Search

Objective: Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas ® EGFR Mutation Test v2., Materials and Methods: Two EGFR mutation tests, a tissue-based assay (cobas ® v1) and a tissue- and blood-based assay (cobas ® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden., Results: Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8-76.1) and a specificity of 97.9% (95% CI 96.0-99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors., Conclusions: Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.

Introduction: Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC., Methods: Individual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival was examined using landmark analyses. Depth of response based on radiologic assessments at 6 weeks and 12 weeks was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline., Results: Of 1081 evaluable patients at 6 weeks with no disease progression, 71.2% achieved Response Evaluation Criteria in Solid Tumors response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio = 0.36, p < .0001); and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, p < .0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (p = .18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (hazard ratio = 0.96, p = .78). Similar results were obtained for 12-week landmark analysis and for OS outcome., Conclusions: The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Pemetrexed is a standard first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for advanced nonsquamous NSCLC with activating EGFR mutations. Pemetrexed and EGFR TKIs have different mechanisms of action and minimally overlapping toxicity profiles; therefore, it is hypothesized that their combination might result in acceptable toxicity, provided that the synergistic antitumor activity observed in preclinical studies is achieved. This review summarizes clinical trials of pemetrexed in combination with an EGFR TKI for the treatment of advanced nonsquamous NSCLC in the first- and second-line settings, using intercalated, sequential, and concurrent treatment strategies. As would be expected, such strategies were most efficacious in patients with the activating EGFR mutations associated with response to an EGFR TKI. In the studies that compared a pemetrexed-EGFR TKI combination with pemetrexed alone or the EGFR TKI alone, the pemetrexed-EGFR TKI combination was more efficacious than the single-agent regimens. The pemetrexed-EGFR TKI combinations were generally associated with a higher incidence of grade 3/4 treatment-related adverse events than the single-agent regimens; however, such toxicities were clinically manageable. Future studies of pemetrexed-EGFR TKI combinations should focus on optimizing treatment strategies in patients with activating EGFR mutations., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: We performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC., Methods: Randomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation-defined subgroups. We used the fixed-effects inverse variance-weighted method to pool estimates of treatment efficacy. Statistical tests were two sided., Results: In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p = 0.03)., Conclusion: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Metastatic spread to the brain is common in patients with non-small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article., Methods: For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81)., Results: In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports., Conclusions: These findings lend support to the clinical activity of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic brain metastases., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment., Objective: To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy., Design, Setting, and Participants: ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2., Interventions: Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion., Main Outcomes and Measures: The primary end point was progression-free survival (PFS1; time to Response Evaluation Criteria in Solid Tumours 1.1 progression or death). Secondary end points included PFS2 (time to off-erlotinib progression if erlotinib therapy was extended beyond progression at patient and/or investigator discretion), objective response rate, disease control rate, overall survival, and safety. The use of plasma-based assessment of EGFR mutations was also investigated., Results: Of 359 patients screened, 208 were enrolled. Median follow-up was 11.3 (95% CI, 10.9-13.0) months. Of the 207 intent-to-treat patients (62.3% female; median age, 60.8 [range, 28-89] y), 176 had a PFS1 event (171 progression and 5 deaths); of these, 78 discontinued and 93 continued erlotinib therapy following progression. Median PFS1 was 10.8 (95% CI, 9.2-11.1) months. Median PFS1 and PFS2 in the 93 continuing patients was 11.0 (95% CI, 9.2-11.1) and 14.1 (95% CI, 12.2-15.9) months, respectively. Median PFS1 and PFS2 was 11.0 (95% CI, 9.3-12.0) and 14.9 (95% CI, 12.2-17.2) months in patients with exon 19 deletions or L585R mutations. Overall response rate was 66.2%; disease control rate was 82.6%. Median overall survival was 31.0 months (95% CI, 27.3 months to not reached). In the safety population (n = 207) serious adverse events were reported in 27.1%, with events of at least grade 3 experienced by 50.2%. Sensitivity and specificity of plasma-based EGFR mutation analysis was 77% and 92%, respectively., Conclusions and Relevance: ASPIRATION supports the efficacy of first-line erlotinib therapy in patients with EGFR mutation-positive NSCLC and that treatment beyond progression is feasible and may delay salvage therapy in selected patients., Trial Registration: clinicaltrials.gov Identifier: NCT01310036.

Introduction: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods., Methods: A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site., Results: Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%-32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme., Conclusions: In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.

