First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non–small-cell Lung Cancer: A Systematic Review and Network Meta-analysis

BackgroundThis study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non–small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.Materials and MethodsA search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.ResultsA total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.ConclusionsFor patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.     

Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC

IntroductionFor patients with NSCLC receiving immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) has been validated as a predictive biomarker for improved overall survival (OS). Nevertheless, its histology-specific predictive value in patients with advanced squamous versus nonsquamous cancers remains unclear. To evaluate the differential value of PD-L1 TPS as a predictive biomarker for OS after first-line pembrolizumab in patients with squamous versus nonsquamous NSCLC.MethodsRetrospective, observational study of patients diagnosed with having advanced NSCLC who were treated between October 2015 and April 2019 at community oncology clinics and academic medical centers in a deidentified electronic health record–derived database. Included patients were diagnosed with having advanced or metastatic NSCLC, received treatment with first-line, single-agent pembrolizumab, and had documentation of PD-L1 testing with a numeric result. Exclusion criteria included alterations in EGFR, ALK, and ROS1. The primary end point was OS from start of first-line pembrolizumab therapy by squamous or nonsquamous histology and PD-1 expression level measured by TPS (low, <50% or high, ≥50%).ResultsThe cohort of 1460 patients with NSCLC who received pembrolizumab as a first-line therapy had a mean age of 72 years. Histology was 28% squamous and 72% nonsquamous. PD-L1 expression was low in 13% and high in 87%. No meaningful differences in age, sex, or smoking history were observed by PD-L1 TPS or histology type. A generalized gamma model adjusting for sex and stage at diagnosis found that for patients with nonsquamous histology, high PD-L1 TPS was significantly associated with improved OS by a median OS difference of 8.4 months (p < 0.001). In contrast, for patients with squamous histology, there was no evidence of association between PD-L1 expression level and OS (p = 0.283). PD-L1–related incremental differences in median OS between the patients with squamous and nonsquamous tumors were significantly different (p = 0.034).ConclusionsAmong patients with NSCLC treated with first-line pembrolizumab, high PD-L1 TPS is associated with OS among patients with nonsquamous NSCLC, but not among patients with squamous NSCLC.     

A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.     

Prognostic Variables Associated With Improved Outcomes in Patients With Stage III NSCLC Treated With Chemoradiation Followed by Consolidation Pembrolizumab: A Subset Analysis of a Phase II Study From the Hoosier Cancer Research Network LUN 14-179

IntroductionThe Hoosier Cancer Research Network (HCRN) LUN 14-179 is a phase II trial of consolidation pembrolizumab after concurrent chemoradiation for the treatment of patients with stage III non–small-cell lung cancer (NSCLC). Time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS) appear to be superior to that in historical controls of chemoradiation alone. Unfortunately, not all patients benefit from consolidation immunotherapy. We performed a univariate analysis to evaluate variables associated with PFS, metastatic disease, and OS.Patients and MethodsWe conducted a retrospective analysis of patients enrolled in HCRN LUN 14-179. Data collected included age, sex, stage, smoking status, programmed death ligand 1 status, Grade (G) ≥ 2 versus G ≤ 1 adverse event, G ≤ 2 versus G ≥ 3 pneumonitis, duration of pembrolizumab (< 4 vs. ≥ 4 cycles), chemotherapy regimen, performance status 0 versus 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), volume of lung receiving at least 20 Gy of radiation (V₂₀; < 20% vs. ≥ 20%). Univariable Cox regression was performed to determine the variables associated with 3 end points: TMDD, PFS, and OS.ResultsFrom April 2015 to December 2016, 93 patients were enrolled and 92 were included in the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes might be associated (P < .1) with stage IIIA and ≥ 4 cycles of pembrolizumab. For PFS, improved outcomes (P < .1) might be seen for ≥ 4 cycles of pembrolizumab, stage IIIA and V₂₀ < 20%. For OS, improved outcomes (P < .1) might be seen for stage IIIA and ≥ 4 cycles of pembrolizumab.ConclusionStage IIIA and longer duration of pembrolizumab treatment might be associated with prolonged TMDD, PFS, and OS for patients with stage III NSCLC treated with chemoradiation followed by pembrolizumab.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.     

