Checkpoint Inhibitors ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Median Number ◽  
Lung Cancer Patients ◽  
Mutation Burden ◽  
Nsclc Patients

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.

scholarly journals Prognostic role of immunosenscence associated with index in elderly non-small cell lung cancer patients treated with an anti-PD-1 antibody.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 100-100
Author(s):  
Tomohiro Tanaka ◽  
Tatsuya Yoshida ◽  
Ken Masuda ◽  
Yuki Takeyasu ◽  
Yuki Shinno ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Multivariate Regression Analysis ◽  
Median Number ◽  
Female Ratio ◽  
Lung Cancer Patients ◽  
Age Related ◽  
Number Of Treatment ◽  
Nsclc Patients

100 Background: Immunosenescence, an age-related impairment of the immune system, dampens acquired immunity and promotes inflammation. Therefore, it could also influence the degree of effectiveness of immune checkpoint inhibitors. Methods: We retrospectively reviewed the data of 52 NSCLC patients aged ≧75 years old treated with nivolumab or pembrolizumab from December 2015 to April 2019. Immunosenescence was assessed by the modified Glasgow Prognostic Scale (mGPS), Neutrophil-to-lymphocyte ratio (NLR), and Charlson Comorbidity Index (CCI), which are related to nutrition, inflammation and comorbidity, respectively. The Cox proportional hazard model and Kaplan-Meier curves were used to identify factors associated with survival. Results: The median follow-up duration was 19.5M (IQR:1-41). The patient characteristics were as follows: median age 79.7 years; male/female ratio, 41/11; PS0/1/2/3, 10/32/8/2; adeno/squamous histology/others, 33/15/4;stage III/IV/recurrence, 2/26/24; PD-L1 (22C3) (%)unknown/0/1-49/50-100, 18/2/8/24; driver mutation status positive/negative, 11/41; nivolumab/pembrolizumab, 29/23; treatment line 1/2/3/4 or more, 28/15/3/6; median number of treatment cycles 7.0 (1-53). The overall response rate (ORR) and disease control rate (DCR) were29.1% and 56.2%, respectively. The median progression-free survival (PFS) was 4.2 months (95% CI 1.8-7.5). The mGPS was significantly associated with the DCR (High/Low = 37.5/68.8%, p = 0.02) and the PFS (score 0-1/2 = 4.1/0.6 months) (HR: 0.37, 95% CI 0.18-0.74, p <0.01). However, neither the CCI nor the NLR wasassociated with the PFS (CCI: High/Low = 3.8/1.8 months, p = 0.64, and NLR: High (>3.5)/Low (≦3.5) = 3.8/5.6 months, p = 0.89). Multivariate regression analysis identified the mGPS as a significant predictor of the PFS(HR: 0.40, p = 0.008). Conclusions: A high mGPS score was significantly associated with a lower DCR and shorter PFS in elderly NSCLC patients treated with anti-PD-1 antibody.

scholarly journals The Predictive Efficacy of Tumor Mutation Burden (TMB) on Nonsmall Cell Lung Cancer Treated by Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Zhang Nan ◽  
Wang Guoqing ◽  
Yu Xiaoxu ◽  
Mi Yin ◽  
He Xin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Cell Lung Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Nonsmall Cell Lung Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Nsclc Patients

Background. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, and the majority of NSCLC patients are diagnosed at the advanced stage. Chemotherapy is still the main treatment at present, and the overall prognosis is poor. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs) as the representative have been extensively applied for treating various types of cancers. Tumor mutation burden (TMB) as a potential biomarker is used to screen appropriate patients for treatment of ICIs. To verify the predictive efficacy of TMB, a systematic review and meta-analysis were conducted to explore the association between TMB and ICIs. Method. PubMed, EMBASE, Cochrane Library, and son on were systematically searched from inception to April 2020. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were estimated. Results. A total of 11 studies consisting of 1525 nonsmall cell lung cancer (NSCLC) patients were included. Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046 ); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001 ); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001 ). Subgroup analysis values: pooled HRs for OS, 0.75 (95% CI 0.29 to 1.92, P = 0.548 ) for blood TMB (bTMB), 0.44 (95% CI 0.26 to 0.75, P = 0.003 ) for tissue TMB (tTMB); for PFS, 0.54 (95% CI 0.29 to 0.98, P = 0.044 ) and 0.43 (95% CI 0.26 to 0.71, P = 0.001 ), respectively. Conclusions. These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB. As opposed to bTMB, tTMB was thought more appropriate for stratifying NSCLC patients for ICI treatment.

