Mutation-positive Advanced Non-small Cell Research Articles

PP01.71 Clinicopathologic Profile of Filipino Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer: A Single Institution Review

PP01.71 Clinicopathologic Profile of Filipino Patients with EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer: A Single Institution Review

A Study of YH25448 in Participants With Epidermal Growth Factor Receptor (EGFR) Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

A Study of YH25448 in Participants With Epidermal Growth Factor Receptor (EGFR) Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.

e20560 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.

Real world treatment and outcomes in patients with EGFR mutation positive advanced non-small cell lung cancer: the Kent Cancer Network experience

Real world treatment and outcomes in patients with EGFR mutation positive advanced non-small cell lung cancer: the Kent Cancer Network experience

P1.03-053 Taiwan Real Word Efficacy of 1st Line EGFR TKIs Treatment in EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer

Previous studies have shown EGFR TKIs provided superior 1st line efficacy to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutation. LUX-Lung7, a phase IIB randomized head-to-head study, showed afatinib significantly improved PFS, TTF, and ORR compared with gefitinib. However, it is still unclear how to choose among these three EGFR TKIs in clinical setting, especially for uncommon mutation, which was excluded in most studies. This retrospective study is aimed to evaluate the treatment pattern in our hospital and efficacy of three EGFR TKI for patients with common mutations and uncommon mutations. Patients with advanced NSCLC were retrospectively reviewed in a university hospital in central Taiwan from Jan 2013 to Mar 2017. In this population, patients with EGFR mutations and have to be taking EGFR TKIs as 1st line treatment more than 30 days were recorded for analysis. 1,951 patients with advanced lung cancer were reviewed. About 75% of lung cancers were adenocarcinomas and 55% were EGFR mutation rate. Clinical data of 467 patients with advanced EGFR mutation lung adenocarcinomas were extracted, 95.7% of them used EGFR TKI as 1st line therapy including gefitinib (n=210), erlotinib (n=147), and afatinib (n=110). The median age was 64 years old. More female was included in the gefitinib cohort and afatinib cohort tended to have higher component of uncommon mutations. The TTF among gefitinib (G), erlotinib (E) and afatinib (A) were 9.8 vs 11.4 vs 12.2 months (p = 0.094). Patients treated with afatinib had improved TTF compared with gefitinib (HR= 0.72, 95% CI: 0.54-0.97, p = 0.035) and showed a trend compared with erlotinib without significantly difference. In del 19, TTF among G, E and A were 9.4 vs 12.0 vs 12.2 months (p = 0.074). In L858R, TTF among G, E and A were 10.4 vs 10.9 vs 11.7 months (p = 0.721). Intriguingly, afatinib showed excellent TTF in uncommon mutations (median TTF G vs E vs A: 7.5 vs 7.0 vs 19.7 months, p = 0.506). Afatinib dose reduction didn’t have impact TTF (median TTF 30 mg vs 40 mg: 16.1 vs 10.3 months. p = 0.923) Consistently, our findings supported improved efficacy as observed from LUX-Lung7. In more resistance mutation type such as uncommon mutation, afatinib tended to have better efficacies. Due to insufficient sample size and the retrospective study design, further confirmatory study is warranted.

468P Osimertinib in patients with T790M mutation positive advanced non-small cell lung cancer (NSCLC): Korean subgroup analysis from pooled phase II data

Background Osimertinib is a potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-sensitizing and T790M resistance mutations. This is the results of a Korean subgroup analysis from a pooled analysis of two global phase II studies in pre-treated patients: AURA extension (NCT01802632) and AURA2 (NCT02094261). Methods Both studies enrolled patients with EGFR/T790M mutation-positive NSCLC who had progressed on or after EGFR TKI therapy. Patients were treated with osimertinib 80 mg orally QD until disease progression. Objective response rate (ORR) was the primary endpoint; duration of response (DoR) and progression-free survival (PFS) were the secondary endpoints. Data cut-off (DCO) was 1 November 2015; results from 411 patients in the global study have been presented previously. Results A total of 66 Korean patients were dosed; median age 60.5 years; 69.7% female; 72.7% never smokers. The median duration of exposure to osimertinib was 13.3 months. Confirmed ORR in the evaluable-for-response population (N = 62) by blinded independent central review was 76% (47/62; 95% confidence interval [CI]: 63, 86). Median DoR was 11.0 months (95% CI: 8.3, not calculable [NC]) and median PFS was 11.0 months (95% CI: 8.3, NC). The results are comparable to the global study population; ORR 66% (262/397, 95% CI: 61, 71), median DoR 12.5 months (95% CI: 11.1, NC), median PFS 11.0 months (95% CI: 9.6, 12.4). The most common causality-related adverse events (AEs) were rash (grouped term) (44%, 0% Grade 2:3), pruritus (27%; 0% Grade 2:3), and paronychia (grouped term) (26%; 0% Grade 2:3); 5 (7.6%) patients experienced Grade 2:3 AEs. Conclusions Overall efficacy and tolerability with osimertinib in this Korean subset was consistent with results from the global study. Osimertinib provides a high ORR, with encouraging DoR and PFS, and a manageable tolerability profile. Clinical trial indentification Clinical trial registration number: NCT01802632, NCT02094261 Legal entity responsible for the study AstraZeneca Funding AstraZeneca Disclosure M-J. Ahn, D-W. Kim: All authors participated in either AURA extension (NCT01802632) or AURA2 (NCT02094261) study as investigators. This author is one of the investigators of AURA extension (NCT01802632) study and other company- sponsored clinical trials. J-S. Lee, J-Y. Han: All authors participated in either AURA extension (NCT01802632) or AURA2 (NCT02094261) study as investigators. This author is one of the investigators of AURA2 (NCT02094261) study and other company- sponsored clinical trials. B.C. Cho, S-W. Kim: All authors participated in either AURA extension (NCT01802632) or AURA2 (NCT02094261) study as investigators. This author is one of the investigators of AURA extension (NCT01802632) study and other company-sponsored clinical trials. J.H. Kang: All authors participated in either AURA extension (NCT01802632) or AURA2 (NCT02094261) study as investigators. This author is one of the investigators of AURA2 (NCT02094261) study and other company- sponsored clinical trials.