Background: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials., Methods: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393., Findings: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%])., Interpretation: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials., Funding: Boehringer Ingelheim., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer., Methods: In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients., Findings: Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded., Interpretation: Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer., Funding: Pfizer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA)., Materials and Methods: A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods., Results: The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40-1.16) and compared with erlotinib was 0.86 (0.50-1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42-1.24) for afatinib compared with erlotinib and 0.60 (0.34-0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments., Conclusions: In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

Background: Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach., Methods: A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted., Results: EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations., Conclusions: This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs., (Copyright © 2011 American Cancer Society.)

Randomized trials comparing gefitinib with chemotherapy as first-line treatment in patients with EGFR mutated advanced NSCLC support gefitinib as a new, highly effective treatment option in this setting. However, its use in clinical practice has several relevant implications and open issues. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. Every effort should be made in order to obtain sufficient tissue. If a clinical enrichment has to be performed for selecting patients to test for EGFR mutation, a reasonable proposal is to test all non-squamous tumors, and patients with squamous tumors only if never smokers. In patients with EGFR mutated tumor, one major issue is the decision about immediate use of gefitinib as first-line, or after failure of standard chemotherapy. First-line gefitinib, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life, and its administration as first-line warrants that all patients have the chance of receiving an EGFR inhibitor. Evidence about the efficacy of erlotinib in the same setting will be soon available, however, at the moment, there are no direct comparisons between gefitinib and erlotinib in EGFR mutated patients. Treatment with gefitinib is usually well tolerated. Typical side effects in most cases are of mild to moderate intensity, and usually manageable with temporary interruption of treatment. When indicated gefitinib appears feasible also in special populations, like elderly or unfit patients, characterized by a significantly poorer risk/benefit ratio with standard chemotherapy. Personalized medicine for patients with lung cancer is now a reality, and patients with EGFR mutation should be treated with first-line EGFR tyrosine kinase inhibitor., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Gefitinib is a small molecule tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR). Since 2004, it was clear that a substantial proportion of non-small-cell lung cancers (NSCLC) obtaining objective response when treated with gefitinib harbour activating mutations in the EGFR gene. Consequently, EGFR mutation has been widely studied, together with other molecular characteristics, as a potential predictive factor for gefitinib efficacy. As of August 2010, four East Asian randomized phase III trials comparing gefitinib to platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) eligible for first-line treatment have been reported or published. Two of these trials were conducted without a molecular selection in patients with clinical characteristics (adenocarcinoma histology, never or light smoking) characterized by higher prevalence of EGFR mutation. In patients selected for the presence of tumor harbouring EGFR mutation, the administration of first-line gefitinib, as compared to standard chemotherapy, was associated with longer progression-free survival, higher objective response rate, a more favourable toxicity profile and better quality of life. The relevant improvement in progression-free survival with first-line administration of gefitinib has been confirmed in the other two randomized trials, dedicated to cases with EGFR mutation. In July 2009, European Medicines Agency granted marketing authorization for gefitinib for the treatment of locally advanced or metastatic NSCLC with sensitizing mutations of the EGFR gene, across all lines of therapy. Gefitinib currently represents the best first-line treatment option for this molecularly selected subgroup of patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Previous exploratory analysis of epidermal growth factor receptor (EGFR) mutational status in tumor samples from randomized clinical studies suggested that patients with activating mutation of the EGFR had better survival than those harboring wild-type EGFR., Methods: We analyzed the EGFR sequence of tumor samples from advanced stage non-small cell lung cancer patients previously participated in treatment clinical trials. Responses to chemotherapy and survival of EGFR mutation-positive or -negative patients were compared., Results: Tumor samples from 122 patients were available for analysis. EGFR mutation was present in 58 patients (47.5%). In 105 stage IIIB/IV patients, there was a nonstatistically significant trend toward a higher chemotherapy response rate of patients with mutated EGFR than those with wild-type EGFR (44.6% versus 30.6%, p = 0.162). Female, never-smoking, and adenocarcinoma patients lived longer than male (p = 0.0139), smoking (p = 0.0045), or nonadenocarcinoma (p = 0.0151) patients. There was no difference in the survival of patients with mutated or wild-type EGFR (p = 0.2159). There was no difference in progression-free survival of first-line chemotherapy between patients with wild-type or mutation in EGFR (6.6 months versus 6.1 months)., Conclusion: There is a nonstatistically significant trend toward a higher chemotherapy response rate in patients with mutated EGFR than those with wild-type EGFR. EGFR gene mutation is not a predictive biomarker for progression-free and overall survival to cytotoxic chemotherapy in East Asians with advanced non-small cell lung cancer.