Clinical Outcomes With Pembrolizumab-Based Therapies in Recurrent/Refractory NSCLC After Chemoradiation and Consolidative Durvalumab

BackgroundOften, patients with NSCLC experience recurrent/refractory (R/R) disease within 2 years of chemoradiation (CRT) and consolidative durvalumab. Despite prior immune checkpoint inhibitor exposure, immunotherapy with or without chemotherapy is typically initiated if a driver-oncogene is absent. However, there remains a paucity of data regarding the efficacy of immunotherapy in this patient population. Here, we present survival outcomes associated with pembrolizumab for R/R NSCLC.Materials and MethodsWe retrospectively assessed adults with NSCLC who received pembrolizumab for R/R disease between January 2016 to January 2023. Primary objective was to estimate OS and PFS in this cohort compared to historical outcomes. Secondary objective was to compare OS and PFS among subgroups.ResultsFifty patients were evaluated. Median follow-up time was 11.3 months (2.9-38.2). OS was 10.6 months (95% CI, 8.8-19.2); 1-year OS rate 49% (95% CI, 36 - 67%). PFS was 6.1 months (95% CI, 4.7-9.0); 1-year PFS rate 25% (95% CI, 15%-42%). Current smokers had significantly better median OS/PFS as compared to former smokers (NA vs. 10.5 and 9.9 vs. 6.0 months, respectively). The addition of chemotherapy demonstrated an OS benefit (median OS 12.9 vs. 6.0 months) but was not statistically significant.ConclusionPatients with R/R NSCLC represent a distinct cohort with inferior survival outcomes when compared to those with de novo stage IV disease treated with pembrolizumab-based regimens. Based on our findings, we recommend oncologists exercise caution when considering checkpoint inhibitor monotherapy in the front-line setting for R/R NSCLC, regardless of PD-L1 expression.     

外周血NLR和PLR评估晚期非小细胞肺癌一线含铂双药化疗疗效和预后的价值

目的:探讨化疗前外周血NLR和PLR与晚期NSCLC患者接受一线含铂双药化疗疗效和预后的相关性。方法:选取在我院确诊的初治晚期NSCLC患者230例,计算化疗前NLR和PLR,并根据ROC曲线图计算其截断值。分析NLR和PLR与NSCLC临床病理特征的关系。分别比较各组患者中位生存时间的差异;采用单因素及多因素 Logistic 回归对预后因素进行分析。结果:根据ROC曲线计算NLR和 PLR临界值分别为:4.5和235。外周血PLR与治疗反应显著相关（P<0.05）,而NLR与治疗反应无明显相关（P>0.05）。高NLR组和低NLR组OS分别为:11个月和15.8个月（P<0.001）;高PLR组和低PLR组OS分别为:12个月和15.2个月（P<0.001）。单因素和多因素结果显示,NLR和PLR是晚期NSCLC预后的独立影响因素。结论:外周血PLR一定程度上可预测化疗反应,NLR和PLR是晚期NSCLC预后的独立影响因素,治疗前评估NLR和PLR可以判断晚期NSCLC患者的预后。     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

Site-Specific Differences in PD-1 Blockade Success and Biomarkers in Urothelial Carcinoma Treated with Pembrolizumab

IntroductionSince tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC.Patients and MethodsA total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration.ResultsSite-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis.ConclusionWe revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.     

