II-IIIA Non-small Cell Lung Cancer Research Articles

Comparison of SP263 and 22C3 pharmDx assays to test programmed death ligand-1 (PD-L1) expression in surgically resected non-small cell lung cancer.

Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II-IIIA non-small cell lung cancer with 1% or more programmed death ligand-1 (PD-L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non-small cell lung cancer. Therefore, our study aimed to compare two PD-L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD-L1 expression between SP263 and 22C3 assays. The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522-0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639-0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD-L1 expression with 22C3 resulted slightly higher than that with SP263. This study showed a high concordance of PD-L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required.

Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer.

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.

HTA17 Comparison of Methods for Modelling the Cost-Effectiveness of Atezolizumab as an Adjuvant Treatment in Stage II-IIIA Non-Small Cell Lung Cancer

HTA17 Comparison of Methods for Modelling the Cost-Effectiveness of Atezolizumab as an Adjuvant Treatment in Stage II-IIIA Non-Small Cell Lung Cancer

EP07.05-04 CDDP/TS1 Followed by Maintenance TS1 as Adjuvant Chemotherapy in Completely Resected Stage II-IIIA Non-Small Cell Lung Cancer

EP07.05-04 CDDP/TS1 Followed by Maintenance TS1 as Adjuvant Chemotherapy in Completely Resected Stage II-IIIA Non-Small Cell Lung Cancer

Cost-effectiveness analysis of atezolizumab as adjuvant treatment of patients with stage II-IIIA non-small cell lung cancer, PD-L1+≥50% of tumor cells in France: A modeling study

IntroductionThe objective of this study was to assess the cost-effectiveness of atezolizumab versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II-IIIA non-small cell lung cancer (NSCLC) whose tumours have a programmed death-ligand 1 (PD-L1) expression ≥ 50% of tumour cells and excluding those with ALK/EGFR mutations, from a French collective perspective. Material and MethodsA five state Markov model over a 20-year time horizon was considered, including disease-free survival (DFS11Abbreviations: AE: adverse event; ALK: anaplastic lymphoma kinase; BSC: best supportive care; DFS: disease-free survival; DSA: deterministic sensitivity analyses; EFGR: epidermal growth factor receptor; EQ-5D: EuroQol-5 dimension; HAS: Haute Autorité de Santé; ICs: immune cells; ICER: incremental cost-effectiveness ratio; IgG1: immunoglobulin G1; IV: intravenous; KM: Kaplan-Meier; LY: life-year; NSCLC: non-small cell lung cancer; OS: overall survival; PD-L1: programmed death-ligand 1; PSA: probabilistic sensitivity analysis; QALY: quality-adjusted life-year; QoL: quality of life; TCs: tumor cells.) from IMpower010 trial, three progression states (locoregional recurrence, first and second-line metastatic recurrence) and death. Utilities, quality-adjusted life year (QALY) decrements associated to adverse events, costs, resource use, and transition probabilities were considered in the model. These inputs were sourced from IMpower010 trial, literature, and clinical experts’ opinion. Model uncertainty was assessed through deterministic, probabilistic sensitivity analyses and scenario analyses. ResultsAtezolizumab was associated with a QALY gain of 1.662, mainly driven by additional time spent in the DFS state, and a life-year gain of 2.112 years. The incremental cost-effectiveness ratio (ICER) for atezolizumab versus BSC was €21,348/QALY gained. The sensitivity analyses highlighted that uncertainty within the model had limited impact on results. Changing the DFS survival curves to other plausible distributions produced ICERs below €20,000/QALY. Introducing an increasing proportion of cured patients (91.5%) from year two to year five reduced the ICER to €13,083/QALY, while including a loss of efficacy at year two in the atezolizumab treatment arm increased the ICER to €33,755/QALY. DiscussionAtezolizumab as adjuvant treatment in stage II-IIIA NSCLC resected patients with PDL1 ≥ 50% and without ALK/EGFR mutations has a lower ICER than other oncology drugs in France and a similar ICER to other adjuvant treatment in oncology.

