First-line Epidermal Growth Factor Receptor Research Articles

PCN14 UPDATED NETWORK META-ANALYSIS OF FIRST-LINE EGFR-TARGETED TYROSINE KINASE INHIBITOR TREATMENTS FOR LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER WITH EGFR-ACTIVATING MUTATIONS

Lung cancer is one of the most common cancers and a worldwide health burden, with 2.1 million new cases reported globally in 2018. The aim of this study was to conduct a network meta-analysis (NMA) utilizing updated/mature randomized controlled trial (RCT) results for overall survival (OS) to examine the efficacy of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) comparators for the treatment of EGFR mutation positive (EGFR+) non-small cell lung cancer (NSCLC). An NMA of EGFR-TKI comparators was previously conducted and published. This updated NMA includes the latest published OS data for dacomitinib and osimertinib. Eleven electronic databases were systematically searched for RCTs of first-line EGFR-TKI therapies that measured OS. Bayesian NMA was used to compare OS among patients receiving afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib in the overall EGFR+ NSCLC population and in subgroup analyses by ethnicity (Asian and non-Asian) and by EGFR mutational status (exon 19 deletion or exon 21 L858R substitution mutations). Based on the NMA dacomitinib demonstrated statistically significant improvement in OS versus gefitinib (hazard ratio (HR): 0.75, 95% credible interval (CrI): 0.59-0.95). Dacomitinib trended toward improved OS versus afatinib (HR:0.87, CrI: 0.61-1.24) and erlotinib (HR: 0.79, CrI: 0.44-1.42), and had comparable OS to osimertinib (HR: 0.94, CrI: 0.69-1.29). In addition, dacomitinib had the highest probability of being ranked first in the network (50.1%) followed by osimertinib (24.6%). Dacomitinib trended towards improved OS compared to other EGFR-TKIs and had the highest probability of being ranked first in the network. Therefore, dacomitinib should be considered as one of the standard first-line treatment options for patients diagnosed with advanced EGFR+ NSCLC.

Prognosis of EGFR-mutant Lung Adenocarcinoma Patients With Malignant Pleural Effusion Receiving First-line EGFR-TKI Therapy Without Pleurodesis: A Single-institute Retrospective Study.

The survival benefit of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy without pleurodesis in EGFR-mutant lung adenocarcinoma patients with malignant pleural effusions (MPE) remains unclear. We retrospectively evaluated overall survival (OS) among EGFR wild-type lung adenocarcinoma patients with MPE who received chemotherapy with pleurodesis (CT+PLD) and without pleurodesis (CT-PLD), and EGFR-mutant lung adenocarcinoma patients with MPE who received EGFR-TKI therapy with pleurodesis (TKI+PLD) and without pleurodesis (TKI-PLD). There was no difference in OS between the CT+PLD and the CT-PLD groups (10.8 months vs. 7.4 months). As compared to the TKI+PLD group, OS tended to be longer in the TKI-PLD group (21.8 months vs. 31.1 months). Patients in the TKI-PLD group had no hypoalbuminemia or deterioration of performance status during management of MPE and could receive second- and further-line therapy. EGFR-mutant patients with MPE who received first-line EGFR-TKI therapy without pleurodesis may show a better prognosis than those with pleurodesis.

A Meta-Analysis of the Effectiveness of Kanglaite Injection Plus First-Line EGFRTKIs Versus First-Line EGFRTKIs Alone Stage IIIB Lung Adenocarcinoma

