Refractory Advanced Non-small Cell Lung Research Articles

Real-World Data of Nivolumab and Pembrolizumab in Platinum Refractory Advanced Non-Small Cell Lung Cancer: Potential Practical Predictors of Treatment

Real-World Data of Nivolumab and Pembrolizumab in Platinum Refractory Advanced Non-Small Cell Lung Cancer: Potential Practical Predictors of Treatment

Salvage anlotinib showed sustained efficacy in heavily pretreated EGFR wild-type lung adenocarcinoma

Rationale:Anlotinib has been proved to be effective in advanced refractory non-small cell lung cancer.Patient concerns:A 47-year-old female non-smoker was admitted due to persistent chest tightness for a month.Diagnoses:Epidermal growth factor receptor (EGFR) wild-type advanced primary lung adenocarcinoma without brain or bone metastasis.Interventions:The patient failed 2 lines of pemetrexed/docetaxel plus carboplatin and third-line erlotinib. Fourth-line anlotinib was administered thereafter.Outcomes:The pulmonary lesions showed partial remission 5 months after anlotinib monotherapy. The patient demonstrated a progression-free survival of more than 7 months and an overall survival of >12 months. The adverse events including hypertension and fatigue were well-tolerated.Lessons:Salvage anlotinib might be a reasonable choice in EGFR wild-type lung adenocarcinoma after failure of chemotherapy. Further well-designed trials are warranted to verify this occasional finding.

HIP1R Expression and Its Association with PD-1 Pathway Blockade Response in Refractory Advanced NonSmall Cell Lung Cancer: A Gene Set Enrichment Analysis.

Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung cancer (NSCLC) patients. HIP1R and PD-L1 immunohistochemical expression was examined in 52 refractory advanced NSCLC patients treated with anti-PD-1 inhibitors. We performed gene set enrichment analysis (GSEA) to detect HIP1R-specific gene sets. Patients in the PD-1 inhibitor responder group had lower HIP1R expression by univariate logistic regression analysis (odds ratio (OR) = 0.235, p = 0.015) and multivariate logistic regression analysis (OR = 0.209, p = 0.014). Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019). The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026). GSEA revealed that HIP1R levels correlate with a set of genes that reflect PD-L1-related immune pathways. HIP1R expression may be a promising predictor for determination of patient responses to anti-PD-1 treatment.

JCSE01.19 ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line

Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline. Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis. Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p= 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97). This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919.

P3.13-09 ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line

Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline. Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis. Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p = 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97). This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919.

Efficacy of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim results of observational prospective study.

e21126Background: We aimed to evaluate quality of life (QoL) in advanced refractory NSCLC pts and clinical outcomes of nivolumab (Nivo) as ≥ 2nd line treatment within the expanded access program in...

A single-arm phase II study of nab-paclitaxel for patients with chemorefractory non-small cell lung cancer

BackgroundWe aimed to evaluate the efficacy and safety of nab-paclitaxel in patients with refractory advanced non-small cell lung cancer who failed previous chemotherapy.MethodsPatients were required to have an Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Patients received nab-paclitaxel, 100 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks. The primary endpoint was the overall response rate. Secondary endpoints were the progression-free survival time, overall survival, and the toxicity profile.ResultsFrom July 2013 to July 2015, a total of 31 patients were enrolled. Fourteen patients received nab-paclitaxel as a second-line and 17 received it as an over third-line therapy. Each patient received a median of 5 treatment cycles (range, 1–11). The overall response rate was 19.3% (95% confidence interval, 9.1–36.2%) (complete response (n = 0), partial response (n = 6), stable disease (n = 17), and progressive disease (n = 8)). The median progression-free survival time was 4.5 months (95% confidence interval 3.5–6.3 months), median overall survival time was 15.7 months, and 1-year survival rate was 54.8%. Most common grade 3 or 4 non-hematological toxicities were elevated aspartate transaminase level (3.2%) and sensory neuropathy (9.6%). Neutropenia was the most common grade 3 or 4 adverse events (38.6%), and febrile neutropenia developed in 12.9% patients. No treatment-related deaths were observed in this study.ConclusionPrimary endpoint was met. Single agent nab-paclitaxel showed significant clinical efficacy and manageable toxicities for patients with chemorefractory advanced non-small cell lung cancer even if late line setting.Trial registrationUMIN000011696. The date of registration was July 11th, 2013.