Non-small-cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLCs that is particularly responsive to EGFR tyrosine-kinase inhibitors (TKIs). A weighted pooled analysis of available studies was performed to evaluate clinical outcome in patients with EGFR-mutated NSCLC who were treated with chemotherapy or EGFR TKIs. Median progression-free survival (PFS) times were pooled from prospective or retrospective studies that evaluated chemotherapy or single-agent EGFR TKIs (erlotinib or gefitinib) in patients with NSCLC and EGFR mutations. Among the studies identified for inclusion in the analysis, 12 evaluated erlotinib (365 patients), 39 evaluated gefitinib (1069 patients) and 9 evaluated chemotherapy (375 patients). Across all studies, the most common EGFR mutations were deletions in exon 19 and the L858R substitution in exon 21. In the weighted pooled analysis, the overall median PFS was 13.2 months with erlotinib, 9.8 months with gefitinib and 5.9 months with chemotherapy. Using a two-sided permutation, erlotinib and gefitinib produced a longer median PFS versus chemotherapy, both individually (P= 0.000 and P= 0.002, respectively) and as a combined group (EGFR TKI versus chemotherapy, P= 0.000). EGFR TKIs appear to be the most effective treatment for patients with advanced EGFR-mutant NSCLC. Ongoing prospective trials comparing the efficacy of first-line chemotherapy and EGFR TKIs in EGFR-mutant disease should provide further insight into the most appropriate way to treat this specific group of patients.

Purpose: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR., Experimental Design: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non-small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non-small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers., Results: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant)., Conclusions: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.

Background The ongoing phase III ARCHER 1050 study (NCT01774721) compared dacomitinib (daco) with gefitinib (gef) as first-line therapy for pts with advanced epidermal growth factor receptor-positive (EGFR+) non-small cell lung cancer (NSCLC). Progression-free survival, duration of response, and OS significantly improved with daco vs gef. The improvement in OS was previously reported after median follow-up of 31.3 months (mo) with 220 (48.7%) total deaths. Here, final OS results are reported after a median follow-up of 47.9 mo in ARCHER 1050 to evaluate the persistence of OS improvement with daco. Methods Pts with newly diagnosed EGFR+ NSCLC were randomized 1:1 to daco or gef. Randomization was stratified by race and EGFR mutation type. Results Over a median follow-up of 47.9 mo as of 13 May 2019, 285 deaths occurred (133 [58.6%] in the daco arm [n = 227] and 152 [67.6%] in the gef arm [n = 225]). OS was still significantly improved with daco vs gef (stratified hazard ratio [HR], 0.748; 95% confidence interval [CI], 0.591–0.947; 2-sided P = 0.0155). Median OS (95% CI) with daco was 34.1 mo (29.5–39.8) vs 27.0 mo (24.4–31.6) with gef. OS30 was 56.4% with daco and 45.7% with gef. Median OS, unstratified HR, and P values for interaction are also reported by race and EGFR mutation type (Table). Dose reductions occurred in 154 (67.8%) pts receiving daco; median OS (95% CI) in pts with and without dose reductions was 42.5 (36.7–not estimable [NE]) and 20.7 (15.4–25.6) mo, respectively. In pts reduced to a lowest daco dose of 30 mg (n = 89) and 15 mg (n = 65), median OS was 36.7 mo (28.8–44.7) and NE (40.1 mo–NE), respectively. Conclusions With extended follow-up (median 47.9 mo), daco continues to improve OS over gef in pts with advanced EGFR+ NSCLC; the same trend was observed in most subgroups defined by race and EGFR status. The benefit of OS was maintained in patients who received dose reductions. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Clinical trial identification NCT01774721. Editorial acknowledgement Jessica Yuan (inScience Communications, Springer Healthcare, New York, NY, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. and SFJ Pharmaceuticals® Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca ; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: Iqvia; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: GeneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group ; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society ; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Company; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): Icon Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Iqvia; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. M.R. Migliorino: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BI; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. A. Pluzanski: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. K. Noonan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. [ABSTRACT FROM AUTHOR]