Objective: Several systematic reviews for Therapeutic Effect of Kanglaite Injection Plus First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) Versus First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) Alone In Stage IIIB Advanced Lung Adenocarcinoma have recently emerged evidence. However, limited data are available regarding the activity of available EGFR TKIs against uncommon EGFR mutations. This meta-analysis evaluates the efficacy of Kanglaite Injection Plus First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) Versus First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) Alone In Stage IIIB Advanced Lung Adenocarcinoma. So therefore, Lung Adenocarcinoma related diseases have a profound economic impact on health care systems global wide, thus Kanglaite Injection combined with First-Line EGFR –TKIs have been shown to have beneficial effects than treatment with First-Line EGFR Tyrosine Kinase Inhibitors (TKIs) Alone. Methods: We electronically searched the literature of the China National Knowledge Infrastructure (Chinese language, English 2010-2019), Pub Med, Cochrane Central Register of Controlled Trails from database inception, CNKI, web of science Wang Fang, and manually searched Chinese-language oncology journals to identify randomized controlled trials (RCTs) of Kanglaite Injection Plus First Line EGFR-TKIs Versus First Line EGFR- TKIs Alone, regardless of their having been published or not, blinding, duration of treatment, or duration of follow-up. The quality of the included trials was assessed using the method recommended by The Cochrane Collaboration (CC). If heterogeneity existed among subgroups, then overall results (OS) were calculated based on a random-effects model; otherwise, a fixed effects model was used. Results: Electronic database searches yielded 1780 citations with NSCLC. Articles or Records Excluded by screening of the title/abstract level total 510, Records which are not Rcts 430, Study with no EGFR mutation analysis 590, Due to duplicated publication 180. Finally, we identified full text articles retrieved for detailled evaluation 70. The sample size of each trial had calculated by Rev Man 5.3. Pooled analyses performed using both fixed- and random-effects models revealed that compared with First Line of Egfr-Tkis alone, KLT injection plus First Line of Egfr-Tkis improved the response rate (relative risk [RR}, 1.34; 95% CI, 1.19-1.51 and RR, 1.35; 95% CI, 1.2 0-1.51, respectively). KLT injection plus First Line of Egfr-Tkis was associated with improvement in the symptoms of cough, dyspnea, chest pain, fatigue, and anorexia.

PNS336 NETWORK META-ANALYSIS (NMA) WITH TIME-VARYING HAZARD: A COMPARATIVE ANALYSIS OF SURVIVAL OUTCOMES

In oncology, the standard approach to NMA of survival outcomes is to assume proportional hazards (PH), i.e. to assume that the hazard ratio (HR, or treatment effect) remains constant over time. This, however, may not always hold true. The objective of this analysis was to perform a NMA with alternative methodologies and compare the results to understand how the selected method might influence survival estimates. Using a Cochrane review as a basis, the studies included in the NMA assessed progression-free and overall survival (PFS/OS) in metastatic colorectal cancer patients (KRAS exon 2 wild-type) receiving first-line epidermal growth factor receptor inhibitors. Kaplan-Meier curves were digitised, individual patient-level data (IPD) reconstructed and the PH assumption tested. The NMA was conducted with the four following methods: 1) using HRs reported in the publications; 2) considering treatment effects on shape and scale of parametric survival curves; 3) fractional polynomials; 4) restricted cubic splines. Methods 2–4 required IPD. Six randomised control trials (RCTs) were included in the analyses, of which five investigated cetuximab/chemotherapy vs chemotherapy alone and one panitumumab/chemotherapy vs chemotherapy alone. The PH assumption did not hold for PFS and/or OS in all RCTs. Substantial differences were observed in hazards, over time, with each of the four methods. Comparing the four NMA methods, differences were observed in the estimated median PFS and OS: for cetuximab/chemotherapy, the standard approach yielded median PFS and OS of 10.1 and 24.2 months, respectively, with up to a 15% variation with the alternative methods. This study highlights the importance of using an appropriate approach to model selection in survival analysis, as model selection may have a substantial impact on the estimated relative treatment effects and consequently on the long-term cost-effectiveness of health technologies.

Validated LC-MS/MS assay for quantification of the newly approved tyrosine kinase inhibitor, dacomitinib, and application to investigating its metabolic stability.

Dacomitinib (DMB) is a second-generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance reported for first-line epidermal growth factor receptor (EGFR) TKIs. Towards the end of 2018, the US Food and Drug Administration approved DMB in the form of VIZIMPRO tablets. In the current study, a validated LC-MS/MS assay was established for DMB quantification in rat liver microsomes (RLMs) with application to the drug metabolic stability assessment. Chromatographic resolution of DMB and lapatinib (internal standard) was achieved using an isocratic mobile phase and a reversed-phase C18 column. The linearity of the established LC-MS/MS assay ranged from 2 to 500 ng/mL with r2 ≥ 0.9999. The limit of detection (LOD) and limit of quantification (LOQ) were 0.35 and 1.1 ng/mL, respectively. The precision and accuracy (both intra-day and inter-day) were 0.84–3.58% and 92.2–100.32%, respectively. The metabolic stability of DMB in the RLM matrix was estimated by calculating two parameters, in vitro t1/2 (0.97 mL/min/kg) and intrinsic clearance (157.5 min). Such values infer that DMB would be excreted very slowly from the human body, which might lead to possible bioaccumulation. To the best of our knowledge, this is the first method for DMB analysis in RLMs with metabolic stability estimation.