1317P - Multicenter observational study of the efficacy and safety of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim analysis

1317P - Multicenter observational study of the efficacy and safety of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim analysis

Observational study of the efficacy of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim analysis.

e14593 Background: Therapy with immune checkpoint inhibitors (ICI) changed the paradigm of treatment in many solid tumors including NSCLC. Recently several ICI were approved for NSCLC second and first line. By now data on Nivo benefits/risks in NSCLC is quite limited. The aim of this study was to evaluate clinical and patient-reported outcomes on Nivo in second plus line within the expanded access program in NSCLC. We report interim analysis on response rates, safety and QoL. Methods: Adult pts with advanced refractory NSCLC received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1., adverse events (AEs) with NCI CTCAE v3.0. and QoL by RAND SF-36. Group comparisons were made using Wilcoxon test. Results: From July of 2015 to January of 2017, 157 pts were enrolled in 7 centers in RF. Median follow-up time was 14 weeks. Clinical characteristics: 66% – males; median age – 62 (29−80); ECOG PS 0-1/2-3 – 81%/19%; former/current smokers – 73%; non squamous NSCLC – 64%; ≥2 lines of previous systemic treatment – 51%. We observed 1.5 increase of Integral QoL index in 53% of pts at 4 weeks; significant improvement was observed for emotional functioning (33.3 vs 50.0; p &lt; 0.05). Efficacy was evaluated in 56 pts: PR – 6/56, SD – 35/56, PD – 15/56. Clinical improvement was noticed in 36 pts. Early deaths from cancer occurred in 9 pts; early deaths not related to cancer – 2 pts. 18 pts discontinued Nivo prematurely ( &lt; 8 weeks) because of rapid clinical worsening. 72 pts were not evaluated for response on cut-off. More pts with quick worsening as compared with responders were with non squamous NSCLC (75% vs 50%) and had brain mets (20% vs 0%). Among responders 33% were with PS &gt; 1 and were &gt; 65 y.o; pts in this group had no brain mets. AEs were registered in 40 pts (median of Nivo treatment – 6 weeks); among them 11 with grade 3-4 AEs. Conclusions: Early data from this study supports thata large number of pts benefits fromNivo treatment. Nivo is well tolerated by this population, with 7% of grade 3 or 4 toxicities. Nivo treatment is accompanied with significant QoL improvement in 53% pts.

113P - Clinical outcomes and quality of life (QoL) in adults with advanced refractory non-small cell lung cancer (NSCLC) patients receiving nivolumab (Nivo) as 2+ line treatment: Interim analysis of expanded access program

113P - Clinical outcomes and quality of life (QoL) in adults with advanced refractory non-small cell lung cancer (NSCLC) patients receiving nivolumab (Nivo) as 2+ line treatment: Interim analysis of expanded access program

Comparing the Adverse Event Profiles of Nivolumab and Docetaxel in Previously-treated or Refractory Advanced Non-small Cell Lung Cancer: A Meta-analysis of Two Phase 3 Trials

Comparing the Adverse Event Profiles of Nivolumab and Docetaxel in Previously-treated or Refractory Advanced Non-small Cell Lung Cancer: A Meta-analysis of Two Phase 3 Trials

PCN288 - Results from a Model to Forecast The Current and Future Number of Patients Eligible for Treatment of Refractory Advanced Non-Small Cell Lung Cancer (NSCLC) in France, Germany, Italy and Spain

PCN288 - Results from a Model to Forecast The Current and Future Number of Patients Eligible for Treatment of Refractory Advanced Non-Small Cell Lung Cancer (NSCLC) in France, Germany, Italy and Spain