Cost-effectiveness analysis of adjuvant atezolizumab in stage II-IIIA non-small cell lung cancer expressing ≥50% PD-L1: A United Kingdom health care perspective

ObjectivesAtezolizumab monotherapy has marketing authorisation by the Medicines and Healthcare products Regulatory Agency as adjuvant treatment following complete resection for adults with stage II–IIIA non-small cell lung cancer (NSCLC) whose tumours have PD-L1 expression on ≥ 50% of tumour cells and whose disease has not progressed following adjuvant platinum-based chemotherapy. This study evaluated the cost-effectiveness of atezolizumab vs best supportive care (BSC) in the licensed patient population from a UK perspective. Materials and MethodsPatient characteristics and clinical inputs were derived from the global, randomised, open-label, phaseIII IMpower010 trial. A Markov model with the following health states was developed: disease-free survival (DFS), locoregional recurrence, first-line metastatic recurrence, second-line metastatic recurrence, and death (all partitioned based on receipt of treatment, excluding death). The base case model used a lifetime time horizon (40 years) and 3.5% discounting annually after the first year. DFS from IMpower010 was analysed with parametric survival models to extrapolate outcomes for time points beyond trial follow-up. The models were adjusted to avoid overestimating results for patients with recurrences in the longer term. Grade ≥ 3 treatment-related adverse events with incidences ≥ 2% were included. Health state utility values were derived from the literature and past NICE appraisals. Sensitivity and scenario analyses assessed uncertainty around assumptions and parameter estimates. ResultsIn the base case analysis, atezolizumab therapy resulted in an expected gain of 1.87 quality-adjusted life-years (QALYs) corresponding to an incremental cost-effectiveness ratio of £20,392/QALY for atezolizumab vs BSC, demonstrating cost-effectiveness. Results were most influenced by discount effects and utility in the on-treatment DFS state. Scenario analyses were consistent with the base case results. ConclusionAtezolizumab after adjuvant chemotherapy is cost-effective for adults with NSCLC in the UK.

EE324 Cost-Effectiveness analysis of Atezolizumab as Adjuvant Treatment of Patients With Stage II-IIIA Non-Small Cell Lung Cancer, With Pd-L1≥50% of Tumor Cells, in France

The study aimed to assess the cost-effectiveness in France of atezolizumab monotherapy as adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II-IIIA non-small cell lung cancer (NSCLC) with PD-L1≥50% of tumour cells vs best supportive care (BSC), excluding EGFR and ALK+.

Combining variant detection and fragment length analysis improves detection of minimal residual disease in postsurgery circulating tumour DNA of stage II-IIIA NSCLC patients.

Stage II–IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard‐of‐care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue‐informed testing of postoperative plasma circulating cell‐free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II–IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10‐fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant‐level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour‐derived or white‐blood‐cell‐derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.

PD-L1 score as a prognostic biomarker in Asian patients with early-stage, EGFR-mutated lung cancer.

8527 Background: Adjuvant Atezolizumab was recently approved in stage II-IIIA non-small cell lung cancer (NSCLC) with PD-L1 ≥1%. However, disease-free survival (DFS) benefit was mainly driven by PD-L1 ≥50% and among EGFR-mutated subgroup, atezolizumab did not demonstrate DFS benefit when PD-L1 0% patients were included. We sought to determine the prognostic value of PD-L1 score in early-stage EGFR-mutated NSCLC. Methods: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent curative surgery at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary endpoints were 2-year DFS and 5-year overall survival (OS) by Kaplan-Meier method. Results: 455 patients were included (267 EGFR-mutant; 188 EGFR-wildtype). Median age at diagnosis was 65 years, 52.3% (238/455) were males and 62.9% (286/455) were never-smokers. Adenocarcinomas comprised 92.1% (419/455) and 92.5% (421/455) had R0 resection. Stage IA comprised 42.4% (193/455), Stage IB 23.1% (105/455), Stage II 15.8% (72/455) and Stage IIIA 18.7% (85/455). Among EGFR-mutant, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-mutant and EGFR-wildtype was 55.8% (149/267) and 60.1% (113/188) respectively (p = 0.361). PDL1 ≥50% was significantly associated with higher stage at diagnosis among EGFR-mutant (p &lt; 0.001) but not EGFR-wildtype (p = 0.319). At median follow up of 47 months, 178 patients had relapsed. Among EGFR-mutant, 2-year DFS comparing PD-L1 0% and PD-L1 ≥1% was 79.0% and 68.9% (p = 0.006) while 5-year OS was 87.6% and 70.6% (p = 0.006) respectively. 2-year DFS and 5-year OS by PD-L1 tertile (as shown in table) revealed that higher PD-L1 score was prognostically worse for both DFS and OS among EGFR-mutant. A similar trend was observed among EGFR-wildtype but did not reach statistical significance, apart from PD-L1 ≥50% which had significantly inferior DFS. Conclusions: Higher PD-L1 score was significantly associated with worse DFS and OS among early-stage EGFR-mutated NSCLC, possibly due to higher stage at diagnosis among PDL1 ≥50%. Our study highlights the poor prognosis of PDL1 ≥50% EGFR-mutated NSCLC in a pre-osimertinib era and underscores the importance of personalised risk-stratified adjuvant strategies. [Table: see text]