Abstract P6-17-30: Changes in patient, tumor, and treatment characteristics over time in first-line trastuzumab plus taxane (paclitaxel/docetaxel) arms in HER2-positive metastatic breast cancer trials

Abstract Background: A retrospective analysis showed improved progression-free survival and consistent underestimation of trastuzumab (H) + taxane (T) efficacy assumptions in first-line (1L) human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) trials over time (ISCB 2016). We evaluated changes in baseline and treatment characteristics and the safety profile of H+T in 1L HER2-positive MBC trials conducted during 1995–2015. Methods: Trial-level data on patient, tumor, and treatment characteristics and safety profiles in H+T arms of 15 randomized trials were extracted from published data and clinical study reports. Characteristic and safety profile changes over time were explored by weighted regression; relevance was assessed by F-test. Results: Patient and tumor characteristics were generally stable over time. We observed relevant changes in types of adjuvant therapy used. Serious adverse events (SAEs) and study withdrawals due to Aes decreased over time; rates of treatment discontinuation due to Aes increased. No. of trials (patients)Difference in patients with characteristic per 5 years, % (95% CI)P valueBaseline characteristics Median age15 (2895)0.5 (0.1, 0.9)*.28ECOG status 012 (2472)0.2 (-1.1, 1.6).87Hormone receptor-positive11 (2124)1.3 (-1.1, 3.6).61HER2 IHC 3+8 (1657)5.8 (3.0, 8.6).08Visceral disease10 (1970)0.5 (-2.5, 3.6).86Adjuvant therapy Hormonal therapy11 (2194)-10.1 (-12.4, -7.8).002Radiotherapy9 (2010)-4.2 -5.8, -2.6).035HER2-targeted therapy9 (2176)20.2 (13.0, 27.4).026Chemotherapy15 (2893)-7.0 (-9.2, -4.7).008Safety Grade 3+ AE6 (1342)-15.4 (-28.4, -2.5).30SAE7 (1462)-12.6 (-15.4, -9.8).006Study withdrawal due to AE8 (1525)-6.8 (-9.0, -4.5).023Treatment discontinuation due to AE6 (1370)11.5 (6.7, 16.3).075*Years (95% CI). AE, adverse events; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IHC, immunohistochemistry; SAE, serious adverse events. Conclusions: In 1L HER2-positive MBC trials, the percentage of patients who received adjuvant chemo-, hormonal, and radio-therapy decreased from 1995 to 2015. These changes in treatment patterns suggest a shift towards a higher percentage of patients with de novo metastatic vs recurrent disease in 1L MBC trials over time. Adjuvant H use increased following approval in 2005 as expected. While SAEs decreased over time, no firm conclusions on safety management can be made. Citation Format: Badovinac Crnjevic T, Restuccia E, Michielin F, Eng-Wong J, Nüesch E. Changes in patient, tumor, and treatment characteristics over time in first-line trastuzumab plus taxane (paclitaxel/docetaxel) arms in HER2-positive metastatic breast cancer trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-30.

Adjunctive Traditional Chinese Medicine Improves Survival in Patients With Advanced Lung Adenocarcinoma Treated With First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs): A Nationwide, Population-Based Cohort Study.

Objectives: The clinical effect of traditional Chinese medicine (TCM) on survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major concern and requires more evidence from large-scale clinical studies. Materials and Methods: This population-based cohort study used the Taiwan National Health Insurance Research Database to enroll patients between 2006 and 2012 who had newly diagnosed locally advanced and metastatic lung adenocarcinoma treated with first-line gefitinib or erlotinib. Survival was tracked until 2013. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and the survival of patients. Results: A total of 1988 patients receiving first-line gefitinib or erlotinib for the treatment of EGFR-mutated advanced lung adenocarcinoma, with the exclusion of TCM users after tumor progression, were included in this cohort study. Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of mortality by 68% (adjusted hazard ratio [HR], 0.32 [95% CI, 0.21-0.50], P < .0001). Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of disease progression by 59% (adjusted HR, 0.41 [95% CI, 0.29-0.58], P < .0001). Conclusion: This cohort study suggests that adjunctive TCM therapy could improve overall survival and progression-free survival in patients with advanced lung adenocarcinoma treated with first-line TKIs. Future randomized, controlled trials are required to validate these findings.

Therapeutic Effect of First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Combined with Whole Brain Radiotherapy on Patients with EGFR Mutation-positive Lung Adenocarcinoma and Brain Metastases.

