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.

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.

Phase II study of amrubicin (AMR) combined with carboplatin (CBDCA) for refractory relapsed small cell lung cancer (SCLC): North Japan Lung Cancer Group 0802.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7086-7086
Author(s):  
Ryota Saito ◽  
Akira Inoue ◽  
Shunichi Sugawara ◽  
Satoshi Oizumi ◽  
Makoto Maemondo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Performance Status ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Median Number ◽  
First Line ◽  
Cancer Group ◽  
Grade 3 ◽  
Line Setting ◽  
Number Of Treatment

7086 Background: AMR, a new anthracycline agent, has achieved some promising results for advanced SCLC both in the first-line and the second-line setting. However the efficacy of AMR alone against refractory relapsed SCLC was relatively low in previous studies. This study was conducted to evaluate the safety and efficacy of the combination of AMR plus CBDCA in patients with refractory relapsed SCLC. Methods: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30 mg/m2, day1-3) and CBDCA (AUC 4.0, day 1) every 3 weeks. The primary endpoint of this study was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 45% in eligible patients would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.10, at least 24 patients were required. Results: From September 2008 to May 2011, 30 patients were enrolled from 10 institutions. One patient was excluded because of ineligible histology. Patient characteristics were: Male/Female 26/3; median age 67 (range 50-81); Performance status 0/1/2 9/16/4. The median number of treatment cycles were 4 (range 1-7). The objective responses evaluated by RECIST were: CR 0, PR 10, SD 14, PD 5. The ORR was 34% and the disease control rate was 83%. Median PFS was 3.5 months and median survival time was 7.3 months. Grade 3-4 neutropenia was observed in 23 patients (79%) and grade 3-4 thrombocytopenia was observed in 7 patients (24%). One patient (3%) suffered from grade 3-4 febrile neutropenia. Other grade 3 non-hematological toxicities such as infection, interstitial lung disease, hyponatremia, hypoglycemia, were observed in 7 patients (24%). No treatment related death was observed. Conclusions: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. Further investigation of this treatment is warranted.

scholarly journals Durvalumab in NSCLC: latest evidence and clinical potential

2018 ◽  
Vol 10 ◽  
pp. 175883591880415 ◽  
Author(s):  
Nerea Muñoz-Unceta ◽  
Isabel Burgueño ◽  
Elizabeth Jiménez ◽  
Luis Paz-Ares
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Significant Activity ◽  
Unresectable Stage ◽  
Favourable Safety ◽  
Favourable Safety Profile ◽  
Nsclc Patients

Advances in immunotherapy have led to radical improvements in outcomes, including overall survival, such as in non-small cell lung cancer (NSCLC) patients with metastatic disease treated with immune checkpoint inhibitors. More recently, promising results have been obtained in earlier disease settings, and combinations with other therapies are being actively investigated. Durvalumab, a monoclonal antibody directed against the programmed death ligand 1, has demonstrated significant activity in NSCLC, including increased progression-free survival rates after chemoradiation for unresectable stage III disease, with a favourable safety profile. Clinical trials, including phase III studies, are ongoing as monotherapy and in combination with chemotherapy, radiotherapy and other immunotherapies, such as the anti-cytotoxic T-lymphocyte antigen 4 drug tremelimumab, in diverse stages of the disease.

Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 415-415
Author(s):  
Arish Noor ◽  
Luis E. Aguirre ◽  
Kirsten Blue ◽  
Trenton Avriett ◽  
Estrella M. Carballido ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Metastatic Disease ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Cancer Center ◽  
Duration Of Response

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

A randomized phase II study of 500 mg/m2 and 1,000 mg/m2 of pemetrexed in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had prior chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7590-7590 ◽  
Author(s):  
Y. Ichinose ◽  
K. Nakagawa ◽  
T. Tamura ◽  
K. Kubota ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Total Sample ◽  
Median Number ◽  
Vitamin Supplementation ◽  
Toxicity Profile ◽  
Prior Chemotherapy ◽  
Line Setting

7590 Background: Pemetrexed (Pem) 500 mg/m2 (Pem 500) is currently the standard treatment for pts with locally advanced or metastatic NSCLC who had prior chemotherapy. In a recent Japanese phase I study with full vitamin supplementation, 1,000 mg/m2 was determined as the recommended dose. This study was to determine if Pem 1,000 mg/m2 (Pem 1,000) could lead to a better treatment outcome with an acceptable toxicity profile compared with Pem 500 in pts with NSCLC in a 2nd or 3rd line setting. Methods: Pts with PS 0–2, measurable, Stage III/IV NSCLC, who had previously received 1 or 2 chemotherapy regimens, were randomized to receive either Pem 500 or Pem 1,000 on day 1 of a 21-day cycle. The primary endpoint was overall response rate (ORR) based on the RECIST. Secondary endpoints included progression-free survival (PFS), duration of response (DR) and toxicity profile. The planned total sample size for the study was 214 pts. Results: From October 2004 to March 2006, 244 pts were enrolled at 28 centers, 226 pts were randomized and treated, and 216 pts were evaluable for efficacy. Baseline patient characteristics (Pem 500/Pem 1,000: 108/108) were: Males 63%/64%; median age 62/62 years (total range: 26–74); PS 0–1 94%/94%; Stage IV 81%/80%. The median number of treatment cycles completed on both arms was 3 (range 1–20+ for Pem 500 and 1–15+ for Pem 1,000). 11% of the Pem 500 pts and 6% of the Pem 1,000 pts completed at least 10 cycles. ORRs were 18.5% (90% CI: 12.6%-25.8%) for Pem 500 and 14.8% (90% CI: 9.5%- 21.6%) for Pem 1,000, and the respective disease control (PR+SD) rates were 55.6% and 46.3%. Median PFS with Pem 500 and Pem 1,000 was 3.0 and 2.4 months and median DR was 4.7 and 3.8 months, respectively. Grade 4 toxicities observed in more than 1% of pts were neutropenia (3.5% with Pem 500, 3.6% with Pem 1,000) and decreased lymphocyte count (2.6%, 1.8%). One drug related death for interstitial lung disease was reported with Pem 500. Conclusions: Pem 1,000 as well as Pem 500 showed remarkable efficacy outcomes with tolerable toxicity. Since Pem 1,000 showed treatment outcomes similar to Pem 500, this study supports the use of Pem 500 for Japanese pts with NSCLC in a 2nd or 3rd line setting. [Table: see text]

Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7011-7011
Author(s):  
D. Steensma ◽  
H. Kantarjian ◽  
P. Wijermans
Keyword(s):  
De Novo ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Two Phase ◽  
Dosing Schedule ◽  
Transfusion Independence ◽  
Improved Outcomes ◽  
Dosing Regimens ◽  
Number Of Treatment

7011 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients using two dosing regimens: 15 mg/m2 intravenous (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days q 6 weeks (wks) and 20 mg/m2 IV over 1 hr once daily for 5 consecutive days q 4 wks. Methods: Results were reviewed from two randomized phase 3 studies comparing the 3-day dosing schedule of decitabine with supportive care, D-0007 and EORTC-06011, and two phase 2 studies with the 5-day dosing schedule, DACO-020 and ID03–0180. Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed. Results: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03–0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03–0180, 70%; DACO-020, 89%). Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table). The duration of improvement ranged between 9.2 and 11.3 months. A trend was observed for improved outcomes with an increased number of decitabine treatment cycles. Conclusions: Overall improvement rates by IWG criteria exceeded 30% in all 4 studies. Higher overall improvement rates corresponded to increased median number of treatment cycles. Increasing the number of decitabine treatment cycles administered may provide additional benefit to MDS patients. [Table: see text] [Table: see text]

Efficacy and safety of amrubicin in patients with advanced or recurrent thymoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17513-e17513
Author(s):  
Kiyotaka Yoh ◽  
Koichi Goto ◽  
Seiji Niho ◽  
Shigeki Umemura ◽  
Hironobu Ohmatsu ◽  
...  
Keyword(s):  
Tumor Size ◽  
Single Agent ◽  
Reduction Rate ◽  
Progression Free Survival ◽  
Median Number ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Kaplan Meier ◽  
Grade 3 ◽  
Number Of Treatment

e17513 Background: Thymoma is rare thoracic tumor, which is chemoresponsive with anthracycline or cisplatin-containing regimen in advanced or recurrent setting. Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small-cell lung cancer. The purpose of this study was to determine the efficacy and safety of amrubicin in patients with advanced or recurrent thymoma. Methods: We reviewed 11 consecutive patients with advanced or recurrent thymoma treated with single-agent amrubicin therapy at our institution from May 2006 to September 2010, retrospectively. Amrubicin was administered intravenously at 40 or 45 mg/m2 on day 1 to 3 of 3-4 weeks until disease progression or development of intolerance. Results: Profile of patients included: median age was 57 years (range 25–74); Male/Female=5/6; PS 0/1= 7/4; and Masaoka stage IVA/IVB/recurrence=7/2/2. All patients had received no prior chemotherapy. The median number of treatment cycles was 4 (range 3-6). A partial response was achieved in 1 patient and 10 patients exhibited stable disease. The overall response rate was 9%, but 3 patients had at least a 20% reduction in tumor size with amrubicin. The median reduction rate in tumor size was 13% (range 0-40). The median progression-free survival period was 5.4 months (range 2.3-15.8 months). The median overall survival has not been reached although a median follow-up time was 2.5 years. Based on the Kaplan-Meier method, the estimated 3-year survival rate was 83%. The most common adverse events were hematological toxicities. Five patients had grade 3/4 neutropenia, but febrile neutropenia was not observed. Non-hematological grade 3 toxicities were less frequent. There were no treatment-related deaths. Conclusions: Single-agent amrubicin showed modest activity and acceptable safety profile as chemotherapy for advanced or recurrent thymoma. Additional testing of amrubicin combined with cisplatin in this disease is warranted.

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.

Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14050-e14050
Author(s):  
Nicholas Willumsen ◽  
Cecilie Liv Bager ◽  
Christina Jensen ◽  
Morten Asser Karsdal ◽  
Daniel Hargbøl Madsen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Metastatic Melanoma ◽  
Cancer Patients ◽  
Hierarchical Clustering ◽  
Immune Checkpoint ◽  
Liquid Biopsy ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Ecm Remodeling

e14050 Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.

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