Background In the ongoing phase 3 comparison of dacomitinib (daco) and gefitinib (gef) (ARCHER 1050; NCT01774721) as first-line therapy for EGFR-mutation-positive (EGFR+) advanced NSCLC, daco was associated with significant improvement in progression free survival (PFS) and overall survival (OS). Here we present results for the subset of Asian patients (pts). Methods Eligible pts with newly diagnosed stage IIIB/IV or recurrent EGFR+ advanced NSCLC were randomized (1:1) to oral daco 45 mg once daily or gef 250 mg. Randomization was stratified by race and EGFR mutation (exon 19 del/exon 21 L858R) status. The primary efficacy endpoint was PFS by blinded independent radiologic central review (BIRC). Secondary endpoints were OS, objective response rate (ORR) and duration of response (DOR) by BIRC, and safety. Results Of 346 Asian pts, 170 were randomized to daco treatment and 176 to gef. Demographics and baseline characteristics of the groups were well balanced. At the July 29, 2016 data cutoff, the hazard ratio for PFS was 0.510 (95% confidence interval [CI] 0.392, 0.664), favoring daco (2-sided p value < 0.0001). Median PFS was 16.5 months (95% CI 12.9, 18.4) for daco and 9.3 months for gef (95% CI 9.2, 11.0). OS, ORR and DOR are shown in the table. Treatment-related adverse events (TRAEs) occurring in ≥ 50% of daco-treated pts were diarrhea (88.2%), paronychia (64.7%), and dermatitis acneiform (56.5%). In the gef arm, diarrhea (52.3%) was the only TRAE that occurred in ≥ 50% of pts. The daco dose was reduced in 67.6% of pts associated with adverse events (AEs); gef dose was reduced to every other day dosing in 9.7% of pts associated with AEs. Conclusions First-line daco was associated with significant prolongation of PFS compared with gef in Asian pts with EGFR+ advanced NSCLC. Daco treatment showed improved OS, ORR, and DOR compared to gef treatment. The AE profile for daco and gef in Asian pts was consistent with the overall ARCHER 1050 study. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Clinical trial identification NCT01774721. Editorial acknowledgement Medical writing support was provided by Michelle Daniels (inScience Communications, Springer Healthcare, Philadelphia, PA, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. LTD.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: IQVIA; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: geneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co.Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc.; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): ICON Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): IQVIA; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. C.H. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. M. Singh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background There is an expanding list of therapeutically relevant biomarkers for NSCLC and effective molecular profiling is paramount. We sought to comprehensively and prospectively evaluate the molecular epidemiology of NSCLC in Asia and ascertain the extent of access to relevant therapies. The study is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – an academic co-operative lung cancer trials group in Asia. Methods ATORG-001 is a prospective, multi-centre study of NSCLC patients (pts) throughout Asia. Eligible pts must have good performance status (ECOG ≤2), adequate organ function and ≤3 prior lines of cytotoxic chemotherapy. Archival tissue specimens are sent to a central laboratory in Singapore (Singapore General Hospital) for profiling, consisting of NGS with the Oncomine Focus Assay (52 gene panel including fusions) and PD-L1 immunohistochemistry. Results are returned to investigators in a clinically relevant timeframe. Baseline demographics, pre-existing molecular profile and prior treatment details are collected. Treatment and pt outcomes are followed for 2 years. Recruitment commenced in Jan 2019 in 3 sites (National Cancer Centre Singapore, Chinese University of Hong Kong, University Malaya Medical Centre). We report an interim analysis for the first 27 of a planned 500 pts. Results As of 01 Jul 2019, 27 pts have enrolled with median age 67 yrs (range 46-79), 59% male, 81% adenocarcinoma, 52% stage IV, 37% non-smokers, median lines of prior therapy 1 (range 0-6) and 85% with no known oncogenic driver. Pre-existing mutation status was known in 89% for EGFR and 63% for ALK. Median turnaround time from tissue acquisition to profiling results was 22 days (range 15-74). New alterations were most common in KRAS (19%), MYC (15%), CDK4 (7%) and ERBB2 (7%). Potentially actionable new alterations were found in 7 (26%) pts, including KRAS G12C mutation (7%), BRAF G469A mutation (4%), ERBB2 exon 20 insertion (4%), ERBB2 amplification (4%), FGFR2 amplification (4%) and MET exon 14 skipping mutation (4%). Conclusions Enrolment is ongoing with additional sites and countries planned to comprehensively evaluate the molecular epidemiology of NSCLC in Asia. Legal entity responsible for the study Asian Thoracic Oncology Research Group. Funding Asian Thoracic Oncology Research Group, Novartis. Disclosure A.C. Tan: Travel / Accommodation / Expenses: ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]