scholarly journals Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer

2018 ◽  
Vol 36 (28) ◽  
pp. 2872-2878 ◽  
Author(s):  
Kathryn C. Arbour ◽  
Laura Mezquita ◽  
Niamh Long ◽  
Hira Rizvi ◽  
Edouard Auclin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Small Cell ◽  
Cancer Center ◽  
Small Cell Lung ◽  
Programmed Death ◽  
Programmed Cell Death 1

Purpose Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. Methods We identified patients who were PD-(L)1–naïve with advanced non–small-cell lung cancer from two institutions—Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center—who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti–PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Results Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). Conclusion Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non–small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.

Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial

2007 ◽  
Vol 25 (12) ◽  
pp. 1545-1552 ◽  
Author(s):  
Ulrich Gatzemeier ◽  
Anna Pluzanska ◽  
Aleksandra Szczesna ◽  
Eckhard Kaukel ◽  
Jaromir Roubec ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Double Blind

Purpose Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). Results A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). Conclusion Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

scholarly journals First line Immunotherapy for Non-Small Cell Lung Cancer

2020 ◽  
Vol 13 (11) ◽  
pp. 373
Author(s):  
Nicola J. Nasser ◽  
Miguel Gorenberg ◽  
Abed Agbarya
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Phase 3 ◽  
Programmed Death

Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 < 50% are candidates for immunotherapy with pembrolizumab as a single agent if PL-1 > 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.

Impact of STK11 and KRAS co-mutations on outcomes with immunotherapy in non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15135-e15135
Author(s):  
Fahmin Basher ◽  
Diana Saravia ◽  
Dino Fanfan ◽  
Jared Addison Cotta ◽  
Gilberto Lopes
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Small Cell ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Small Cell Lung ◽  
Modifiable Factors

e15135 Background: While the use of monoclonal antibodies targeting the PD-1 axis in metastatic non-small cell lung cancer (NSCLC) continues to expand since initial FDA approval in 2015, factors predictive of response still remain to be determined. Mutation status may provide insight as to which subgroups exhibit resistance to checkpoint inhibitor therapy. Methods: We conducted a single center retrospective analysis of patients with metastatic NSCLC treated at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) and identified patients that harbor either STK11 mutation alone (S) or co-mutations with STK11 and KRAS (S/K). Genomic results were obtained from Guardant360 and Foundation One testing in blood and tissue, respectively. Results: We identified 37 S patients and 36 S/K patients and determined no significant differences in progression-free survival (PFS). However, overall survival (OS) was significantly increased in patients with S/K co-mutation (20.3 ± 4.1 months) vs. patients with S alone (11.9 ± 1.9 months, p = 0.028). Furthermore, S/K patients who received immunotherapy had longer OS (20.7 ± 5.6 months) vs. S patients (13.6 ± 3.4 months, p = 0.049). We further investigated any population-specific factors that may contribute to the enhanced survival in the S/K cohort that had received immunotherapy, as previous studies have reported that STK11/KRAS co-mutations may confer a resistance to PD-1 axis-directed therapy. We found that S/K patients were older at diagnosis and were more likely to have received nivolumab (as compared to newer therapies pembrolizumab and atezolizumab). In addition, S/K patients were more likely to have longer smoking histories (81% smoked more than 30 pack-years at diagnosis) vs. S patients (53%, p = 0.01) and also had a higher number of additional targetable mutations found on NGS (4.7 ± 0.4 vs. 2.9 ± 0.3, p = 0.001). The most commonly identified mutations were TP53 (30%), KEAP1 (19%), CDKN2A/B (18%), SMARCA4/BRG1 (16%), and ARID1A (11%). Conclusions: Our study reveals an interesting analysis of potential predictors of resistance to immunotherapy with the utilization of precision medicine in combination with patient characteristics to identify the most appropriate treatment regimens for patients with NSCLC. Further studies will explore whether patients receiving immunotherapy as first line could overcome any inherent resistance to PD-1 axis-directed therapy from non-modifiable factors at diagnosis.