Open, Video- and Robot-Assisted Thoracoscopic Lobectomy for Stage II-IIIA Non-Small Cell Lung Cancer

BackgroundThis study compares the short- and long-term outcomes of open vs robotic vs video-assisted thoracoscopic surgery (VATS) lobectomy for stage II-IIIA non-small-cell lung cancer (NSCLC). MethodsOutcomes of patients with stage II-IIIA NSCLC (excluding T4 tumors) who received open and minimally invasive surgery (MIS) lobectomy in the National Cancer Database from 2010 to 2017 were assessed using propensity score-matched analysis. ResultsA propensity score-matched analysis of 4652 open and 4652 MIS patients demonstrated a decreased median length of stay associated with MIS compared with open lobectomy (5 vs 6 days; P < .001). There were no significant differences in 30-day mortality, 30-day readmission, or overall survival between the open and MIS groups. A propensity score-matched analysis of 1186 VATS and 1186 robotic patients showed that compared with VATS, the robotic approach was associated with no significant differences in 30-day mortality, 30-day readmission, and overall survival. However, the robotic group had a decreased median length of stay compared with VATS (4 vs 5 days; P < .001). The conversion rate was also significantly lower for robotic compared with VATS lobectomy (8.9% vs 15.9%, P < .001). ConclusionsNo significant differences were found in long-term survival between open and MIS lobectomy and between VATS and robotic lobectomy for stage II-IIIA NSCLC. However, the MIS approach was associated with a decreased length of stay compared with the open approach. The robotic approach was associated with decreased length of stay and decreased conversion rate compared with the VATS approach.

Different exposure duration of adjuvant icotinib in stage II-IIIA non-small cell lung cancer patients with positive EGFR mutation (ICOMPARE study): A randomized, open-label phase 2 study.

8521 Background: EGFR-TKI has been widely used in the treatment for advanced non-small cell lung cancer (NSCLC). Previous studies, such as the EVIDENCE study and the ADAURA study, have confirmed that patients with EGFR-mutated NSCLC could benefit from adjuvant EGFR-TKI treatment. However, the optimal duration time of adjuvant EGFR-TKIs has not been clearly defined. Methods: In this multicenter, randomized, phase 2 trial, eligible patients with II-IIIA stage EGFR mutation-positive NSCLC after R0 resection were randomized in 1:1 to receive adjuvant icotinib for 1 year (group A) or 2 years (group B). The primary endpoint was disease-free survival (DFS). Results: Between September 2013, and September 2018, 109 patients from 8 centers were enrolled in this study, among whom 55 were randomized to group A and 54 to B. As of August 24, 2020 (data cutoff), the median follow-up was 44.1 months (95%CI 37.1-49.9), 31 (56%) of 55 patients in the 1-year group and 25 (46%) of 54 patients in the 2-year group had DFS events. The median DFS was 48.92 months (95%CI 33.15, 70.11) in 2-year group and 32.89 month (95%CI 26.61, 44.78) in 1-year group, respectively. 2-year icotinib significantly prolonged DFS (HR 0.521, 95%CI 0.278, 0.976; p = 0.039). OS events were observed in 20 patients, the OS was not mature yet. Icotinib was re-given for 32 patients with disease recurrence or metastasis as first-line treatment, objective response occurred in 66.7% of 30 patients with measurable disease. Treatment-related adverse events were recorded in 41 of 55 (75%) patients in 1-year group and 36 of 54 (67%) patients in 2-year group, and grade 3 or 4 treatment-related adverse events occurred in 4 (7%) of 55 patients in the 1-year group versus 3 (6%) of 54 in the 2-year group, respectively. No treatment-related deaths or interstitial lung disease were reported. Conclusions: 2-year adjuvant treatment with icotinib resulted in a significantly lower risk of recurrence than 1-year adjuvant icotinib in patients with stage II-IIIA NSCLC positive EGFR mutations and was not associated with increased toxic effects. Clinical trial information: NCT01929200.

