Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Aim: In this study, the roles of biomarkers from a peripheral blood sample in the diagnosis of Coronavirus Disease of 2019 (COVID-19) patients who have visited the emergency room have been evaluated. Materials & methods: Peripheral blood parameters, systemic inflammatory index (SII), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio were compared in patients with and without confirmed COVID-19 infection. Results: Comparisons made according to real-time PCR test results revealed that while no statistically significant difference was observed between test groups (negative-positive) regarding lymphocyte and platelet lymphocyte ratio values (p > 0.05), a statistically significant difference (p < 0.05) was found between the test groups regarding platelet, hemoglobin, leukocyte, neutrophil, NLR and SII values. Conclusion: Leukocyte, neutrophil, platelet count, NLR and SII values can be used in the diagnosis of COVID-19.

Role of hematological parameters in COVID-19 patients in the emergency room.

BACKGROUND. 
The authors compared gemcitabine and carboplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) or mitomycin, vinblastine, and cisplatin (MVP) in patients with advanced nonsmall cell lung carcinoma (NSCLC). The primary objective was survival. Secondary objectives were time to disease progression, response rates, evaluation of toxicity, disease-related symptoms, World Health Organization performance status (PS), and quality of life (QoL). METHODS. Three hundred seventy-two chemotherapy-naive patients with International Staging System Stage III/IV NSCLC who were ineligible for curative radiotherapy or surgery were randomized to receive either 4 cycles of gemcitabine (1000 mg/m2 on Days 1, 8, and 15) plus carboplatin (area under the serum concentration-time curve, 5; given on Day 1) every 4 weeks (the GC arm) or MIC/MVP every 3 weeks (the MIC/MVP arm). 

RESULTS. 
There was no significant difference in median survival (248 days in the MIC/MVP arm vs. 236 days in the GC arm) or time to progression (225 days in the MIC/MVP arm vs. 218 days in the GC arm) between the 2 treatment arms. The 2-year survival rate was 11.8% in the MIC/MVP arm and 6.9% in the GC arm. The 1-year survival rate was 32.5% in the MIC/MVP arm and 33.2% in the GC arm. In the MIC/MVP arm, 33% of patients responded (4 complete responses [CRs] and 57 partial responses [PRs]) whereas in the GC arm, 30% of patients responded (3 CRs and 54 PRs). Nonhematologic toxicity was comparable for patients with Grade 3-4 symptoms, except there was more alopecia among patients in the MIC/MVP arm. GC appeared to produce more hematologic toxicity and necessitated more transfusions. There was no difference in performance status, disease-related symptoms, of QoL between patients in the two treatment arms. Fewer inpatient stays for complications were required with GC. 

CONCLUSIONS. 
The results of the current study failed to demonstrate any difference in efficacy between the newer regimen of GC and the older regimens of MIC and MVP. © 2003 American Cancer Society.

Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma

Predictive value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

Background: Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study’s aim was to validate EPSILoN score in a different population group. Methods: 193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan–Meier and Cox hazard methods were used for survival analysis. Results: Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71, p = 0.036) and baseline LDH < 400 mg/dL (HR 0.66, p = 0.026) as independent positive factors and liver metastases (HR 1.48, p = 0.04) and NLR ≥ 4 (HR 1.49, p = 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94, p < 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40, p < 0.001). Conclusions: EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).

https://www.mdpi.com/2072-6694/11/12/1954/pdf

EPSILoN: A Prognostic Score for Immunotherapy in Advanced Non-Small-Cell Lung Cancer: A Validation Cohort.

Background Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC) Methods Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses Results A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74) The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 6035, 307, and 144 Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 034, 95%CI 015-076, P = 0006; HR for NLR = 046, 95%CI 022-099, P = 0048; HR for PLR = 039, 95%CI 017-094, P = 0025) and OS (HR for SII = 016, 95%CI 005-051, P = 0005; HR for NLR = 020, 95%CI 006-062, P = 0002; HR for PLR = 020, 95%CI 006-073, P = 0008) NLR ≤ 307, PLR ≤ 144, SII ≤ 6035 were independently associated with longer PFS and OS Conclusion The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.22964

Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.

BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). While rapid progression (RP) has been proposed as a non-negligible pattern of response to ICIs, its definition and related factors remain unclear. This study aimed to develop a clinical definition of RP and to identify related factors. METHODS We retrospectively evaluated Chinese patients who had received an ICI as second-line or later treatment for locally advanced or metastatic NSCLC at a single center. We defined RP as radiological progression at the first response assessment (<2 months after starting the ICI), as well as confirmation of progressive disease or cancer-related death occurring at <3 months. The clinical outcomes were compared for patients with RP or non-RP to identify prognostic factors. RESULTS The study evaluated 74 eligible patients with detailed records regarding their ICI therapy, including 25 patients (33.8%) who had experienced RP. Relative to patients with non-RP, patients with RP had significantly shorter median progression-free survival (1.7 months [95% CI: 1.4-2.0 months] vs. 6.3 months [95% CI 5.2-7.3 months], P < 0.001; hazard ratio: 0.14, 95% CI: 0.08-0.25) and significantly shorter median overall survival (8.2 months [95% CI 3.0-13.4 months] vs. 22.6 months [95% CI 17.0-28.1 months], P < 0.001; hazard ratio: 0.27, 95% CI: 0.15-0.49). Multivariate analysis revealed that RP was independently predicted by the presence of ≥3 metastatic sites (P = 0.039) and a neutrophil-to-lymphocyte ratio of ≥3 (P = 0.044). CONCLUSIONS Among NSCLC patients, RP was a common response to ICI monotherapy and was associated with dramatically reduced progression-free and overall survival. Care is needed when selecting ICI monotherapy for these patients, especially if they have ≥3 metastatic sites or a neutrophil-to-lymphocyte ratio of ≥3. KEY POINTS Significant findings of the study: Patients with rapid progression after immune checkpoint inhibitor monotherapy had poor survival outcomes. The number of metastatic sites and the neutrophil-to-lymphocyte ratio may independently predict treatment response in this setting. WHAT THIS STUDY ADDS This is the first study to evaluate rapid progression after second-line or later single-agent immunotherapy in a Chinese population. Our findings may help establish effective immunotherapy strategies for NSCLC.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1759-7714.13370

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

BACKGROUND Immunotherapy has afforded new treatment options for extensive small cell lung cancer (ES-SCLC). However, reports on the effectiveness of immune checkpoint inhibitors (ICIs) combined with chemotherapy on survival in ES-SCLC patients are inconsistent. Therefore, we conducted a meta-analysis on the efficacy and safety of ICI combined with chemotherapy for ES-SCLC. METHODS We searched for randomized controlled clinical trials related to first-line treatment of ES-SCLC with ICI combined with chemotherapy in PUBMED, ESMO, ASCO, and WCLC since 2018. The primary outcome was overall survival (OS). RESULTS Four studies were included. Compared to chemotherapy alone, ICI in combination with chemotherapy as first-line treatment reduced the risk of death (hazard ratio [HR]: 0.76; 95% CI: 0.68-0.86; P < 0.00001) and disease progression (HR: 0.76; 95% CI: 0.68-0.84; P < 0.00001). The objective response rate (ORR) with ICI plus chemotherapy was significantly higher than that with chemotherapy alone (HR: 1.10; 95% CI: 1.02-1.19, P = 0.01). The duration of response (DoR) rate at one year was also better with ICI plus chemotherapy (HR: 3.46; 95% CI: 2.24-5.33; P < 0.00001). Security analysis revealed that the incidence of immune-mediated adverse events (imAEs) (HR: 3.77; 95% CI: 1.99-7.15, P < 0.0001) and grade 3/4 imAEs (HR: 7.01; 95% CI: 2.48-19.81; P = 0.0002) increased significantly with ICI plus chemotherapy. CONCLUSIONS ICI combined with chemotherapy as first-line treatment can significantly improve the OS and progression-free survival (PFS) of ES-SCLC patients, but the toxicity caused by immunotherapy should be carefully considered. KEY POINTS Significant findings of the studyOur meta-analysis shows that PD-L1/PD-1 plus chemotherapy can significantly improve the OS and PFS of ES-SCLC patients when used as first-line therapy. WHAT THIS STUDY ADDS This study fills gaps regarding the efficacy of immunotherapy combined with chemotherapy as first-line treatment for ES-SCLC, and provides better evidence for the use of PD-L1/PD-1 immunotherapy plus chemotherapy for patients with ES-SCLC.

Efficacy and safety of PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small cell lung cancer: A systematic review and meta-analysis.

