F. Biello

Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors

Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) to treat EGFR‐mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non‐small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR‐wild‐type A549 and the EGFR‐mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single‐agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1‐nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro‐positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR‐TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.

Serum proteomic test in advanced non-squamous non-small cell lung cancer treated in first line with standard chemotherapy

Background:VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed.Methods:The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted.Results:Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately.Conclusions:The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.

Releasing the brake: safety profile of immune check-point inhibitors in non-small cell lung cancer

ABSTRACT Introduction: Immune check-point inhibitors are now employed as single-agents in current practice for the treatment of advanced non-small cell lung cancer (NSCLC), while combinations of different inhibitors are being evaluated in clinical trials. Although the safety profile of these compounds, with particular reference to drugs targeting programmed death protein 1 (PD-1) and its ligand (PD-L1), is generally considered manageable, peculiar, immune-related toxicities may onset. Areas covered: This review focuses on the immune-related adverse events (irAEs) observed during immune check-point blockade in NSCLC and their management. The authors report the incidence of irAEs based on the currently available data involving NSCLC and provide recommendations on the general approach to irAEs, as well as indications for the most relevant site-specific events. Expert opinion: Since irAEs may involve a wide range of organs and systems and are potentially reversible if promptly treated, early diagnosis should always be achieved; this might be particularly challenging when other potential causes of toxicity are suspected, such as infections or concurrent treatments. Finally, drugs active on the PD-1/PD-L1 axis appear to be generally manageable even when they are administered to patients with relevant comorbidities, provided that adequate clinical monitoring is performed.

Circulating tumor DNA reflects tumor metabolism rather than tumor burden in chemotherapy-naive patients with advanced non–small cell lung cancer: 18F-FDG PET/CT study

We aimed to evaluate the relationships between circulating tumor cells (CTCs) or plasma cell–free DNA (cfDNA) on one side and a comprehensive range of 18F-FDG PET/CT–derived parameters on the other side in chemotherapy-naive patients with advanced non–small cell lung cancer (NSCLC). Methods: From a group of 79 patients included in a trial evaluating the role of pretreatment circulating tumor markers as predictors of prognosis in chemotherapy-naive patients with advanced NSCLC, we recruited all those who underwent 18F-FDG PET/CT for clinical reasons at our institution before inclusion in the trial (and thus just before chemotherapy). For each patient, a peripheral blood sample was collected at baseline for the evaluation of CTCs and cfDNA. CTCs were isolated by size using a filtration-based device and then morphologically identified and enumerated; cfDNA was isolated from plasma and quantified by a quantitative polymerase chain reaction using human telomerase reverse transcriptase. The following 18F-FDG PET/CT–derived parameters were computed: maximum diameter of the primary lesion (T), of the largest lymph node (N), and of the largest metastatic lesion (M); SUVmax; SUVmean; size-incorporated SUVmax; metabolic tumor volume; and total lesion glycolysis. All parameters were independently measured for T, N, and M. The associations among CTCs, cfDNA, and 18F-FDG PET/CT–derived parameters were evaluated by multivariate-analysis. Patients were divided into 2 groups according to the presence of either limited metastatic involvement (M1a or M1b due to extrathoracic lymph nodes only) or disseminated metastatic disease. The presence or absence of metabolically active bone lesions was also recorded for each patient, and patient subgroups were compared. Results: Thirty-seven patients recruited in the trial matched our PET-based criteria (24 men; age, 64.5 ± 8.1 y). SUVmax for the largest metastatic lesion was the only variable independently associated with baseline cfDNA levels (P = 0.016). Higher levels of cfDNA were detected in the subgroup of patients with metabolically active bone lesions (P = 0.02), but no difference was highlighted when patients with more limited metastatic disease were compared with patients with disseminated metastatic disease. Conclusion: The correlation of cfDNA levels with tumor metabolism, but not with metabolic tumor volume at regional or distant levels, suggests that cfDNA may better reflect tumor biologic behavior or aggressiveness rather than tumor burden in metastatic NSCLC.

Vinflunine for the treatment of non-small cell lung cancer

ABSTRACT Introduction: Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC). Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed. Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors.

P2.04-02 Predictive Value of Circulating Tumor Cells and Circulating Free DNA in NSCLC Patients Treated with Nivolumab

methylation reached nadir at best response and gradually increased thereafter. An elevation of mutation AF or the emergence of new mutation(s) (molecular PD) was observed in 4 patients prior to PD assessed by imaging. In all patients, an elevation of DNA methylation was observed prior to PD assessed by imaging; among them, 3 had changes in DNA methylation prior to molecular PD, suggesting DNA methylation may be a more sensitive biomarker. Conclusion: Collectively, our study demonstrates DNA methylation, continuously increasing from the nadir (best response), can be utilized as a biomarker for treatment monitoring.

1315PSERUM MASS-SPECTROMETRY TEST IN FIRST LINE ADVANCED NSCLC PATIENTS TREATED WITH STANDARD CHEMOTHERAPY REGIMENS

ABSTRACT Aim: The mass-spectrometry based serum test VeriStrat□ (VS) was shown to be prognostic in various therapies and predictive of differential overall survival (OS) benefit for erlotinib vs. chemotherapy (CT) in second line NSCLC setting. Performance of the test in CT is of clinical interest. We investigated the role of VS in 1st line advanced NSCLC patients (pts) treated with Cisplatin (Cis) or Carboplatin (Carbo) plus Pemetrexed (P). Methods: VS classification was available for 55 eligible stage IV,pts with non-squamous histology; pts were classified as VS Good (VSG) or VS Poor (VSP), VS testing of pretreatment serum samples was done blinded to clinical data. OS and progression-free survival (PFS) were analyzed by Kaplan-Meier method and compared using log-rank p-values; Cox models were used in multivariate analysis. Association with categorical variables was analyzed by Fishers exact test. Results: 36 (65%) pts were classified as VSG and 19 (35%) as VSP. In the overall population, median PFS was 5.7 months (mo) for VSG vs.1.4 mo for VSP (hazard ratio (HR) 0.37 [0.19-0.72], p = 0.002 ); adjusted HR (AHR) 0.38 [0.17-0.86], p = 0.021). Median OS was 10.8 mo for VSG vs. 3.4 mo for VSP (HR 0.23 [0.11-0.51], p Conclusions: In Platinum-based doublet CT, VSP pts had much shorter PFS and OS than VSG. The behavior was similar in CisP and CarboP arms. Further research is needed to find alternative treatments to improve outcomes for VSP pts. ClinicalTrials.gov Identifier: NCT02055144. Disclosure: J. Grigorieva: stock options of Biodesix; H. Roder: stock options of Biodesix. All other authors have declared no conflicts of interest.