Patterns of disease progression in advanced non-small cell lung cancer patients treated with PD-1 inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20607-e20607
Author(s):  
Angel Qin ◽  
Gregory Peter Kalemkerian ◽  
Bryan J. Schneider ◽  
Khaled Aref Hassan ◽  
Kemp Bailey Cease ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Duration Of Response

e20607 Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.

Phase I-II Study of Gemcitabine and Carboplatin in Stage IIIB-IV Non–Small-Cell Lung Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 921-921 ◽  
Author(s):  
Rosario Vincenzo Iaffaioli ◽  
Anna Tortoriello ◽  
Gaetano Facchini ◽  
Francesco Caponigro ◽  
Maria Gentile ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage Iiib ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Duration Of Response

PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non–small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non–small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non–small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity. RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m2. Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months). CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.

Evaluation of platinum-based chemotherapy, glutathione metabolic genes, and survival in advanced non small cell lung cancer: A NCCTG 97–24–51 based study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13013-13013 ◽  
Author(s):  
P. Yang ◽  
S. J. Mandrekar ◽  
S. L. Hillman ◽  
K. L. Allen ◽  
Z. Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Metabolic Pathway ◽  
Dna Markers ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

13013 Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

Prognostic role of filgrastim and derived neutrophil-to-lymphocyte ratio (dNLR) in the effectiveness of PD1/PDL1 inhibitors in previously treated non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21729-e21729
Author(s):  
Juan Francisco Marin Pozo ◽  
Carmen Lucia Muñoz Cid ◽  
Macarena Merino Almazán ◽  
Raquel Claramunt García ◽  
Elvira Marin Caba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lymphocyte Ratio ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Previously Treated ◽  
The Mean

e21729 Background: A neutrophil/lymphocyte ratio (NLR)> 5 or its derivative (dNLR)> 3 have been proposed as a prognostic factor for non-effectiveness of nivolumab in non-small-cell lung cancer (NSCLC). Filgrastim (GSGF) increases the absolute counts of neutrophils in patients (pts) with neutropenia. The aim of this study is to determine whether the use of GSGF, during the first line therapy of nSCLC, influences the effectiveness of the anti-PD1/PDL1 inhibitors (aPD1-i) used in subsequent line. Methods: We designed a single center, observational and retrospective study. We included NSCLC pts treated with Nivolumab (NIV), Pembrolizumab (PEM) or Atezolizumab (ATE) between January-16 and November-19 after primary platinum-based chemotherapy at one hospital from south Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results were assessed using Kaplan-Meier method for GSGF-use stratified by NLR, dNLR, or aPD1-i. Results: 79 pts were enrolled (91% men), mean age was 66.7 years, 78.8% of pts had ECOG = 0-1. NIV was used at 55.7%, ATE 25.3% and PEM 19.0% of pts. 50.6 % of tumors were squamous histology. GSGF was used at 19 pts (24.1%). The mean WBC at the start of therapy with aPD1-I was 9300 cell/µL (sd=3900), range 3600-25800 cell/µL. NLR was less than 5 in 46 pts (58.2%) and dNLR was less than 3 in 51 pts (64.6%). The mean time from the start of line previously to start the treatment with aPD1-i was 9.7 months (sd=8.6). The median for treatment duration was 4.1 months [IC 95%; 2.3-5.8].OS was 7.3 months [IC 95%:3.4-11.3] and PFS was 4.4 months [IC95%:2.3-6.5]. We found statistically significant difference in OS between patients with dNLR <3, median 13.9 months [IC95%; 5.4-22.4] vs patients with dNLR> 3, median 3.6 months [IC95%; 2.4-4.7], p=0.037. The median OS was higher in pts GSGF-treated (6.1 months) vs pts no GSGF-treated (3.3 months), p=0.347, no reaching statistical significance. No difference was found in OS by NLR. The analysis for OS by GSGF use stratified by dNLR is shown in the table. Conclusions: The effectiveness of aPD1-i in nSCLC patients previously treated and with dNLR>3, a priori poor prognosis, is greater in the group of patients treated with GSGF, reaching OS like pts with dNLR <3. [Table: see text]

Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer

2009 ◽  
Vol 27 (12) ◽  
pp. 2038-2045 ◽  
Author(s):  
Egbert F. Smit ◽  
Sjaak A. Burgers ◽  
Bonne Biesma ◽  
Hans J.M. Smit ◽  
Pier Eppinga ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Group Performance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Randomized Phase Ii ◽  
Platinum Based Chemotherapy

PurposeWe performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy.Patients and MethodsMain eligibility criteria were histologic or cytologic proof of advanced non–small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m2(arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m2(arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (α = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, γ-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients.ResultsTwo hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03).ConclusionPC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.