This study compared the therapeutic effect of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with that of EGFR-TKI plus whole brain radiotherapy (WBRT) on patients with EGFR mutation-positive lung adenocarcinoma and brain metastases. A total of 139 patients with lung adenocarcinoma and brain metastases treated with first-line EGFRTKI therapy from September 2008 to December 2017 were enrolled in this study. The study endpoints were intracranial time to progression (TTP) and overall survival (OS). The effects of clinical pathological parameters and EGFR gene status on the study endpoints were compared. The results showed that the intracranial TTP was significantly longer in EGFR-TKI plus WBRT group than in EGFR-TKI group (median 30.0 vs.18.2 months, χ2=10.824, P=0.001), but no significant difference in the OS was noted between the two groups (median 48.0 vs. 41.1 months, χ2=0.012, P=0.912). Also, there was no statistically significant difference in the OS between patients treated with early and late radiotherapy (P=0.849) and between those with asymptomatic and those with symptomatic intracranial metastases (P=0.189). The OS and intracranial TTP of patients with intracranial oligometastases (≤3 metastatic sites) were not significantly different from those of patients with multiple intracranial metastases (P=0.104 and P=0.357, respectively), and exon 19 and exon 21 mutations didn't show significant effects on the OS and intracranial TTP of patients (P=0.418 and P=0.386, respectively). In conclusion, there was no statistically significant difference in the OS between the EGFR-TKI alone group and EGFR-TKI plus WBRT group. However, simultaneous use of WBRT was found to significantly prolong intracranial TTP and improve cerebral symptoms, and thus EGFR-TKI and WBRT combined may be clinically beneficial for patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.

Transition Rate from EGFR-TKI to Cytotoxic Chemotherapy Patients with EGFR Mutation-positive Lung Adenocarcinoma.

The transition rate from first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to cytotoxic chemotherapy (Ct) is poor. The prognosis according to treatment sequence and the reasons patients could not shift from first-line EGFR-TKIs to Ct were herein analyzed. Overall, 159 epidermal growth factor receptor mutation-positive adenocarcinoma patients were enrolled in this study. The median survival times of EGFR-TKIs combined with Ct and EGFR-TKIs were 59.8 months and 22.5 months, respectively (p<0.001) and of patients who received EGFR-TKIs first and Ct first were 38.8 months and 66.4 months, respectively (p=0.016). The main reasons patients could not make the transition to Ct was worsening of performance status and patient's preference. EGFR-TKIs and Ct lead to a good prognosis in EGFR mutation-positive adenocarcinoma patients. It is necessary to consider the timing when changing the treatment strategy before treatment options are limited.

Best Response According to RECIST During First-line EGFR-TKI Treatment Predicts Survival in EGFR Mutation-positive Non–Small-cell Lung Cancer Patients

IntroductionThe association between the response to first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and survival in EGFR mutation-positive non–small-cell lung cancer (NSCLC) remains unclear. We studied the association between the response to first-line EGFR-TKIs and survival using Response Evaluation Criteria In Solid Tumors (RECIST) and maximal tumor shrinkage. Materials and MethodsWe analyzed data from patients with advanced EGFR mutation-positive NSCLC enrolled in first-line gefitinib and afatinib trials. A total of 98 patients who achieved a response or stable disease and had ≥ 1 measurable target lesion were included. The association between the best response by RECIST or maximal tumor shrinkage and survival was analyzed in Kaplan-Meier and Cox regression models with the landmark method. The specified landmark time points were 8 weeks, the median time to maximal tumor shrinkage (16.5 weeks), and median progression-free survival (PFS; 56 weeks). ResultsA total of 76 patients (77%) responded to gefitinib or afatinib. Of these 76 patients, 49 (64%) and 75 (99%) had achieved a response at 8 and 16.5 weeks, respectively. All responders had achieved a response by 56 weeks. The responders had a significantly longer PFS and overall survival (OS) compared with those with stable disease at 16.5 weeks (PFS, P = .003; OS, P < .001) and 56 weeks (PFS, P = .026; OS, P = .016) but not at 8 weeks (PFS, P = .104; OS, P = .313). Among the responders, greater tumor shrinkage was not associated with longer PFS or OS. ConclusionThose with a response to first-line gefitinib or afatinib had more favorable PFS and OS compared with those with stable disease. A sufficient observation period was required for the response to occur and predict outcomes. Greater maximal tumor shrinkage in the responders was not predictive of survival.