Association of Immune-Related Adverse Events and Efficacy Outcomes With Consolidation Pembrolizumab After Chemoradiation in Patients With Inoperable Stage III Non–Small-Cell Lung Cancer

BackgroundMany patients with non–small-cell lung cancer (NSCLC) treated with immunotherapy experience immune-related adverse events (irAEs). Patients with metastatic NSCLC who receive checkpoint inhibitors (CPI) and experience irAEs generally receive fewer cycles of CPI without decreased efficacy. However, the association between irAEs and efficacy outcomes in patients with locally advanced NSCLC treated with curative intent with CPI after chemoradiation has never been reported. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the Hoosier Cancer Research Network (HCRN) LUN 14-179 single-arm phase 2 trial of consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC.Patients and MethodsA total of 92 eligible patients were enrolled from March 2015 to November 2016. Demographics, disease characteristics, and number of pembrolizumab cycles received were reported in patients with and without irAEs. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS). A log-rank test was used to compare groups.ResultsAny grade irAEs occurred in 55.4% of patients. There was no significant difference in number of pembrolizumab cycles received, TMDD, OS, or PFS in patients with and without irAEs. Patients who discontinued pembrolizumab early because of irAEs received significantly fewer cycles of pembrolizumab (5 vs 15, P = .0016) without a significant difference in TMDD, PFS, or OS. Similarly, patients who received immunosuppressive therapy received fewer numbers of cycles of pembrolizumab (4 vs 16, P < .001) without significantly reduced TMDD, PFS, or OS.ConclusionirAEs due to pembrolizumab, regardless of grade or number of irAEs, were not associated with decreased efficacy outcomes. Furthermore, early discontinuation of pembrolizumab because of irAEs and/or treatment of irAEs with immunosuppressive therapy was not associated with a decrease in treatment efficacy.     

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non–Small-Cell Lung Cancer and High PD-L1 Tumor Expression

BackgroundIn clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent.Patients and MethodsNinety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics.ResultsThe objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease.ConclusionThe outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.     

Association Between Survival and Very High Versus High PD-L1 Expression in Patients Receiving Pembrolizumab as First-line Treatment for Advanced Non-Small Cell Lung Cancer

BackgroundA prior study found that, among advanced non-small cell lung cancer (aNSCLC) patients with PD-L1 expression 50% to 100% receiving immunotherapy as monotherapy, PD-L1 expression ≥ 90% was associated with longer survival. We sought to replicate this finding using real-world data from community oncology practices across the US.MethodsRetrospective cohort study of aNSCLC patients who initiated pembrolizumab monotherapy for first line and had a PD-L1 expression ≥ 50% using a nationwide, deidentified longitudinal electronic health record–derived real-world database. The exposure of interest was very high PD-L1 expression, which was defined as ≥ 90%, compared to high PD-L1 expression, defined as 50% to 89%. The primary outcome was overall survival, measured from initiation of pembrolizumab to date of death, with censoring at last healthcare encounter. Multiple imputation was used to impute missing covariates. Propensity score-based inverse probability weighting (IPW) was used to address confounding in Kaplan-Meier curves and Cox proportional hazard regression models.ResultsThe cohort included 1952 aNSCLC patients receiving first-line pembrolizumab monotherapy. Half of cohort members were female, median age was 73 years (interquartile range, 65-80), 71% had non-squamous histology, 94% had a history of smoking, and 46% had very high PD-L1 expression. Median overall survival in the propensity score-weighted sample was 15.84 months for very high PD-L1 expression and 12.72 months for high PD-L1 expression. Having a very high PD-L1 expression was associated with lower hazard of mortality (IPW hazard ratio 0.79, 95% CI 0.69-0.91).ConclusionsIn this large national US cohort, patients with very high PD-L1 expression (≥ 90%) aNSCLC receiving first-line pembrolizumab experienced better median survival than those with high PD-L1 expression (50% to 89%).     