Background Anlotinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis which has shown activity in several malignancies and approved for the treatment of small cell lung cancer (SCLC) in China. However, there are no markers can predict the clinical outcomes of anlotinib. We aimed to evaluate the efficacy of anlotinib in extensive stage SCLC (ES-SCLC) patients who failed at least two regimens treatment and to explore potential factors related to its survival benefit. Methods Patients with ES-SCLC treated with anlotinib monotherapy were screened between March 2017 and May 2019, prognostic nutritional index (PNI) before treatment were collected. Progression free survival (PFS) and overall survival (OS) were calculated and compared using the Kaplan-Meier method and the log-rank test. The prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses. Results A total of 41 patients with ES-SCLC were received anlotinib treatment, the median age was 57 (range, 33-76). Median OS was significantly longer in the PNI high arm compared with the low arm [8.4 months (95% CI, 5.1-9.6 months) vs. 4.7 months (95% CI, 2.1-6.3 months); hazard ratio (HR) 0.42 (95% CI, 0.21-0.85); P=0.01]. The median PFS of two arms were 4.1 months (95% CI, 2.1-8.2 months) and 2.6 months (95% CI, 0.7-3.9 months), respectively (HR =0.53, 95% CI, 0.27-1.02, P=0.05). Multivariate analysis confirmed that PNI (P<0.01) and LDH (P<0.01) were significant independent biomarkers for OS. Conclusions The present study demonstrated that pretreatment PNI can be used as a novel and convenient biomarker to predict the prognosis in ES-SCLC patients treated with anlotinib.

/pdf/pretreatment-prognostic-nutritional-index-is-a-prognostic-1ihhc2me2y.pdf

Pretreatment prognostic nutritional index is a prognostic marker for extensive-stage small cell lung cancer patients treated with anlotinib

Background This meta-analysis evaluated the efficacy of PD-L1/PD-1 immunotherapy compared with chemotherapy in IIIB or IV or recurrent squamous non-small cell lung cancer (NSCLC) patients. Methods We performed a literature search on the PubMed, EMBASE, Web of Science, and Cochrane databases, in addition to the abstracts from major conference proceedings of the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the World Conference on Lung Cancer (WCLC) from 2004 to May 2019. Randomized controlled trials that compared PD-L1/PD-1 immunotherapy with chemotherapy in IIIB or IV or recurrent squamous NSCLC were included. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-y OS rate, and 1-y PFS rate. Results A total of 3,213 IIIB or IV or recurrent squamous NSCLC patients from 12 trials of high quality were included in this meta-analysis, among whom 1,677 were in the PD-L1/PD-1 immunotherapy group and 1,536 were in the chemotherapy group. The results indicated that compared with chemotherapy, immunotherapy significantly prolonged OS (HR =0.75; 95% CI, 0.68-0.83; P<0.001) and PFS (HR =0.66; 95% CI, 0.60-0.73; P<0.001) in patients with advanced squamous NSCLC. The pooled model showed that ORR, DCR, and 1-y PFS rate were also significantly higher with immunotherapy compared with chemotherapy (ORR: RR =1.43; 95% CI, 1.11-1.83; P=0.005; DCR: RR =1.14; 95% CI, 1.05-1.24; P=0.003; 1-y PFS rate: RR =2.30; 95% CI, 1.69-3.13; P<0.001). The 1-y OS rate tended to be higher in the immunotherapy group, but there was no significant difference compared with chemotherapy (RR =1.28; 95% CI, 0.95-1.72; P=0.104). Conclusions Our study proves that PD-L1/PD-1 immunotherapy can significantly improve OS, PFS, ORR, DCR, and 1-y PFS of metastatic squamous NSCLC patients compared with chemotherapy.

/pdf/the-effect-of-pd-l1-pd-1-immunotherapy-in-the-treatment-of-3ft5h5e632.pdf

The effect of PD-L1/PD-1 immunotherapy in the treatment of squamous non-small-cell lung cancer: a meta-analysis of randomized controlled clinical trials

Shuang Li

Papers

Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

Efficacy and safety of PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small cell lung cancer: A systematic review and meta-analysis.

Pretreatment prognostic nutritional index is a prognostic marker for extensive-stage small cell lung cancer patients treated with anlotinib

The effect of PD-L1/PD-1 immunotherapy in the treatment of squamous non-small-cell lung cancer: a meta-analysis of randomized controlled clinical trials