Immune Checkpoint Inhibitor Outcomes for Patients With Non–Small-Cell Lung Cancer Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative Indications

2019 ◽  
Vol 37 (22) ◽  
pp. 1927-1934 ◽  
Author(s):  
Biagio Ricciuti ◽  
Suzanne E. Dahlberg ◽  
Anika Adeni ◽  
Lynette M. Sholl ◽  
Mizuki Nishino ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Corticosteroid Administration ◽  
Programmed Cell Death 1 ◽  
Significant Difference ◽  
Poor Outcomes

PURPOSE Baseline use of corticosteroids is associated with poor outcomes in patients with non–small-cell lung cancer (NSCLC) treated with programmed cell death-1 axis inhibition. To approach the question of causation versus correlation for this association, we examined outcomes in patients treated with immunotherapy depending on whether corticosteroids were administered for cancer-related palliative reasons or cancer-unrelated indications. PATIENTS AND METHODS Clinical outcomes in patients with NSCLC treated with immunotherapy who received ≥ 10 mg prednisone were compared with outcomes in patients who received 0 to < 10 mg of prednisone. RESULTS Of 650 patients, the 93 patients (14.3%) who received ≥ 10 mg of prednisone at the time of immunotherapy initiation had shorter median progression-free survival (mPFS) and median overall survival (mOS) times than patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months, respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When analyzed by reason for corticosteroid administration, mPFS and mOS were significantly shorter only among patients who received ≥ 10 mg prednisone for palliative indications compared with patients who received ≥ 10 mg prednisone for cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone (mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the three groups). There was no significant difference in mPFS or mOS in patients receiving ≥ 10 mg of prednisone for cancer-unrelated indications compared with patients receiving 0 to < 10 mg of prednisone. CONCLUSION Although patients with NSCLC treated with ≥ 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to < 10 mg of prednisone, this difference seems to be driven by a poor-prognosis subgroup of patients who receive corticosteroids for palliative indications.

Gemcitabine-induced Thrombocytosis as a Potential Predictive Factor in Non-small Cell Lung Cancer: Analysis of 318 Patients

2016 ◽  
Vol 103 (2) ◽  
pp. 143-147 ◽  
Author(s):  
Stefania Canova ◽  
Federica Cicchiello ◽  
Francesco Agustoni ◽  
Giampaolo Bianchini ◽  
Maria Ida Abbate ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Factor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Small Cell ◽  
Platinum Compound ◽  
Small Cell Lung ◽  
First Line

Introduction In spite of the progress in the treatment of non-small-cell lung cancer (NSCLC), the majority of patients with advanced disease still receive chemotherapy. Gemcitabine alone or combined with a platinum compound is a valid option. Thrombocytosis is a recognized prognostic factor in lung cancer and an adverse event that may occur during gemcitabine infusion. Methods We retrospectively evaluated all patients with NSCLC treated with first-line gemcitabine-based chemotherapy in two Italian hospitals. We assessed the onset of thrombocytosis within the third cycle of therapy and the relation between thrombocytosis and survival. Results We included 318 patients. Thrombocytosis occurred in 156 patients (49.1%). Median progression-free survival (PFS) was 5.6 months (95% CI, 4.7-6.9 months) in patients who developed thrombocytosis versus 6 months (95% CI, 5.1-7.2 months) in patients without thrombocytosis (p = 0.21). Median overall survival (OS) was 11.2 months (95% CI, 9.8-13.4 months) in patients with thrombocytosis versus 12 months (95% CI, 10.1-14.4 months) in patients without thrombocytosis (p = 0.25). We observed no difference in terms of PFS or OS according to age, sex, stage, chemotherapy (single-agent versus combination chemotherapy) and thrombocytosis. Conclusions Thrombocytosis is neither a prognostic nor a predictive factor for PFS or OS in patients with advanced NSCLC treated with first-line gemcitabine-based chemotherapy.