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer

BackgroundConcurrent chemoradiotherapy is a standard therapy for patients with stage III non-small-cell lung cancer (NSCLC). Durvalumab is an approved treatment option following concurrent chemoradiotherapy in the absence of disease progression. The multicenter, phase III, randomized, placebo- and active-controlled, double-blind KEYLYNK-012 study evaluates whether initiation of immunotherapy with pembrolizumab concurrently with chemoradiotherapy, followed by post-chemoradiotherapy pembrolizumab with or without olaparib improves outcomes for participants with stage III NSCLC. (ClinicalTrials.gov: NCT04380636)MethodsEligible participants are aged ≥18 years with previously untreated, pathologically confirmed, stages IIIA-C, squamous or nonsquamous NSCLC not suitable for surgery with curative intent. Participants will be randomized 1:1:1 to platinum-doublet chemotherapy plus radiotherapy with pembrolizumab (Groups A and B) or concurrent chemoradiotherapy alone (Group C) for 3 cycles. In the absence of disease progression, participants will receive pembrolizumab plus olaparib placebo (Group A), pembrolizumab plus olaparib (Group B), or durvalumab monotherapy (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by independent central review and overall survival.ResultsEnrollment began on July 6, 2020, and is ongoing at approximately 190 sites.ConclusionKEYLYNK-012 will provide important information on the efficacy and safety of pembrolizumab combined with concurrent chemoradiotherapy and subsequent pembrolizumab with or without olaparib in participants with unresectable stage III NSCLC.     

Neutrophil-to-lymphocyte ratio is correlated to driver gene mutations in surgically-resected non-small cell lung cancer and its post-operative evolution impacts outcomes

Background: We sought to evaluate prognostic value of neutrophil-to-lymphocyte ratio (NLR) in surgically resected non-small cell lung cancer (NSCLC) and its correlation to oncogenic drivers.We retrospectively reviewed data of patients who underwent anatomic lung resection for NSCLC and whose mutational status was known, from 4 department of thoracic surgery, over the period 2008 to 2019. Primary endpoints were overall survival (OS) and time to recurrence (TTR). Clinical and molecular factors were investigated in the univariate and multivariate analysis for their association with the primary endpoints.Results: 2027 patients were included in the analysis. Correlations between NLR and OS (R²=0.21), NLR and TTR (R²=0.085) were significant (P<0.0001), with corresponding Pearson R of -0.46 (P<0.0001) and -0.292 (P<0.001), respectively. ROC curve analysis defined NLR cut-off value at 4.07.In the univariable analysis, the median OS was 66 months (95% CI: 62.94 – 69.06) in case of pre-operative NLR ≤ 4.07 and 38 months (95% CI: 36.73 – 39.27) in case of pre-operative NLR > 4.07 (P<0.0001), with corresponding 5-y OS of 72% and 29% respectively. Median TTR was associated with pre-operative NLR. Median TTR was 25 months (95% CI: 21.52 – 28.48) in case of pre-operative NLR ≤ 4.07 and 17 months (95% CI: 16.04 – 17.96) in case of pre-operative NLR > 4.07 (P<0.0001), with corresponding 5-years TTR of 18% and 9% respectively. Significant correlations between NLR >4.07 and KRAS (Cramer's V = 0.082, P < 0.0001) and EGFR mutations (Cramer's V = 0.064, P = 0.004) were observed.Conclusions: Low pre-operative NLR is associated with longer OS in patients with resected NSCLC. Low pre-operative NLR is not associated with longer TTR in multivariate analysis. Correlation between the high NLR and KRAS/EGFR mutations were observed.     

Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies

BackgroundExtended onset of treatment effect and longer-term survival with anti–programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non–small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources.Materials and MethodsStudies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival.ResultsPD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%).ConclusionThis NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.     

How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients.     

外周血中性粒细胞与淋巴细胞比值预测晚期非小细胞肺癌免疫治疗疗效的价值

目的:探讨外周血中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio,NLR）预测晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）免疫治疗近期疗效的可行性。方法:回顾分析2018年08月至2019年12月收治的60例一线及以上治疗进展后应用帕博丽珠单抗治疗的NSCLC患者的近期疗效及NLR水平变化。根据ROC曲线,将患者治疗前NLR值分为NLR＜2.605组和NLR≥2.605组,分析两组患者治疗前NLR水平,以及治疗前后NLR水平动态变化与患者近期疗效相关性。采用RECIST1.1评价疗效。结果:共计60例患者纳入统计,NLR＜2.605组患者41例, NLR≥2.605组患者19例 ,两组间基本资料差异均无统计学意义（P＞0.05）。NLR＜2.605 组的疾病控制率（disease control rate,DCR）为82.9%,明显优于NLR≥ 2.605组的26.3%,差异有统计学意义 （P＜0.05）。两组患者治疗2个周期后NLR升高≥30%患者的DCR明显低于NLR升高不明显或下降患者（P＜0.05）。结论:外周血NLR水平以及治疗过程中NLR动态变化,可预测非小细胞肺癌免疫治疗的近期疗效。     

