Epidermal Growth Factor Receptor Mutation-positive Non-small Cell Research Articles

Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. A retrospective observational cohort study was performed, including patients receiving 40-80mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166µg/L was taken to explore the exposure-efficacy relationship. A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3-19.1) months and 9.3 (95% CI: 7.2-11.1) months for patients with Cmin,pred < 166µg/L and Cmin,pred ≥ 166µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60-2.01;p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18-7.08;p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer

ObjectivesTyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).Materials and methodsRandomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.ResultsEighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.Conclusion1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.

Overall survival comparison in patients with and without brain metastases treated with osimertinib for metastatic EGFR mutation positive non-small cell lung cancer (NSCLC).

e21216 Background: With the development of Epidermal Growth factor receptor (EGFR) tyrosine kinase inhibitors such as Osimertinib, the landscape of lung cancer treatment and outcomes has changed. We aimed to describe the outcomes of patients treated with Osimertinib who have brain metastasis compared to those without brain metastases. Methods: This study involved patients diagnosed with metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, from January 2010 to December 2018, who had treatment with Osimertinib at a dose of 80 mg daily. Retrospective data was collected through the electronic medical records from Sunnybrook Health Sciences Centre. Descriptive statistics were used to summarize the population characteristics. The log rank test was used to compare the survival distributions. Results: A total of 56 patients were included, the mean age at initial diagnosis was 63 years (range 27 – 85 years). Overall, 82.2% of this patient population received Osimertinib in 2nd line setting. A total of 50% (n = 28) had brain metastasis, and14.3% (n = 8) had leptomeningeal metastasis. Of the patients with brain metastasis, 14.3% (n = 4) had brain surgery. All patients with brain metastasis received central nervous system (CNS) radiation. With respect to radiotherapy modalities, 67.9% (n = 19) of patients with brain metastasis received gamma knife radiation, 42.85% (n = 12) were treated with stereotactic radiosurgery (SRS), and whole brain radiation was given to 57.1% (n = 16). Of those with brain metastasis, equal numbers of patients, 46.4% (n = 13), had EGFR mutations with exon 19-deletion and exon 21-L858R, 7.1% (n = 2) had unknown gene location EGFR mutation. The median OS for patients without brain metastasis was 38.6 months (95% confidence interval [CI] 37.5 – 39.8 months], compared to 35.9 months (95% [CI] 28.3 – 43.5 months] for those with brain metastasis ; log Rank (Mantel-Cox) p = 0.874. The median OS for patients diagnosed with leptomeningeal metastasis was 21 months (95% [CI] 2.9 – 39.0 months); log rank (mantel-cox). When brain metastasis was examined by EGFR mutation sub-groups, the median OS for patients with EGFR-exon 19-deletion was 26.4 months (95% CI [14.3 – 38.4 months], compared to 36.8 months, 95% CI [34.3 – 39.2 months] for those with EGFR-Exon 21-L858R; log Rank (Mantel-Cox) p = 0.49. Conclusions: Although there is an equivalent prevalence of brain metastasis between the two NSCLC EGFR mutation populations, in unadjusted analyses, no difference in OS was seen between patients with brain metastases compared to those without brain metastases. However, in the small number of patients with leptomeningeal disease, survival was shorter and a larger population should be studied to further explore this finding.

Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore

Objective Non-small cell lung cancer (NSCLC) accounts for 80–90% of all lung cancer cases and is usually associated with a poor prognosis. However, targeted therapy with first and second generation tyrosine kinase inhibitors (TKIs) has so far improved progression-free survival of epidermal growth factor receptor (EGFR) mutant NSCLC patients. Osimertinib, a third generation EGFR TKI has recently shown improved overall survival of 6.8 months in previously untreated EGFR mutant NSCLC patients. We assessed the cost-effectiveness of osimertinib versus standard EGFR TKIs (gefitinib or erlotinib) as first-line treatment for advanced or metastatic EGFR mutant NSCLC patients in Singapore. Methods A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from the Singapore healthcare payer perspective. Survival curves based on the overall trial population from the FLAURA trial were extrapolated beyond trial period over a 10-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from public healthcare institutions in Singapore. Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. Results Compared with first or second generation TKI, osimertinib had a base-case incremental cost-effectiveness ratio (ICER) of SG$418,839 (US$304,277) per quality-adjusted life year gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon and variations in progression-free utility values. Scenario analyses showed that a 50% reduction in the cost of osimertinib was still associated with a high ICER that was unlikely to be deemed cost effective. Conclusions Osimertinib is not cost effective as a first-line treatment compared to standard EGFR TKIs in advanced EGFR mutant NSCLC patients in Singapore. The findings from our evaluation, alongside other considerations including the lack of survival benefit in the Asian subgroup of the FLAURA trial, will be useful to inform policy makers on funding decisions for NSCLC treatments in Singapore.

