scholarly journals KRAS mutations predict better response to first-line monotherapy with pembrolizumab for patients with PD-L1high metastatic Non-Small Cell Lung Cancer: a retrospective study

2021 ◽  
Author(s):  
Ella A Eklund ◽  
Clotilde Wiel ◽  
Henrik Fagman ◽  
Levent M Akyurek ◽  
Sukanya Raghavan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Retrospective Study ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Kras Mutations ◽  
Metastatic Nsclc ◽  
Negative Factor ◽  
Mutational Status

Background: Pembrolizumab, a humanized antibody targeting Programmed Cell Death 1 (PD-1), is used as first-line therapy for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) expressing Programmed Death Ligand 1 (PD-L1). However, not all PD-L1 expressing patients respond to pembrolizumab. Thus, there is an urgent need to identify new predictive biomarkers for response to immune checkpoint blockade (ICB) therapy. KRAS mutational status has been suggested to affect treatment outcome, but no clear consensus could be drawn for previous studies. Methods: All consecutive patients diagnosed between 2016-2018 with metastatic NSCLC (stage IV) in the region of West Sweden with molecular characterization available were included in this multi-centers retrospective study. Primary study outcome was overall survival (OS). Baseline patients characteristics, histology type, mutational status, PD-L1 expression and first-line treatment were collected from patient charts and the Swedish Lung Cancer registry. Results: Out of 580 stage IV NSCLC patients, 35.5% harbored a mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet, KRASMUT (n = 219) is a significant (p = 0.001) negative factor for survival with median OS 9 months vs KRASWT 14 months. Patients on KRAS mutational status and PD-L1 expression levels had a significant better OS in KRASMUT with increased PD-L1 expression (p = 0.036) but not for KRASWT. On first-line ICB, KRASMUT had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status and Performance Status (PS) 0-1 were independent prognostic factors for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016 and HR 0.398, 95 % CI 0.165-0.963, p =0.041). Conclusions: KRAS mutations combined with PD-L1high is a better predictive marker for response to first-line monotherapy with pembrolizumab than only PD-L1high in patients with metastatic NSCLC.

266 Tumour mutation burden (TMB) and efficacy outcomes in the phase III DANUBE study of advanced urothelial carcinoma (UC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A292-A292
Author(s):  
Sophie Wildsmith ◽  
Jill Walker ◽  
Anne L’Hernault ◽  
Weimin Li ◽  
Hannah Bye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stage Iv ◽  
Small Cell ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Line Treatment ◽  
Small Cell Lung ◽  
First Line ◽  
Unresectable Stage ◽  
First Line Treatment

BackgroundThe phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. The study did not meet its co-primary endpoints of improving overall survival (OS) for D monotherapy vs SoC in patients with high tumor PD-L1 expression or for D+T vs SoC in the intention-to-treat population.1 TMB measurement in blood (bTMB) or tumour (tTMB) has been linked to improved efficacy with PD-1/PD-L1 inhibitors in UC and with D+T in non-small cell lung cancer,2 thus providing a rationale to explore TMB in the DANUBE trial.MethodsBaseline plasma samples from DANUBE were assessed for bTMB using the Guardant OMNI platform, while baseline tTMB was measured in formalin-fixed paraffin-embedded (FFPE) tumour samples using the FoundationOne CDx gene panel. Associations between progression-free survival (PFS) and median and landmark OS with bTMB and tTMB levels at various cutoffs were assessed as part of a pre-specified exploratory analysis. The data cutoff occurred on January 27, 2020.ResultsAmong 1032 patients randomised in DANUBE, 536 (51.9%) were evaluable for bTMB and 623 (60.4%) were evaluable for tTMB. For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB (table 1).Abstract 266 Table 1Association between TMB and survival outcomes with D+TAssociation between TMB and survival outcomes with D+TConclusionsBoth bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy. Cutoffs of 24 mut/Mb for bTMB and 10 mut/Mb for tTMB appear optimal for D+T in the setting of previously untreated, advanced UC.Trial RegistrationThe trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.ReferencesAstraZeneca. Update on phase III DANUBE trial for IMFINZI and tremelimumab in unresectable, stage IV bladder cancer [press release] March 6, 2020. [https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html]Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: The MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020:6:661–674.Ethics ApprovalThe study protocol was approved by the Ethics Board at each investigator’s institution.