Clinical responses and survival in Hispanic patients with non-small cell lung cancer treated with immunotherapy compared with non-Hispanic whites.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18109-e18109
Author(s):  
Luis E. Raez ◽  
Diana Saravia ◽  
Rossana Ruiz ◽  
Daniel Sumarriva ◽  
Teresita Munoz-Antonia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Small Cell ◽  
Second Line ◽  
Small Cell Lung ◽  
First Line ◽  
First Line Therapy

e18109 Background: The main immunotherapy (IMMUNO) trials that led to the approval of these agents for non-small cell lung cancer (NSCLC) accrued a minimum number of Hispanic (HISP) patients (pts) or, in some studies, no HISP pts at all. Additional data is thus needed to validate outcomes in HISP pts with NSCLC treated with IMMUNO. While it is known that genomic profiles and cancer survivals are different between HISP, Non-Hispanic Whites (NHW), and African-Americans; no study has yet looked at differences in IMMUNO outcomes between these populations. Methods: We present data in 436 NSCLC pts treated with IMMUNO at 5 large institutions (3 in the US, 2 in Latin America). The agents evaluated include: nivolumab, pembrolizumab and atezolizumab. 256 pts were HISP and 180 pts were NHW. Most of the pts were treated with single agent therapy as second line (or beyond) while a small group of pts were treated as first line. The primary endpoints of the study were: response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: Among NHW pts, disease control rate (DCR) was 67% for Adenocarcinomas (Adeno) and 46% for squamous cell carcinomas (SQCC). In HISP pts there were no differences in DCR rates between both histologies: 68% for Adeno and 67% SQCC. There were no statistical significant differences among HISP and NHW pts regarding ORR, PFS, OS, and responses according to PD-L1 status. Conclusions: This is the largest publication and comparison of NSCLC immunotherapy outcomes in HISP vs NHW pts. No significant differences were found in the clinical outcomes between these 2 ethnic groups despite expected genomic differences. Pts with actionable mutations were excluded as they usually do not get IMMUNO as first or second line; an approach that might change after IMPOWER 150. These results are comparable to the ones seen in Checkmate and Keynote studies. As expected, higher response rates were seen in first line therapy and pts with PD-L1 (+) status. Further comparisons will be better addressed by a larger prospective study.[Table: see text]

scholarly journals Subgroup-Level Network Meta-Analysis for the Efficacy of First-Line Immunotherapy-Based Treatments in Advanced Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Wentao Tian ◽  
Chenghui Cao ◽  
Jiawen Ke ◽  
Nuopei Tan ◽  
Yuwen Cai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Smoking Status ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Programmed Death

Abstract Background Immunotherapy has unequal efficacies in different populations. This study aims to explore inter-subgroup differences in responses to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and find the optimal treatments for each subgroup. Methods We performed (network) meta-analyses of phase III random controlled trials, in which efficacies of 10 immunotherapy-based treatments were compared with each other and chemotherapy, including anti-programmed death receptor-1 (PD-1) (+chemotherapy), anti-programmed death ligand-1 (PD-L1) (+chemotherapy), anti-PD-L1+anti-cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-PD-1+anti-CTLA-4 (+chemotherapy), anti-CTLA-4+chemotherapy, anti-PD-1+anti-angiogenic therapy (AT)+chemotherapy, and anti-PD-L1+AT+chemotherapy, for 19 subgroups by sex, age, smoking status, metastatic site, histological type, and PD-L1 expression, using subgroup-level hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and their 95% confidence intervals (CIs). Results 22 studies comprised of 12678 patients were included in our analyses. The results showed survival advantages of immunotherapy-based treatments in 16 out of 19 subgroups comparing with chemotherapy. In patients with PD-L1 tumor proportion score (TPS)<1%, anti-CTLA-4+anti-PD-1 and anti-PD-1+anti-CTLA-4+chemotherapy had OS benefits comparing with anti-PD-L1 monotherapy (HR 0.6, 95% CI 0.44-0.81; HR 0.6, 95% CI 0.41-0.87; respectively) and anti-PD-L1+AT+chemotherapy (HR 0.66, 95% CI 0.48-0.92; HR 0.66, 95% CI 0.45-0.98; respectively). In patients with liver metastases, anti-PD-L1+AT+chemotherapy showed PFS advantage comparing with anti-PD-L1+chemotherapy (HR 0.51, 95% CI 0.33-0.77). As for other populations, anti-PD-1+chemotherapy showed promising efficacies in multiple subgroups. Conclusions Patients with advanced NSCLC generally benefit from immunotherapy. Specific immunotherapy treatments should be applied according to different clinical or histological features. Meanwhile, we expect more studies to investigate treatments for populations with impaired responses towards immunotherapy.