PCN30 THE FIRST-LINE TKI TREATMENTS FOR LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER WITH EGFR-ACTIVATING MUTATIONS AMONG ASIAN POPULATIONS: A NETWORK META-ANALYSIS

Dacomitinib is a human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The direct comparison between Dacomitinib and Gefitinib as first-line treatments for EGFR mutation positive Non-Small Cell Lung Cancer (NSCLC) has been observed. This study was conducted to discover the efficacy of dacomitinib versus other relevant TKI comparators, which haven’t been reported before.

1450P - Frequency of epidermal growth factor receptor (EGFR) mutations in stage IB–IIIA EGFR mutation positive non-small cell lung cancer (NSCLC) after complete tumour resection

BackgroundData on the frequency of EGFR mutations in patients (pts) with NSCLC potentially eligible for adjuvant therapy are limited. Osimertinib, a 3rd-generation, irreversible, oral EGFR-tyrosine kinase inhibitor (TKI), potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations, and has shown efficacy in the CNS. The ADAURA study (NCT02511106) will assess osimertinib as adjuvant therapy in early-stage NSCLC after complete resection. Here we report frequency of the most common EGFR activating mutations from pts screened for ADAURA. MethodsADAURA is a Phase III, double-blind, randomised, placebo-controlled study assessing efficacy and safety of osimertinib vs placebo in adult pts with mainly non-squamous histology, stage IB–IIIA EGFRm NSCLC, following complete tumour resection, without or after adjuvant chemotherapy. At screening, EGFR mutations associated with EGFR-TKI sensitivity (ex19del, L858R), alone or in combination with exon 20 insertion, G719X, S768I, T790M or L861Q were centrally assessed from resected tumour samples using the cobas® EGFR Mutation Test (Roche Molecular Systems). Some pts may have been pre-screened for EGFR mutations using local tests. ResultsIn total, 2447 pts were screened. Median age was 63 years (range 23–88), 54% were female, and 61% were non-Asian. At screening, 1087 (44%) pts were EGFR mutation positive; 110/2447 (4%) pts had an unknown/unevaluable test result. Of pts EGFR mutation positive, the most common mutations were ex19del and L858R in 572 (53%) and 458 (42%) pts, respectively; exon 20 insertion, G719X, T790M, S768I, and L861Q mutations occurred in 28 (3%), 24 (2%), 19 (2%), 11 (1%) and 8 (1%) pts, respectively. Mutations occurred alone or in combination. A higher proportion of EGFR mutation positive pts were Asian vs non-Asian (681 [63%] vs 402 [37%]; 4 pts missing) and female vs male (755 [69%] vs 331 [30%]; 1pt missing). ConclusionsThis analysis shows a high prevalence of EGFRm mutations in Asian and female pts with stage IB–IIIA NSCLC following complete resection, which is consistent with the advanced setting. International screening for EGFR mutations in the adjuvant setting should be considered. Clinical trial identificationNCT02511106. Editorial acknowledgementNatalie Griffiths, PhD, from iMed Comms, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureM. Tsuboi: Research grant / Funding (institution): Boehringer Ingelheim Japan; Honoraria (self): Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Boehringer Ingelheim Japan, Daiichi-Sankyo, Chugai Pharmaceutical, Taiho Pharma, Covidien Japan, Ono Pharmaceutical, Merck Sharp & Dohme, Bristol-Myers Squibb KK, Teijin Pharma. R.S. Herbst: Advisory / Consultancy, Consulting: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serrano, Genentech/Roche, Genmab, Heat Biologics, Halozyme, Loxo Oncology, Merck & Company, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics,; Research grant / Funding (institution): AstraZeneca, Eli Lilly, Merck; Advisory / Consultancy, Scientific Advisory Boards: Neon Therapeutics, Infinity Pharmaceuticals, NextCure; Leadership role, Board Member (non-executive/independent): Junshi Pharmaceuticals. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. J.W. Goldman: Research grant / Funding (institution): AbbVie; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): AstraZeneca. S. Novello: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Roche, Merck Sharp & Dohme, Takeda, Pfizer, AbbVie, AstraZeneca, Celgene. D. Urban: Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca. C. Akewanlop: Travel / Accommodation / Expenses: Amgen, AstraZeneca, Roche. D. Kowalski: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim. D. Marmol: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Marotti: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Roche; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Eli Lilly, Pfizer, Merck Sharp & Dohme, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

The role of EGFR inhibitors as adjuvant therapy for EGFR mutation positive non-small cell lung cancer.