Clinical management and outcome of patients with advanced NSCLC carrying EGFR mutations in Spain

BackgroundAlthough the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain.MethodsAll consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated.ResultsBetween March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations.ConclusionEGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC.

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma.

PurposeThe main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)‒mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR‒tyrosine kinase inhibitor (TKI) treatment.Materials and MethodsWe enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status.ResultsA total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032).ConclusionPFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746-A750 mutation are associated with the frequency of T790M mutation.

P3.01-016 Factors Associated with Symptoms Improvement and HRQoL for First-Line EGFR-TKIs in NSCLC: A Multicenter Prospective SMILE Study

First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) offer an advantage compared to doublet chemotherapy in progression free survival, tolerability, and quality of life (QOL) in EGFR-mutated advanced non-small cell lung cancer (NSCLC) patients. In Taiwan, gefitinib, erlotinib and afatinib are all reimbursed as first-line therapy. It provides a rare opportunity to investigate factors associated with the extent of symptoms and QOL improvement in real-world patient population.

Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development. Recommendations New or revised recommendations include the following. Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; if the patient has low PD-L1 expression, clinicians should offer standard chemotherapy. All other clinical scenarios follow 2015 recommendations. Regarding second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy, if NSCLC tumor is positive for PD-L1 expression, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab; if tumor has negative or unknown PD-L1 expression, clinicians should use nivolumab or atezolizumab. All immune checkpoint therapy is recommended alone plus in the absence of contraindications. For patients who received a prior first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy. For patients who cannot receive immune checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with nonsquamous NSCLC, pemetrexed is recommended. In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and T790M mutation, osimertinib is recommended; if NSCLC lacks the T790M mutation, then chemotherapy is recommended. Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy.

Characterization of Liver Metastasis and Its Effect on Targeted Therapy in EGFR-mutant NSCLC: A Multicenter Study

BackgroundThe risk factors for liver metastasis (LM) in patients with non–small-cell lung cancer (NSCLC) remain unknown. Whether LM predicts for the effect of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC needs to be explored. Patients and MethodsA total of 598 NSCLC patients from 3 centers underwent EGFR testing, and 293 had EGFR-mutant NSCLC. Of the 598 NSCLC patients, 99 had LM; 56 patients with EGFR-mutant NSCLC received EGFR-TKIs as first-line therapy. ResultsEGFR mutation was not associated with LM in NSCLC patients (relative ratio, 1.305, P = .261). In the EGFR-mutant group that received first-line EGFR-TKIs, patients with LM had shorter progression-free survival (PFS; 7.5 vs. 11.8 months; P = .0003) and overall survival (OS; 20.8 vs. 30.6 months; P = .0190) than patients without LM. The significant difference in PFS was observed in both patients with EGFR exon 19 deletion (19del) and Leu858Arg mutation (L858R). However, patients with EGFR 19del and LM showed marginally significantly shorter OS (P = .0531) and patients with EGFR L858R and LM had OS similar to that of patients without LM (P = .1883). Regardless of EGFR status, patients with LM who received first-line chemotherapy had PFS and OS similar to those of patients without LM. Univariate analyses identified only never smoking (hazard ratio, 0.536; P = .012) was significantly associated with better OS for patients with NSCLC and LM. ConclusionEGFR mutation is not an independent risk factor for LM in NSCLC patients. However, the presence of LM is a negative predictive factor for first-line EGFR-TKI therapy for patients with EGFR-mutant NSCLC.

Impact of epidermal growth factor receptor gene expression level on clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients taking first-line epidermal growth factor receptor-tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are first-choice treatments for advanced non-small-cell lung cancer patients harboring EGFR mutations. Although EGFR mutations are strongly predictive of patients' outcomes and their response to treatment with EGFR-TKIs, early failure of first-line therapy with EGFR-TKIs in patients with EGFR mutations is not rare. Besides several clinical factors influencing EGFR-TKI efficacies studied earlier such as the Eastern Cooperative Oncology Group performance status or uncommon mutation, we would like to see whether semi-quantify EGFR mutation gene expression calculated by 2-ΔΔct was a prognostic factor in EGFR-mutant non-small cell lung cancer patients receiving first-line EGFR-TKIs. This retrospective study reviews 926 lung cancer patients diagnosed from January 2011 to October 2013 at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. Of 224 EGFR-mutant adenocarcinoma patients, 148 patients who had 2-ΔΔct data were included. The best cutoff values of 2-ΔΔct for in-frame deletions in exon 19 (19 deletion) and a position 858 substituted from leucine (L) to an arginine (R) in exon 21 (L858R) were determined using receiver operating characteristic curves. Patients were divided into high and low 2-ΔΔct expression based on the above cutoff level. The best cutoff point of 2-ΔΔct value of 19 deletion and L858R was 31.1 and 104.7, respectively. In all, 92 (62.1%) patients showed high 2-ΔΔct expression and 56 patients (37.9%) low 2-ΔΔct expression. The mean age was 65.6 years. Progression-free survival of 19 deletion mutant patients with low versus high expression level was 17.07 versus 12.04 months (P = 0.004), respectively. Progression-free survival of L858 mutant patients was 13.75 and 7.96 months (P = 0.008), respectively. EGFR-mutant lung adenocarcinoma patients with lower EGFR gene expression had longer progression-free survival duration without interfering overall survival.