Study Design and Rationale for Espera Trial: A Multicentre,Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction

BackgroundImprovement in radiotherapy techniques and expected outcomes, as well as in understanding the underlying biological mechanisms contributing to its action (immunomodulation in primis), led to the integration of this therapeutical approach in the current management of advanced non-small cell lung cancer (NSCLC), not only in oncogene-driven tumors, but also in non-oncogene addicted NSCLC where the combination of platinum-based chemotherapy plus pembrolizumab represents nowadays the pivotal strategy. In this light, we have designed a randomized phase II (ESPERa) trial to evaluate the efficacy and safety of adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab-pemetrexed maintenance in advanced NSCLC patients experiencing disease response or stability after chemo-immunotherapy induction.Patients and MethodsAdvanced non-oncogene addicted NSCLC patients with ECOG performance status of 0 or 1, who obtained disease response or stability after 4 cycles of platinum-based chemotherapy plus pembrolizumab will be randomized 2:1 to receive pembrolizumab-pemetrexed maintenance plus SBRT vs pembrolizumab-pemetrexed alone. The primary endpoint is progression-free survival (PFS). Concomitant translational researches will be performed to identify potential prognostic and/or predictive biomarkers, as well as to analyze and monitor tumour microenvironment and tumor-host interactions.ConclusionsAlthough available data suggest the safety and efficacy of combining immunotherapy and radiotherapy, their systematic integration in the current first-line landscape still remains to be explored. If the pre-planned endpoints of the ESPERa trial will be achieved, the addition of SBRT to pembrolizumab-pemetrexed maintenance as a strategy to consolidate and ideally improve the awaited benefit could be considered as a promising strategy in NSCLC undergoing first-line therapy, as well as an interesting approach to be evaluated in other disease setting, as well as in other oncological malignancies where immunotherapy represents nowadays the standard-of-care.     

Immunotherapy in Squamous Cell Cancer of the Esophagus

Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.     

Bevacizumab-containing chemotherapy for non-small cell lung cancer patients: a population-based observational study by the Ibaraki thoracic integrative (POSITIVE) research group

To evaluate the efficacy and safety of bevacizumab-containing chemotherapy for non-small cell lung cancer (NSCLC), we performed a population-based observational study. The efficacy and safety of bevacizumab-containing chemotherapy for NSCLC patients were evaluated at 14 sites (17 hospital departments) in a prefecture of Japan between December 2009 and August 2011. Complete data sets were obtained from 159 patients with NSCLC. The median age was 66?years, and 34.0?% of the patients were 70?years or older. The overall response rate to bevacizumab therapy was 41.6?%, and the disease control rate was 78.5?%. In 88 patients who received bevacizumab-containing chemotherapy as first-line therapy, the response and disease control rates were 55.0 and 78.9?%, respectively. The incidence of clinically significant (grade 3 or more) adverse events was generally low: proteinuria occurred in 2 (1.3?%) patients, hypertension in 2 (1.3?%), hemoptysis in 1 (0.6?%), and interstitial pneumonia in 1 (0.6?%). The time to treatment failure (TTF) in the 159 patients was 169?days, and the median overall survival (OS) was 580?days. In patients who received bevacizumab-containing chemotherapy as first-line therapy, the TTF and OS were 152 and 520?days, respectively. The difference in TTF between patients who received bevacizumab-containing chemotherapy as first-line therapy and those who received it as second-line or later-line therapy was not significant (p?=?0.4971). With regard to first-line therapy, the difference in TTF between patients treated with carboplatin?+?pemetrexed?+?bevacizumab and those treated with carboplatin?+?paclitaxel?+?bevacizumab was not significant (p?=?0.9435). We deduced that bevacizumab-containing chemotherapy is effective against NSCLC and also tolerable in clinical practice.