A randomized phase II study of S-1 monotherapy versus cisplatin with vinorelbine for completely resected stage II/IIIA non-small cell lung cancer: rationale and study protocol design for the LOGIK1702 study

BackgroundThe current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed.Methods/designThe purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m2 orally administrated twice daily, at day 1–14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m2 at day 1,vinorelbine 25 mg/m2 at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing.DiscussionThis study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL.Trial registrationRegistry number: UMIN000027435. Registered May 22, 2017.

Prospects for the development of adjuvant therapy for non-small cell lung cancer

The standard approach for stage IB and IIIIIA non-small cell lung cancer (NSCLC), associated with the high risk of relapse, after total lung resection is adjuvant chemotherapy, nowadays. The 5-year survival benefit for this approach is about 5%, and the risk of relapse reduces from 11 to 15%, depending on the stage. However, the relapse rate within 5 years after surgery and adjuvant chemotherapy in stage IBIIIA NSCLC is up to 70%. This fact requires the search for new solutions. The efficacy and safety profile of targeted drugs in metastatic NSCLC show the possibility to use them as adjuvant therapy in the early stages of the disease. This approach was actively studied in patients with mutations in the EGFR gene, and the most promising were the results of the ADAURA trial, which had been studied the use of Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, as adjuvant therapy. The use of adjuvant targeted therapy in ALK-positive patients is currently less studied and its efficacy will be determined as the results of the ALINA and ALCHEMIST trials are obtained.

Genomic Signature for Personalized Adjuvant Therapy in Resected &lt;i&gt;EGFR&lt;/i&gt;-Mutant Stage II-III Non-Small Cell Lung Cancer: Results from Phase 3 ADJVANT/CTONG1104 Study

Background: The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival (DFS) of resected EGFR-mutated stage II-IIIA non-small cell lung cancer (NSCLC). However, inconsistent clinical benefits have necessitated precise genetic categorization to reevaluate the benefit and risk assessment. Methods: Total 171 baseline surgical specimens from the ADJUVANT trial (n=95, gefitinib arm; n=76, VP arm) underwent targeted sequencing of 422 cancer-related genes. Predictive biomarkers of DFS were identified by Cox proportional hazard regression with gene-by-treatment interactions. A multi-gene composite score, MINERVA (Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies), that incorporates the predictive value of selected biomarkers, was developed for survival stratification based on the ratio of 2-year DFS rate and the difference in median DFS. The model was internally validated using ten-fold and leave-one-out cross-validation methods. Findings: TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC were identified as significant predictors for DFS and integrated into MINERVA score. Although updated overall OS presented no difference between adjuvant TKI and chemotherapy, MINERVA categorized patients into three subgroups. In Highly TKI-Preferable group (n=60, 35%), gefitinib achieved significantly longer median DFS than chemotherapy (34.5 vs 9.1 months; hazard ratio (HR) 0.21; p<0.001), higher 2-year DFS rate (70.3% vs 11.0%, 6.4 times) and 5-year OS rate (67.3% vs 38.3%; HR 0.43; p=0.018). Conversely, in the Chemo-Preferable group (n=24, 14%), gefitinib led to shorter median DFS (19.3 vs 34.2 months; HR 3.06; p=0.041), lower 2-year DFS rate (41.6% vs 69.2%, -1.7 times) and 5-year OS rate (28.3% vs. 61.5%; HR 2.47; p=0.12). Finally, in the TKI-Preferable group (n=87, 51%), relative survival benefit was similar to that of the pre-categorized cohort. Interpretation: MINERVA score of integrated genomic signature has potential for personalized adjuvant therapy of resected stage II-IIIA EGFR-mutant NSCLCs. Funding Statement: The study was sponsored by the Chinese Thoracic Oncology Group (CTONG) and the following grants: Key Lab System Project of Guangdong Science and Technology Department -Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Prof. Yi-Long Wu), National Natural Science Foundation of China (Grant No.81872510, to Prof. Wen-Zhao Zhong), and Guangdong Provincial People's Hospital Intermural Program (Grant No. DFJH201917, to Dr. Si-Yang Liu). Declaration of Interests: LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. W-ZZ declares speaker fees from AstraZeneca and Roche. Y-LW reports consulting and advisory services and declare speaker fees for Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Sanofi, MSD and BMS. HB, YeC, XT, XW, and YS are employees of Geneseeq Technology Inc., Nanjing, China. All other authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the research ethics boards of the participating hospitals, and was conducted in accordance with the ethical principles of the Declaration of Helsinki. All the patients provided written informed consent for participating in this predefined biomarker study.