113P - Anlotinib as Third-Line Treatment in Patients with Refractory Advanced Non-Small Cell Lung Cancer: a Multicentre, Randomized, Double-Blind, Placebo-Controlled, Phase Ii Trial (NCT01924195)

113P - Anlotinib as Third-Line Treatment in Patients with Refractory Advanced Non-Small Cell Lung Cancer: a Multicentre, Randomized, Double-Blind, Placebo-Controlled, Phase Ii Trial (NCT01924195)

Primary Human Non‐Small Cell Lung and Pancreatic Tumorgraft Models—Utility and Applications in Drug Discovery and Tumor Biology

The number of therapeutic options for lung and pancreatic cancer is increasing because of the identification of new druggable molecular targets and development of new drug combinations. Reproducible, biologically relevant in vivo pre-clinical models are critical for this effort. The generation of patient-derived tumor xenografts has proven useful for integrating drug screening with biomarker discovery, discovering fundamental information in tumor biology, prioritizing drugs for clinical investigation, and personalizing treatments for these tumors. The protocol described in this unit details how to establish a direct in vivo subcutaneous primary tumorgraft and maintenance passages. The predictive value of a tumorgraft platform to guide personalized medicine is illustrated with the case of a patient with refractory advanced non-small cell lung cancer (NSCLC). The outcome of a patient for whom their own pancreatic tumorgraft revealed a remarkable sensitivity to mitomycin C based on a PALB2 mutation is also detailed.

Gemcitabine combined with vinorelbine in the treatment of refractory patients with advanced non-small cell lung cancer: a multi-center retrospective study

背景与目的本研究旨在回顾性分析使用吉西他滨+长春瑞滨（GN）方案治疗复治晚期非小细胞肺癌的疗效和安全性。方法通过非干预的方式收集国内4家医院2004年1月1日-2010年6月30日间行GN方案治疗的晚期非小细胞肺癌二线或二线以上的患者，评价该化疗方案的疗效、无进展生存期、中位生存期和毒副反应。卡方检验比较二线和二线以上患者的疗效差异，应用Kaplan-Meier法进行生存比较和分析。结果共53例患者在二线或二线以上采用了GN方案，其中二线患者28例，三线或三线以后的患者25例，所以患者均可评价疗效和不良反应。客观缓解率（objective response rate, ORR）为9.4%，疾病控制率（disease control rate, DCR）为56.6%，中位无进展生存期（progression free survival, PFS）为3.0个月，中位总生存期为17.6个月，多数患者的毒副反应可以耐受。单因素分析显示体能状况评分（performance status, PS）是影响患者PFS的因素。结论吉西他滨联合长春瑞滨方案在晚期非小细胞肺癌复治患者中有较好的疗效和安全性，可以作为一种治疗选择。

Phase II study of topotecan and bevacizumab in advanced refractory non-small cell lung cancer (NSCLC).

7563 Background: Bevacizumab in combination with carboplatin and paclitaxel improves survival of patients with NSCLC in a first-line setting. We hypothesized that non-cross-resistant, second-line salvage therapy with the topoisomerase 1 inhibitor, topotecan, in combination with bevacizumab would have activity in NSCLC. Methods: Forty-two patients were enrolled between 10/2006-9/2010. Patients received topotecan 4.0 mg/m2 on days 1, 8 and 15 and bevacizumab 10 mg/kg on days 1 and 15 as IV infusions. Treatment was repeated every 28 days in the absence of disease progression or unacceptable toxicity. Eligibility criteria included age older than 18 years, ECOG PS of 0-1, and adequate organ function. Patients with treated brain metastases were permitted to enter this study. Response assessment (using RECIST) was performed every two cycles. Primary endpoint of this study was progression-free survival (PFS). Results: Forty-two patients were enrolled in the study. Median age was 60.6 years (range = 36-81). Patients had a median of 3 prior treatment regimens (range 1-7), and 93% had prior platinum therapy. The primary objective of PFS was 238 days (95% CI, 117-332 days). Overall survival (OS) was 345 days (95% CI, 213-464 days). Response rates were as follows: 14.3% partial response (PR), 54.8% stable disease (SD), 28.6% progressive disease (PD). Grade 3 hematologic toxicities seen in participants included thrombocytopenia (16.7%), neutropenia (9.5 %), and anemia (4.8%). There was no grade 4 or higher hematologic toxicities. Only one toxic death, due to pulmonary hemorrhage, occurred during the study. The only grade 4 toxicity was a pulmonary embolism in one patient. Grade 3 non-hematologic adverse events were minimal (<8%) and included: hyperglycemia, bone pain, gastroesophageal reflux, diarrhea, infection, shortness of breath, bowel obstruction, DVT, abdominal pain, pseudogout, and SVC thrombosis. Conclusions: The combination of bevacizumab and topotecan as a salvage therapy for metastatic NSCLC appears to be well tolerated and provides significant progression-free survival. A randomized trial should be performed to compare this combination with other NSCLC regimens.