Impact of baseline number of metastases on the efficacy of PD-1 inhibitor monotherapy for non-small cell lung cancer with high PD-L1 expression.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20551-e20551
Author(s):  
Taichi Miyawaki ◽  
Hirotsugu Kenmotsu ◽  
Eriko Miyawaki ◽  
Nobuaki Mamesaya ◽  
Takahisa Kawamura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
P Value ◽  
Tumour Burden ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Nsclc Patients

e20551 Background: Pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy are the standard therapies for advanced non-small cell lung cancer (NSCLC) patients with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) ≥ 50%. Apart from PD-L1 status, predictive factors for the efficacy of pembrolizumab treatment remain unclear. High tumour burden has been shown to be a negative predictor for the efficacy of PD-1 inhibitors in melanoma. Hence, the purpose of this study was to evaluate the association between tumour burden and efficacy of pembrolizumab in NSCLC patients with PD-L1 TPS ≥ 50%. Methods: This single-center retrospective observational study evaluated patients with advanced NSCLC with PD-L1 TPS ≥ 50% who received pembrolizumab monotherapy as first line therapy between March 2016 and November 2018. The primary endpoint was progression-free survival (PFS). Tumour burden was estimated by the baseline number of metastases (BNM) and the baseline sum of the target lesions’ longest diameters (BSLD; measured according to RECIST criteria). Results: Of 52 patients with target lesions, the median age was 69 years; ECOG-PS 0-1 94%; non-squamous histology 79%; and PD-L1 TPS ≥ 75% was 65%. The optimal cut-off values for predicting PFS were 4 for BNM and 115 mm for BSLD, based on the minimum P-value method for PFS. The low BNM group included 20 (38%) patients, and the low BSLD group 33 (63%). Low BNM was significantly associated with longer PFS (median PFS not reached vs 4.0 months, HR = 0.35, P = 0.021) and with higher response rate (60% vs 31%, P = 0.041) compared to high BNM. There was no significant difference in PFS between low BSLD and high BSLD groups (12.4 vs 4.0 months, HR = 0.52, P = 0.098). Multivariate analysis showed that both low BNM (≤ 4 vs. > 4, HR = 0.32, P = 0.02) and PD-L1 TPS (75-100% vs. 50-74%, HR = 0.41, P = 0.032) were significantly associated with longer PFS. There was no association between PD-L1 TPS and BNM (Spearman’s rho = -0.0985, P = 0.487) Conclusions: BNM may be an independent predictive factor of efficacy of pembrolizumab monotherapy. Patients with low BNM can be candidates for pembrolizumab monotherapy.

KEAP1/NFE2L2 as a prognostic biomarker on immunotherapy and correlation with immune infiltrates in non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21551-e21551
Author(s):  
Hongyuan Zhu ◽  
Yunfang Yu ◽  
Yating Zheng ◽  
Bin Xu ◽  
Shaopeng Zheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cells ◽  
Small Cell ◽  
Study Cohort ◽  
Small Cell Lung ◽  
Significant Difference ◽  
Nsclc Patients