Surgical Outcomes After Neoadjuvant Chemotherapy and Ipilimumab for Non-Small Cell Lung Cancer

The objective of this study was to evaluate the safety and feasibility of using neoadjuvant chemotherapy plus ipilimumab followed by surgery as a treatment strategy for stage II-IIIA non-small cell lung cancer. From 2013 to 2017, postoperative data from patients who underwent surgery after neoadjuvant chemotherapy plus ipilimumab in the TOP1201 trial, an open label phase II trial (NCT01820754), were prospectively collected. The surgical outcomes from TOP1201 were compared with outcomes in a historical cohort of patients receiving standard preoperative chemotherapy followed by surgery identified from our institution's prospectively collected thoracic surgery database. In the TOP1201 trial, 13 patients were treated with preoperative chemotherapy and ipilimumab followed by surgery. In the historical cohort, 42 patients received preoperative chemotherapy by a platinum doublet regimen preoperative chemotherapy by a platinum doublet regimen without ipilimumab followed by lobectomy or pneumonectomy. The 30-day mortality in both groups was 0%. The most frequently occurring perioperative complications in the TOP1201 group were prolonged air leak (n= 2, 15%) and urinary tract infection (n= 2, 15%). The most common perioperative complication in the preoperative chemotherapy alone group was atrial fibrillation (n= 6, 14%). One patient (8%) had atrial fibrillation in the TOP1201 group. There was no apparent increased occurrence of adverse surgical outcomes for patients in the TOP1201 group compared with patients receiving standard of care neoadjuvant chemotherapy alone before surgery for stage II-IIIA non-small cell lung cancer. This report is the first to demonstrate the safety and feasibility of surgical resection after treatment with ipilimumab and chemotherapy in stage II-IIIA non-small-cell lung cancer.

Adjuvant treatment of non-small cell lung cancer: focus on targeted therapy.

In patients with completely resected stage II-IIIA non-small cell lung cancer (NSCLC), adjuvant platinum-based chemotherapy is associated with a modest, albeit significant, improvement in survival of approximately 5% at 5 years. However, regardless of whether adjuvant chemotherapy has been administered or not, the 5-year survival of these patients remains poor. In recent years, the discovery of targetable gene alterations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements has revolutionized the therapeutic approach to advanced NSCLC, owing to the introduction for clinical use of selective tyrosine kinase inhibitors (TKIs). The outstanding activity shown by EGFR- and ALK-TKIs in advanced NSCLC patients with EGFR mutations or ALK rearrangements, respectively, leads to the logical question of what role these agents may have if used in the adjuvant setting. In the present review we will discuss the emerging data that support the potential benefit of targeted therapy as adjuvant treatment of patients with completely resected NSCLC, and summarize the ongoing clinical trials which will eventually address this issue.

Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): A randomized, Phase III trial (CTONG 1104).