Training and validation study for sequential monitoring of CAMLs in circulation to predict ongoing progression in lung cancer patients undergoing definitive radiotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3053-3053
Author(s):  
Daniel Adams ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
Hui Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Cancer Patients ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Training Set ◽  
Lung Cancer Patients ◽  
Therapeutic Decisions ◽  
Validation Set ◽  
Nsclc Patients

3053 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of cancer patients that are prognostic for progressive disease. Further, it has been shown that changes in CAML size (i.e. enlargement above 50µm) can predict progression free survival (PFS) in thoracic cancers (e.g. lung). We enrolled 104 unresectable non-small cell lung cancer (NSCLC) patients, with an initial training set review of 54 patients, to determine if change in CAML size after radiation therapy was predictive PFS. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of chemo radiation, or radiation therapy. To achieve a 2-tailed 90% power (α = 0.05) we recruited a training set of 54 patients and validation set of 50 patients all with pathologically confirmed unresectable NSCLC: Stage I (n = 14), Stage II (n = 16), Stage III (n = 61) & Stage IV (n = 13). Baseline (BL) blood samples were taken prior to start of therapy & a 2nd blood sample (T1) was taken after completion of radiotherapy (~30 days). Blood was filtered by CellSieve filtration and CAMLs quantified. Analysis by CAML size of < 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate & multivariate analysis. Results: CAMLs were found in 95% of samples averaging 2.7 CAMLs/7.5mL sample at BL, with CAMLs ≥50 µm having reduced PFS (HR = 2.2, 95%CI1.3-3.8, p = 0.003). At T1, 18 patients had increased CAML size ≥50 µm with PFS (HR = 4.6, 95%CI2.5-8.3, p < 0.001). In total, ≥50 µm CAMLs at BL was 76% accurate at predicting progression within 24 months while ≥50 µm CAMLs at T1 was 83% accurate at predicting progression. Conclusions: In unresectable NSCLC patients, enlargement of CAMLs during treatment is an indicator active progression. We identify that a single ≥50 µm CAML after induction of radiotherapy, in our training set and confirmed in our validation set, is an indicator of poor prognosis. We suggest that changes in CAML size during therapy may indicate the efficacy of therapy and could potentially help shape subsequent therapeutic decisions.

Immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients with WNT pathway mutations (APC/CTNNB1).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15137-e15137
Author(s):  
Patricia Iranzo ◽  
Ana Callejo ◽  
Anna Pedrola ◽  
Nuria Pardo Aranda ◽  
Alejandro Navarro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Wnt Pathway ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Whole Exome ◽  
Pathway Activation ◽  
Metastatic Setting ◽  
Targeted Ngs ◽  
Unknown Significance ◽  
Nsclc Patients

e15137 Background: APC and CTNNB1 mutations (mut) lead to an aberrant activation of the WNT pathway which has been linked to lack of benefit of immunotherapy in patients (pts) with lung cancer. Our aim is to describe the pts’ characteristics of a NSCLC cohort with APC or CTNNB1 mut and their association with outcomes (Overall survival [OS] and Progression-Free-Survival [PFS]) when treated with ICI. Methods: We selected NSCLC pts with mut in APC or CTNNB1 by targeted NGS (tissue), whole exome sequencing (tissue) or Guardant 360(plasma) between January 2014 and October 2019. Functionality of mut and β-catenin protein expression by immunohistochemistry (IHC) were correlated with outcome. Results: We identified a total of 37 patients with 44 mutually-exclusive mutations in APC (31) or CTNNB1 (6), 25 adenocarcinomas (68%). Of APC mut cohort, 16 had pathogenic mut (52%) and 15 of unknown significance (48%). All 6 CTN NB1 mut were known pathogenic. Median OS (mOS) in metastatic setting was 21.6 months (m) (CI95% 14.9-NR), without differences between APC and CTNNB1 groups (HR 1.5, p = 0.4) or when stratified by mut functionality (HR 1.1, p = 0.8). Globally, 21 pts received treatment with ICI (57%, 19 APC, 2 CTNNB1), median PFS (mPFS) was 5.43m (1.8-21.7), with trend for shorter mPFS in CTNNB1 mut (mPFS 1.7m) vs. APC mut (mPFS 6.6m, HR 1.5, p = 0.1). Among patients treated with ICI, 8 (38%) had coexisting driver targetable alterations ( EGFR, ERBB2 or MET) and 13 (62%) other functional mut were found ( TP53, KRAS, STK11, BRCA2, ATM). mPFS was 3.9m (1.8-NR) in the subgroup with driver mut vs. 6.6m (1.4-NR) for remaining pts (HR 1.36, p = 0.5). In 15 pts β-catenin IHC was performed, being positive in 7 cases (47%), 4 of them received ICI with a mPFS 12.1m. Conclusions: In our experience, benefit with ICI is not influenced by the presence of APC mut, and small numbers of CTNNB1 cohort limit conclusive statements. Additional studies are required to assess WNT pathway activation on top of genomics and correlate with the ICI efficacy.