468P Osimertinib in patients with T790M mutation positive advanced non-small cell lung cancer (NSCLC): Korean subgroup analysis from pooled phase II data

468P Osimertinib in patients with T790M mutation positive advanced non-small cell lung cancer (NSCLC): Korean subgroup analysis from pooled phase II data

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

Background and ObjectiveAfatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib.MethodsThis was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30–59 mL/min/1.73 m2 and 15–29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration–time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls.ResultsPharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3–213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28–39 % for moderate impairment, 34–42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal.ConclusionModerate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population.Registered at ClinicalTrials.gov as NCT02096718.

Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer

ObjectivesGefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC. Patients and methodsPharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing. ResultsThe subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168–781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698–13991) ng/mLh. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%–93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD. ConclusionElevated gefitinib exposure might be associated with drug-induced ILD.

60 Afatinib in EGFR mutation positive advanced non-small cell lung cancer

60 Afatinib in EGFR mutation positive advanced non-small cell lung cancer

Phase IB study to evaluate efficacy and tolerability of olaparib (AZD2281) plus gefitinib in patients (P) with epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) (NCT=1513174/GECP-GOAL).

8079 Background: Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. High BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesized that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P. Methods: This is a Phase IB dose escalation study (standard 3+3 design) to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. P were treated with gefitinib 250mg once daily plus olaparib at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: Twenty-two P were included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg ...

Overcoming resistance to first generation EGFR TKIs with cetuximab in combination with chemotherapy in an EGFR mutated advanced stage NSCLC patient

We report the case of a female never-smoking patient with an epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) who received multiple lines of treatment. When she evolved clinical resistance to first generation EGFR tyrosine kinase inhibitors (TKI), she was treated with a fifth-line combination therapy with cetuximab and vinorelbine. This combination was highly active with a treatment response lasting for 9 months supporting the hypothesis that EGFR monoclonal antibodies in combination with chemotherapy may play a role in reversing EGFR-TKI resistance in EGFR mutation-positive NSCLC.

1255P - Population Based Evaluation of Chemotherapy Use After First Line Gefitinib in Epidermal Growth Factor Receptor (EGFR) Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Introduction The IPASS trial demonstrated superior progression free survival for Asian, light/never smoking, advanced, adenocarcinoma patients treated with first line Gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were EGFR mutation positive (MUT+). In IPASS 39% of Gefitinib treated patients went on to receive platin based therapy. We hypothesize that in a population-based setting fewer patients receive second line platin based chemotherapy. Methods The Iressa Alliance Program provided standardized EGFR mutation testing and appropriate access to Gefitinib to all patients in British Columbia (population 4.5 million) with advanced, non squamous NSCLC. EGFR mutation testing was limited to the most common mutations; exon 19 and 21. We retrospectively analyzed clinical, pathologic and outcomes for all patients tested in this program between March 2010 and June 2011. Results A total of 548 patients were referred for testing and 107 (19%) patients were MUT+. Baseline characteristics of MUT- and MUT + ; median age 67/65, male 41%/31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Overall survival was 10.9 versus 14.9 months (p Conclusions This North American population based study shows similar efficacy of Gefitinib in MUT+ patients compared to the IPASS trial. Clinicians often continued Gefitinib past progression, likely due to ongoing clinical benefit. Contrary to our hypothesis, delivery of second line chemotherapy was feasible in a significant proportion of Gefitinib treated patients, similar to results seen in clinical trials. MUT+ patients have a better prognosis and this may contribute to their ability to receive further therapy. Disclosure All authors have declared no conflicts of interest.

PCN110 Economic Evaluation of Gefitinib for First-Line Treatment of EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer Patients in Greece

PCN110 Economic Evaluation of Gefitinib for First-Line Treatment of EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer Patients in Greece