8500 Background: Cisplatin-based adjuvant chemotherapy is standard of care for patients (pts) with stage II-IIIA non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have shown no benefits in the adjuvant setting for pts with unselected resected NSCLC in the BR19 and RADIANT trials. ADJUVANT (NCT01405079) is the first randomized trial to compare gefitinib (G) with vinorelbine+cisplatin (VP) in completely resected pathological stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Methods: Completely resected stage II-IIIA (N1-N2) NSCLC pts with EGFR-activating mutation were randomized 1:1 to receive G (250 mg once daily) for 24 months or vinorelbine (25 mg/m2 Day 1 and Day 8) plus cisplatin (75 mg/m2 Day 1) every 3 weeks for 4 cycles. Stratification factors were lymph node status (pN1/N2) and EGFRmutation status. The primary endpoint was disease-free survival (DFS) in the intent-to-treat population. Results: A total of 222 pts were randomly assigned (Sep 19 2011 to Apr 24 2014). Baseline characteristics were balanced. At the time of data cutoff, the median duration of treatment was 21.9 months in the G arm, and 4 cycles in the VP arm. The median follow-up period was 36.5 months (range 0.1 to 62.8). G had significantly longer median DFS (28.7 months, 95% confidence interval [CI] 24.9 to 32.5) than VP (18.0 months, 95% CI 13.6 to 22.3; hazard ratio 0.60; 95% CI 0.42 to 0.87; p= 0.005). 3-year DFS was significantly better with G (34.0% vs 27.0%; p= 0.013). The number of overall survival events was 76 (34.2%). In the subgroup analysis of patients treated with G, lymph node status (pN1/N2) demonstrated significant correlation with DFS ( p&lt; 0.05). Grade 3 or higher adverse events were less common with G than with VP (12.3% vs 48.3%; p&lt; 0.001). No interstitial lung disease was observed with G. Conclusions: Adjuvant G significantly prolonged DFS compared with VP in pts with resected stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Adjuvant gefitinib should be considered as an important option for stage II-IIIA lung cancer pts with EGFR mutation. Clinical trial information: NCT01405079.

OA09.03 Randomized Controlled Study Comparing Adjuvant versus Neo-Adjuvant Chemotherapy in Resectable Stage IB to IIIA NSCLC

Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival (DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC. Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued. Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1. Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.

Icotinib versus vinorelbine/platinum as adjuvant therapy in stage II-IIIA non-small cell lung cancer with EGFR-mutations: A multicenter, randomized, positive-controlled, phase 3, indication-expanding study (EVIDENCE, CCTC-1501).

TPS8570Background: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been recognized as the standard of care in patients with NSCLC harboring sensitive EGFR mutat...

Negative effect of cyclin D1 overexpression on recurrence-free survival in stage II-IIIA lung adenocarcinoma and its expression modulation by vorinostat in vitro.

BackgroundThis study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers.MethodsExpression levels of cyclin D1, cyclin A2, cyclin E, and p16 proteins that are involved in the G1-to-S phase progression of cell cycle were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 372 samples of stage II-IIIA NSCLC. The effect of vorinostat on the expression of these proteins, impacts on cell cycle, and histone modification was explored in lung cancer cells.ResultsAbnormal expression of cyclin A2, cyclin D1, cyclin E, and p16 was found in 66, 47, 34, and 51 % of 372 cases, respectively. Amongst the four proteins, only cyclin D1 overexpression was significantly associated with poor recurrence-free survival (adjusted hazard ratio = 1.87; 95 % confidence interval = 1.12 – 2.69, P = 0.02) in adenocarcinoma but not in squamous cell carcinoma (P = 0.44). Vorinostat inhibited cell cycle progression to the S-phase and induced down-regulation of cyclin D1 in vitro. The down-regulation of cyclin D1 by vorinostat was comparable to a siRNA-mediated knockdown of cyclin D1 in A549 cells, but vorinostat in the presence of benzo[a]pyrene showed a differential effect in different lung cancer cell lines. Cyclin D1 down-regulation by vorinostat was associated with the accumulation of dimethyl-H3K9 at the promoter of the gene.ConclusionsThe present study suggests that cyclin D1 may be an independent prognostic factor for recurrence-free survival in stage II-IIIA adenocarcinoma of lung and its expression may be modulated by vorinostat.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-2001-7) contains supplementary material, which is available to authorized users.