Impact of SWI/SNF complex mutations in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors: Immuno-oncology biomarker study in LC-SCRUM-Japan (LC-SCRUM-IBIS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9530-9530
Author(s):  
Kiyotaka Yoh ◽  
Shingo Matsumoto ◽  
Naoki Furuya ◽  
Kazumi Nishino ◽  
Shingo Miyamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

9530 Background: The SWI/SNF chromatin remodeling complex is reported to be involved in sensitivity and resistance to immune checkpoint inhibitor (ICI). However, their role in non-small cell lung cancer (NSCLC) remains unclear. We examined the relationship between SWI/SNF complex mutations and clinical outcomes of ICI in patients with NSCLC. Methods: Of 1017 lung cancer patients enrolled in LC-SCRUM-IBIS, 350 patients were analyzable for whole-exome sequencing (WES). WES data were used to analyze the presence of mutations in 29 major subunits of the SWI/SNF complexes. ARID1A and SMARCA4 mutations were also evaluated in a targeted NGS panel (Oncomine comprehensive assay, OCA). PD-L1 expression by 22C3, tissue tumor mutational burden (tTMB) by WES, STK11 and KEAP1 mutations by WES or OCA were also assessed. Durable clinical benefit (DCB) including CR, PR and SD > 6 mos to ICI, progression-free survival (PFS) and overall survival (OS) were compared in status of each of SWI/SNF complex mutations and other factors. Results: At least one mutation in any subunits of the SWI/SNF complex was present in 28% of NSCLC patients. The most common mutated subcomplexes were SMARCA4 (12%), BAF (7%: ARID1A, 4%), non-canonical BAF (3%), PBAF (3%), and SMARCA2 (2%). Of 101 NSCLC patients treated with PD-1/PD-L1 inhibitors, SMARCA4 mutations tended to be associated with lower DCB (16 vs 31%) and shorter median PFS (1.9 vs 3.6 m) and OS (7.4 vs 18.1m). Patients with ARID1A mutations tended to have better clinical outcomes (DCB, 40 vs 28%) compared to those without mutations. No significant associations were found between PD-L1 expression and SMARCA4 or ARID1A mutations. Patients with STK11/KEAP1 mutations had lower rate of PD-L1 expression (TPS > 50%) (18% vs 48%, P = 0.03) and worse clinical outcomes (DCB, 6 vs 33%) compared to those without mutations. There was no significant association between a tTMB status and clinical outcome. Conclusions: SMARCA4 and ARID1A mutations appear to affect clinical outcomes of ICI in NSCLC patients. These findings indicate that SWI/SNF complex mutations may serve as a predictive biomarker for ICI in NSCLC patients.

Baseline systemic inflammatory immune index may predict overall survival and progression-free survival in patients with non-small cell lung cancer patients on immune checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21202-e21202
Author(s):  
John P. Palmer ◽  
Yenong Cao ◽  
Samer Ibrahim ◽  
Natasha Dhawan ◽  
Muhammad Zubair Afzal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
The Mean ◽  
Nsclc Patients

e21202 Background: Increased systemic inflammatory state and increased inflammation within tumor micro-environment (TME) have been associated with a worse prognosis and lower responsiveness to immune checkpoint inhibitors (ICI). Systemic inflammatory immune index (SII) reflects the changes in the systemic inflammatory matrix. Studies have shown the association of SII with cancer survival and treatment outcomes. We aim to study the effect of SII on treatment outcomes in non-small cell lung cancer (NSCLC) patients being treated with ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs (pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab) alone or in combination with chemotherapy. SII is the product of platelets multiplied by neutrophils divided by lymphocytes. Baseline and 8-week SIIs were obtained. Radiographic response, duration of radiographic response (date of best response to radiographic progression), overall survival (OS), and progression-free survival (PFS) were evaluated. A high SII was defined as a value greater than the median SII. Cox regression univariate and multivariate analyses were performed. Logistic regression, t-test, and Chi-square tests were applied. Results: Overall, 81% patients had adenocarcinoma and 19% patients had squamous, adenosquamous or large cell carcinoma. The majority of the patients were female (56.2% vs. 43.8%). Median SII at baseline was 1335. The objective response rate (ORR) was 45.1%. The disease control rate was 75.8%. The ORR was 51% in patients receiving ICI first-line compared to 35% in those who received ICI as a second-line therapy. At baseline, there was no difference in the mean SII between responders and non-responders (2146.2 vs. 1917.5, P = 0.5); however at 8 weeks, the mean SII was significantly lower in responders compared to non-responders (1198.8 vs. 2880.2, P = 0.02). A total of 15 (10.9%) patients were found to have pseudoprogression or mixed response on follow-up imaging. Among these, 11(73.3%) patients had low SII at 8 weeks (P = 0.04). The median OS was significantly higher in patients with low SII at baseline (29.6 months vs. 10.1 months, P = 0.001 95% CI 10.6 – 22.1). Similarly, there was a significant difference in median PFS in patients with low SII (14.6 months vs. 6.7 months, P = 0.002, 95% CI 5.6 – 11.6). There was no correlation between high or low SII on the incidence of immune-related adverse events. Conclusions: SII may have significant impact on OS and PFS and could be serially monitored to assess the response to ICI. A low SII may help to differentiate pseudoprogression vs. true progression. Prospective studies are needed to validate these findings. Further, it will be interesting to see if SII could be incorporated into predictive models to determine the duration of cytotoxic therapy in selected patients.

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