Abstract 955: Specific forms of mutant KRAS predict patient benefit from targeted therapy in the BATTLE-1 clinical trial in advanced non-small cell lung cancer

Abstract Mutant KRAS (mut-KRAS) is present in 17-25% of all human cancers, where it plays a critical role in driving cancer cell growth and resistance to therapy. Despite numerous attempts, there is still no effective therapy for mut-KRAS tumors. Understanding the signaling mechanisms activated by mut-KRAS and finding agents to inhibit mut-KRAS signaling are important unmet needs in cancer therapy today. The recently completed BATTLE-1 clinical trial, a prospective, multi-arm, biopsy-mandated, biomarker-driven, clinical trial in advanced refractory non-small cell lung cancer (NSCLC), found that mut-KRAS did not accurately predict patient outcome (progression-free survival) to targeted intervention. This finding contradicted published evidence for such a relationship from colon cancer and some previous NSCLC studies. We explored more specifically the nature of the KRAS mutations, which are primarily found at codons 12 and 13, where different base substitutions lead to alternate amino acid (aa) substitutions. NSCLC has a much higher proportion of mut-KRAS G12C(cysteine) aa substitutions (47%) due to carcinogens in tobacco smoke, and only 15% mut-KRAS have G12D(aspartate). These data contrast those in other solid tumors, such as colon or pancreas, which predominantly manifest mut-KRAS G12D (50%) and only 9% mut-KRAS G12C. In a subset analysis of the BATTLE-1 data, we showed significantly worse progression-free survival in patients with mut-KRAS G12C, versus other mut-KRAS including G12D (p=.041) and who were treated with erlotinib, vandetanib or sorafenib. In a panel of NSCLC cell lines with known mut-KRAS aa substitutions to identify pathways activated by the different mut-KRAS genotypes, we found that mut-KRAS G12D activates both PI-3-K and MEK signaling, while mut-KRAS G12C does not and alternatively activates PKCζ and RAL signaling. This finding was confirmed in immortalized human bronchial epithelial (HBEC) cells stably transfected with wt-KRAS or different forms of mut-KRAS. Our molecular modeling studies show that the different conformation imposed by mut-KRAS G12C could lead to altered association with downstream signaling transducers, compared to mut-KRAS G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRAS may be addictive; and that different combinations of inhibitors of downstream signaling may be needed for different mut-KRAS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2011-955

A phase II study of topotecan and bevacizumab in advanced refractory non-small cell lung cancer: Interim analysis.

e18040 Background: Previous studies have suggested improved outcomes with a single topoisomerase I inhibitor for chemotherapy naive advanced non-squamous non-small cell lung (NSCLC). Bevacizumab is...

Phase I study of regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, administered continuously in patients (pts) with advanced refractory non-small cell lung cancer (NSCLC).

7585 Background: Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR- β, FGFR), and oncogenic kinases (KIT, RET, RAF). In in vivo models, i...

Gefitinib in the treatment of 41 cases with refractory non-small cell lung cancer

Objective We observe the curative effect, median survival time, time to progression, quality of life and adverse effect of patients with advanced refractory non-small cell lung cancer (NSCLC) after gefitinib (Iressa) treatment.