Efficacy of Second-line Tyrosine Kinase Inhibitors in the Treatment of Metastatic Advanced Non-small-cell Lung Cancer Harboring Exon 19 and 21 EGFR Mutations.

Background: Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity, the sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of second-line EGFR-TKIs in the treatment of NSCLC patients according to different EGFR genotypes.Methods: The treatment outcomes of 166 NSCLC patients with different EGFR mutations treated by second-line TKIs were retrospectively reviewed. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model.Results: The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the exon 19 L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p<0.001), OS: (13.7 vs. 7.9 months, p=0.006)]. No significant difference on PFS and OS was observed between exon 19 deletion and L858R mutation group for patients with bone metastasis. EGFR genotype and ECOG PS were independent predictors of PFS. Never smoking, exon 19 deletion, EGOC PS (0-1) and no brain metastasis were correlated with longer OS. No significant difference on side effect between exon 19 and 21 mutation group was observed.Conclusions: NSCLC patients harboring exon 19 deletion achieved better PFS and OS than those with L858R mutation, indicating that EGFR mutation is a significant prognostic factor for advanced NSCLC patients with and without brain metastasis receiving second-line EGFR-TKIs treatment.

P3.02b-002 Treatment Outcome Comparison between Exon 19 and 21 EGFR Mutations after Second-Line TKIs in Advanced NSCLC Patients: Topic: EGFR Biomarkers

Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity. The sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of NSCLC patients with and without brain and/or bone metastases in different EGFR tumor genotypes receiving EGFR-TKIs as a second-line treatment. The treatment outcomes of 166 NSCLC patients harboring either the exon 19 deletion or the L858R point mutation of EGFR treated by second-line TKIs were retrospectively reviewed. The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p<0.001), OS: (13.7 vs. 7.9 months, p=0.006)]. The median PFS and OS for NSCLC patients with bone metastasis were 4.8 months (95% Cl, 4.0-5.6 months) and 12.9 months (95% Cl, 8.7-17.1 months), respectively. No significant difference was observed for patients with bone metastasis for different mutations. EGFR genotype and ECOG PS were independent predictors of PFS for both NSCLC patients with and without brain metastasis. Never smoking (P=0.001), exon 19 deletion (P=0.03), EGOC PS (0-1) (P<0.001) and no brain metastasis (p=0.01) were correlated with longer OS for all NSCLC patients. For patients with brain metastasis, age at disease progression (p=0.009), genotype (p=0.02) and EGOC PS (p<0.001) were independent predictors of OS. For patients with bone metastasis, EGOC PS (p<0.001) was an independent predictor for both PFS and OS. Female (P=0.01), never smoking (P=0.005), number of bone metastases (P=0.03) and EGOC PS (0-1) (P=0.002) were related to a longer PFS. EGOC PS (0-1) (P<0.001) was associated with a longer OS. Rash, fatigue, and anorexia were the three most frequent side effects observed No significant side effects difference between exon 19 and 21 mutation groups were observed. NSCLC patients harboring exon 19 deletion achieved better PFS and OS than those with L858R mutation, indicating that EGFR mutations are significant prognostic factors for advanced NSCLC patients with and without brain metastasis receiving second-line EGFR-TKIs treatment.

Efficacy according to blind independent central review: Post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC

ObjectiveThe Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. Patients and methodsEligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m2). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). ResultsScans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. ConclusionBICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.

A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

BackgroundHead-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). MethodsA PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point. ResultsThree trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68–0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/‘other’ RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab. ConclusionsThis meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.