e21551 Background: Molecular characterization studies revealed recurrent KEAP1/ NFE2L2 alterations in non-small cell lung cancer (NSCLC). Previous studies have confirmed that KEAP1/NFE2L2 mutations are a poor prognostic factor for chemotherapy in patients with NSCLC. Nevertheless, it is unclear whether KEAP1/NFE2L2 mutations (MUT) of liquid biopsy can predict the efficacy of immunotherapy in NSCLC. Methods: Two independent cohorts (the OAK and POPLAR study cohort) with data from approximately 853 patients with advanced NSCLC were used to analyze the prognostic effect of KEAP1/NFE2L2 on immunotherapy. In addition, based on a deconvolution algorithm (known as CIBERSORT), we comprehensively analyzed the tumor-infiltrating immune cells present in NSCLC. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and KEAP1/NFE2L2 mutation status utilizing data from 1268 patients by lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) in TCGA pan-cancer cohort. Results: The OAK and POPLAR study cohort of NSCLC patients showed that KEAP1/NFE2L2 MUT was associated with poorer overall survival (OS), and progression-free survival (PFS) (OS: HR = 1.7, P < 0.001; PFS:HR = 1.4, P < 0.001) on immunotherapy, even after EGFR and ALK mutations were excluded, significant difference can also be gained (OS:HR = 1.8, P < 0.001; PFS:HR = 1.5, P < 0.001). Then, the NSCLC patients were subdivided into LUAD and LUSC, the OS and PFS of patients with KEAP1/NFE2L2 MUT is lower than wild-type (WT) (OS:HR = 1.8, P < 0.001; PFS:HR = 1.4, P = 0.0014) in LUAD, significant differences were obtained even when EGFR and ALK mutations were excluded (OS:HR = 1.9, P < 0.001;PFS:HR = 1.6, P < 0.001). In LUSC, patients with KEAP1/NFE2L2 MUT have lower OS (HR = 1.4, P = 0.0473),and there was no difference on PFS (HR = 1.2, P = 0.1588) between KEAP1/NFE2L2 MUT and WT, when EGFR and ALK mutations were excluded, the survival results did not change significantly. In addition, KEAP1/NFE2L2 MUT was positively correlated with infiltrating levels of plasma cells, T cells CD4 memory activated, T cells follicular helper, and Macrophages M1, but negatively correlated with infiltrating levels of T cells CD4 memory resting, monocytes, Dendritic cells activated, Mast cells resting, and Neutrophils in NSCLC. The immunoinfiltration of LUAD was significantly different from that of LUSC. Conclusions: These findings suggest that KEAP1/NFE2L2 can be used as a poorer biomarker for determining prognosis on immunotherapy and immune infiltration in NSCLC.

Real-world outcomes after second-line treatment in non-small cell lung cancer (NSCLC) patients treated with immunotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21620-e21620
Author(s):  
Melina Elpi Marmarelis ◽  
Wei-Ting Hwang ◽  
Yu-Xiao Yang ◽  
Christine Agnes Ciunci ◽  
Aditi Puri Singh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Real World ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
National Guidelines ◽  
Significant Difference

e21620 Background: In patients (pts) with advanced non-small cell lung cancer (NSCLC), national guidelines recommend against retrial of immunotherapy (IO) if there is disease progression on IO in the 1st-line (1L). However, optimal 2nd-line (2L) therapy after 1L IO remains unclear and there is significant practice variation. We compared outcomes of 2L approaches after 1L IO or chemoimmunotherapy (chemoIO). Methods: This retrospective cohort study utilized the Flatiron Health EHR-derived de-identified advanced NSCLC database. The study population included pts with disease progression on 1L IO or chemoIO and who subsequently received 2L therapy. Pts with targetable alterations were excluded. We defined the exposure by type of 2L therapy (IO, chemoIO, chemo). Multivariate covariates included age, sex, race, 1L progression-free survival (PFS) and PDL1 level. Median overall survival (mOS) and median real-world PFS (mPFS, based upon abstraction of clinician documentation) times were estimated from Kaplan-Meier curves. A multivariate Cox proportional hazard model computed hazard ratios (HRs) to assess the effectiveness of 2L treatment. Results: 532 NSCLC pts received 1L IO and a 2L therapy, of which 393 (74%) received 1L IO and 139 (26%) received 1L chemoIO. Among 1L IO patients, 2L therapies included chemo (315 (80%)), IO (39(10%), 18/39 (46%) switched IO), and chemoIO (39(10%)). Among 1L chemoIO patients, 2L therapies included: chemo (121 (87%)), IO (8(6%), 6/8 switched IO) and ChemoIO (10 (7%), 8/10 changed chemo used). All pts who received 2L ChemoIO continued the same IO agent. Demographics were well balanced between 2L groups except for higher PDL1 level in the IO-based groups and older age in the IO alone group. There was no statistically significant difference in mPFS or mOS between 2L IO and non-IO containing regimens (Table), nor were there differences among patients switching IO agents in the 2L (multivariate p interaction = 0.2 (PFS), 0.06 (OS)) (Table). Conclusions: Despite national guidelines against this practice, a small proportion of pts in routine care receive 2L IO-based therapies after disease progression on 1L IO or chemoIO. We found similar outcomes between IO and non-IO based 2L therapies after progression on 1L IO or chemoIO. [Table: see text]

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