8508 Background: Cisplatin-based chemotherapy as adjuvant therapy for resected NSCLC has reached its plateau, and was limited by high risk of recurrence and significant toxicities. The clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected non-small cell lung cancer (NSCLC) harboring EGFR mutations remains controversial. In this study, we performed a meta-analysis to evaluate the role of EGFR inhibitors as adjuvant therapy for targeted patients. Methods: Studies were identified via an electronic search on Pubmed, EMBASE, ISI Web of Science, ScienceDirect, SpringerLink, The Cochrane library and so on. Pooled odds ratio (OR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis. Registration number: PROSPERO (CRD42018093144). Results: There were 11 trials (1,152 resected NSCLC patients with EGFR sensitive mutations) in this meta-analysis. Results showed that adjuvant treatment with EGFR-TKIs can prolong both OS and DFS when compared to treatment without TKIs as adjuvant therapy (OS: OR, 0.63; 95% CI, 0.46 to 0.87, P = 0.004; heterogeneity I2= 61%, P = 0.008; DFS: OR, 0.56; 95% CI, 0.43 to 0.72, P &lt; 0.00001; heterogeneity I2= 37%, P = 0.1). Results of predefined subgroup analyses in this meta-analysis suggested a greater DFS with EGFR-TKI mono compared with chemotherapy, whereas the OS benefit failed to show a similar difference between the two arms (p = 0.3). And we also find that treatment with EGFR-TKI plus chemotherapy was associated with significantly longer DFS as well as OS than chemotherapy mono in patients with completely resected EGFR-mutant NSCLC (DFS: OR, 0.48; 95%CI, 0.34-0.68; P &lt; 0.00001; heterogeneity I2= 15%, P = 0.29; OS: OR, 0.50; 95% CI, 0.31-0.78; P = 0.003; heterogeneity I2 = 57%, P = 0.05). And less grade 3 or higher AEs were observed in the TKIs group (OR, 0.22; 95% CI, 0.14 to 0.37, P &lt; 0.00001; heterogeneity I2= 22%, P = 0.28). Conclusions: Adjuvant EGFR-TKIs may be a potential treatment option compared to adjuvant chemotherapy in completed resected patients with EGFR mutation-positive NSCLC. This project was supported by the National Natural Science Foundation of China (Grant No. 81502667), Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167).

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

PurposeNext to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib. Materials and methodsEight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6). ResultsFour out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2–5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4–5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3–6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification. ConclusionCrizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms.

Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.

e20589 Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]

Patient-reported outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.

e20590 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Limited data are available regarding patient-reported outcomes (PROs) in patients who experience progression on 1st-/2nd-generation TKI treatment, which was the focus of this study. Methods: A retrospective chart review of patients with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed between 1/1/2008 and 1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Eligible patients with ≥1 Patient Care Monitor record were included in this subset analysis. Linear mixed models were used to evaluate select PROs. Results: The study included 364 patients: 77.7% white, 17.3% African American; and mean (SD) age 66.3 (11.3) years. Of the 241 patients who received systemic anticancer therapies after progression, 33.2% continued on TKIs ± chemotherapy (66.8% chemotherapy alone). PROs were available for 71 of 364 patients. We found that progression was associated with worsening in acute distress, despair, and difficulty breathing ( P&lt; .001, P&lt; .001, P= .048, respectively). Disease progression was also associated with worsening of vomiting and nausea ( P&lt; .001, P= .023, respectively). Patient-reported rash symptoms improved from the TKI treatment period to the post-progression period ( P= .044), which aligned with the incidence of rash in the patient records (61.0% during TKI, 32.9% after progression). Conclusions: As expected, disease progression was associated with worsening of patient psychological symptoms and difficulty in breathing. Interestingly, as disease progressed and patients transitioned from TKI therapies to chemotherapies, there was worsening of vomiting and nausea and a decrease in patient-reported rash symptoms. These findings underscore the need for therapeutic options that improve patient symptomatology after progression on 1st-/2nd-generation EGFR TKIs.

A population-based review of the feasibility of platinum-based combination chemotherapy after tyrosine kinase inhibition in EGFR mutation positive non-small cell lung cancer patients with advanced disease

IntroductionThe IPASS trial demonstrated superior progression free survival for Asian, light/never smoking, advanced, pulmonary adenocarcinoma patients treated with first-line gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were epidermal growth factor receptor (EGFR) mutation positive. In IPASS 39% of gefitinib treated patients went on to receive platin based polychemotherapy. We hypothesized that in a population-based setting fewer patients receive second-line platin based chemotherapy than those enrolled in a clinical trial. MethodsThe Iressa Alliance program provided standardized EGFR mutation testing and appropriate access to gefitinib to all patients in British Columbia with advanced, non squamous non small cell lung cancer (NSCLC). We retrospectively analyzed clinical, pathologic data and outcomes for all patients tested in this program between March 2010 and June 2011. ResultsA total of 548 patients were referred for testing and 22% of patients were mutation positive. Baseline characteristics of mutation negative and mutation positive; median age 67/65, male 41%/31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Median overall survival was 12 months in mutation negative patients and not yet reached in mutation positive (p<0.0001). In mutation positive patients 5% of patients had a complete response, 46% partial response, 34% stable disease, 6% progressive disease. Twenty percent of patients continued on gefitinib after radiographic progression and clinical stability. Sixty-one gefitinib treated patients progressed at the time of analysis; 10% of patients received further gefitinib only, 38% platinum based doublet, 8% other chemotherapy and 44% no further treatment. Performance status most strongly predicted for delivery of second line chemotherapy. ConclusionsThis North American population based study shows similar efficacy of gefitinib in mutation positive patients compared to the IPASS trial. Contrary to our hypothesis, delivery of second line chemotherapy was feasible in a significant proportion of gefitinib treated patients.