Impact of KRAS allele subtypes and concurrent genomic alterations on clinical outcomes to programmed death 1 axis blockade in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9082-9082 ◽  
Author(s):  
Biagio Ricciuti ◽  
Gonzalo Recondo ◽  
Renato Umeton ◽  
Mizuki Nishino ◽  
Lynette M. Sholl ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Genomic Alterations ◽  
Programmed Death ◽  
The Impact

9082 Background: Immune checkpoint inhibitors (ICI) treatment can result in durable responses for KRAS-mutant (mut) non-small cell lung cancer (NSCLC). The impact of KRAS allele subtypes and concurrent genomic alterations on ICIs efficacy is unknown. Methods: We collected clinicopathologic and genomic data from patients (pts) with advanced NSCLC treated with programmed death (PD)-1 axis inhibition at the Dana-Farber Cancer Institute. We evaluated outcomes to ICIs according to KRAS mut alleles and concurrent STK11 and KEAP1 mut. Results: Of 617 ICI-treated NSCLCs, 181 (29.3%) had KRAS mut. Median TMB (mTMB) and median PD-L1 tumor proportion score (TPS) were similar between KRAS mut and KRAS wild type (wt) tumors. Among tumors with KRAS codon 12 mut, mTMB was higher in G12V (n = 37, 12.2 mut/Mb) compared to G12C (n = 84, 11.4 mut/Mb), G12D (n = 20, 9.4 mut/Mb) and G12A (n = 13, 10.1 mut/Mb), P = 0.05. Tumors with KRAS transversions (Tv) (n = 156) had higher mTMB compared to those with KRAS transitions (Ti) (n = 25) (10.9 vs 7.6 mut/Mb, P = 0.03). Median PD-L1 TPS was similar across KRAS mut alleles. Pts with KRAS G12V had longer median progression-free survival (mPFS) (5.5 vs 2.7 months, HR:0.62 [95%CI:0.40-0.96], P = 0.03) and overall survival (mOS) (17.5 vs 9.7 months, HR:0.62 [95%CI:0.36-0.99], P = 0.05), compared to non-G12V. Pts with KRAS Tv had longer mPFS and mOS compared to pts with Ti (mPFS: 3.4 vs 2.0 months, HR: 0.58 [95%CI:0.37-0.92], P = 0.02; mOS: 10.9 vs 5.4 months, HR:0.59 [95%CI:0.35-0.99], P = 0.048). Clinicopathologic features and STK11/KEAP1 mut were balanced across all KRAS mut alleles. Among KRAS mut pts, those with KEAP1 (n:52) and STK11 (n:50) concurrent mut had shorter mPFS (KEAP1 mut 1.8 vs. KEAP1 wt 4.1 months, HR: 0.55 [95%CI:0.38-0.80], P = 0.002; STK11 mut 1.8 vs STK11 wt 4.6 months, HR:0.46 [95%CI:0.32-0.67], P < 0.0001) and mOS (KEAP1 mut 4.8 vs KEAP1 wt 15.1 months, HR: 0.51 [95%CI:0.34-0.76], P = 0.001; STK11 mut 4.8 vs STK11 wt 13.6 months, HR:0.51 [95%CI:0.34-0.76], P = 0.001). KEAP1 and STK11 mut did not impact outcome in KRAS wt pts. Conclusions: KRAS allele subtypes and concurrent genomic alterations impact ICI efficacy in NSCLC.

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