scholarly journals Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

2021 ◽  
Vol 9 (4) ◽  
pp. e002421
Author(s):  
Alessio Cortellini ◽  
Massimo Di Maio ◽  
Olga Nigro ◽  
Alessandro Leonetti ◽  
Diego L Cortinovis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Metastatic Nsclc ◽  
The Impact

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

Improving time to molecular testing results in patients with newly diagnosed, metastatic non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 244-244
Author(s):  
Stephanie Ossowski ◽  
Elad Neeman ◽  
Charles Borden ◽  
Amy Ying Ju Lin ◽  
Raymond Liu
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Turnaround Time ◽  
Small Cell ◽  
Pathological Diagnosis ◽  
Genomic Testing ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
First Line ◽  
Metastatic Nsclc

244 Background: Next generation sequencing (NGS) is a crucial component of evaluation of newly diagnosed patients with metastatic non-small cell lung cancer (NSCLC) to determine appropriate first line treatment. Delays in NGS can lead to psychologic distress for patients and can affect choices in first line therapy, especially for patients with underlying targetable mutations. While more data is needed to benchmark turnaround time for NGS results, guidelines and expert consensus suggest time from diagnosis to treatment should be 15 days and turnaround time for genomic testing 10-14 days. This study was aimed at reducing time to NGS results in a large integrated health care system. Methods: Through the ASCO Quality Training Program, we reviewed electronic medical records of 25 patients with newly diagnosed, untreated metastatic NSCLC from 12/2018 to 9/2020 and determined number of days from pathological diagnosis to NGS results. We reviewed process maps for oncology, pathology, the internal data management division, and a genomic testing company to determine factors leading to significant preventable delays. Since 11/2020, we created an automated weekly report using CoPath to identify new pathological diagnoses of potential metastatic NSCLC. The oncology department reviewed these cases weekly and NGS orders were placed for patients with metastatic NSCLC. Eleven additional patients with newly diagnosed metastatic NSCLC were included in the prospective cohort. Results: Demographic characteristics are noted in Table. Our intervention reduced median time from pathological diagnosis to NGS results from 24 to 19 days. Median time from biopsy results to NGS order was reduced from 7 to 1 day. Time from specimen being sent from pathology to NGS vendor was a median of 6 days in both cohorts. Total time from pathological diagnosis to appropriate treatment was reduced from a median of 33 to 25 days. Conclusions: Delays in time to NGS results can be reduced by improved communication between departments and simple, automated interventions to ensure results are efficiently released to an oncologist. Additional Plan-Do-Study-Act cycles are currently being developed to further reduce time from biopsy results to NGS results. [Table: see text]

First-line systemic treatment with gefitinib in stage IV non-small cell lung cancer

2005 ◽  
Author(s):  
Tobias Lange ◽  
Carsten Müller-Tidow ◽  
Hubert Serve ◽  
Petra Hoffknecht ◽  
Wolfgang Berdel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Systemic Treatment ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line

scholarly journals Cost‐Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels

2020 ◽  
Vol 28 (2) ◽  
pp. 117-125
Author(s):  
Xiuhua Weng ◽  
Shaohong Luo ◽  
Shen Lin ◽  
Lixian Zhong ◽  
Meiyue Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Sensitivity Analysis ◽  
Cost Effective ◽  
Cost Utility ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Expression Levels ◽  
Metastatic Nsclc ◽  
The Us

To evaluate the cost‐utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic non-small cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of ≥50%, ≥20%, and ≥1%, with corresponding incremental cost of 53,784, 47,479, and 39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were 47,596, 47,184, and 68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of 180,000/QALY in the context of the US health care system.

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