EGFR Mutation-positive Advanced NSCLC Research Articles

Longitudinal Analyses of Circulating Tumor DNA for the Detection of EGFR Mutation-Positive Advanced NSCLC Progression During Treatment: Data From FLAURA and AURA3

IntroductionEGFR tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma through circulating tumor DNA (ctDNA). Circulating tumor DNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. MethodsThis was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced NSCLC with EGFR mutations and on-study PD (RECIST [Response Evaluation Criteria in Solid Tumors]), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD and the first subsequent treatment (FLAURA only). ResultsCirculating tumor DNA PD preceded or co-occurred with RECIST-defined PD in 93 out of 146 patients (64%) in FLAURA and 82 out of 146 patients (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (mo) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, the median time from ctDNA PD to the first subsequent treatment (mo) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). ConclusionsAmong patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

P8‐99: Efficacy of repeat re‐biopsy and osimertinib in patients with EGFR mutation positive advanced NSCLC

P8‐99: Efficacy of repeat re‐biopsy and osimertinib in patients with EGFR mutation positive advanced NSCLC

A phase I/II study of TQ-B2450, a PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies.

e21062 Background: Platinum-based chemotherapy is the standard therapy for the patients(pts) with EGFR-mutation–positive advanced NSCLC failed to prior EGFR TKI therapies. However, the IMpower150 study subgroup analyses showed Atezolizumab (PD-L1) plus bevacizumab and chemotherapy improved overall survival in EGFR TKI treated NSCLC. This ongoing phase I/II study designed to assess the benefit of the chemo-free combination of TQ-B2450, a humanized PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC pts failed to prior EGFR TKI therapies. Methods: Pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies were eligible. Pts with previous received platinum-based chemotherapy were excluded. Anlotinib was given orally at dose of 8mg to 12mg for 2 weeks of a 21-day cycle (days 1-14), with TQ-B2450 given at 1200mg every 3 weeks on day 1. Phase I determined RP2D. In the phase II part, pts were assessed for efficacy and tolerability. The primary endpoint for the phase II part is the progression free survival (PFS). Secondary endpoints were objective response rate (ORR) disease control rate (DCR), overall survival (OS), and safety. Assuming an expected the median PFS of 9 months (5 months in chemotherapy), and a loss to follow-up of 10%, a total of 54 pts were required to have 90% power at a two-tailed alpha of 0.05 at the phase II part. Results: As of 12 Jan 2021, 22 pts were enrolled (9 in phase 1, 14 in phase 2). 18 pts were included in efficacy and safety analysis. The median age was 64.5 years with 61% male. 50% pts harbored EGFR exon19 deletion, 44% pts had exon21 L858R mutation. While 39% pts had T790M mutation who progressed after osimertinib treatment. The dose escalation cohort included 9 pts, no dose limiting toxicity occurred. 13 pts in the phase II part were administered with dose of 12 mg for anolitinib and 1200mg for TQ-B2450. Of the evaluable pts(n = 18), ORR was 11.1%, DCR was 77.8%, median PFS was 8.0 months (95% CI 4.9 to 11.1). Most frequent TRAE included hypertension (27.8%), hand and foot skin reaction (22.2%) and proteinuria (16.7%). Grade 3 TRAE occurred in 16.7% pts(3/18 pts), all were hypertension, and no Grade 4/5 TRAE were observed. Dose delay due to TRAE occurred in 22.2% patients while no one discontinued treatment due to TRAE. Conclusions: The chemo-free combination of TQ-B2450, a PD-L1 mAb, plus anlotinib has shown a promising anti-tumor efficacy with a more favorable safety profile for pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (PFS, DOR and OS). Clinical trial information: ChiCTR1900026273. Clinical trial information: ChiCTR1900026273.

P03.02 Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA

Background: Approximately 30% of patients with NSCLC present with resectable disease. Primary treatment for resectable NSCLC is curative surgery; patient prognosis following surgery alone remains poor. Neoadjuvant chemotherapy is recommended in resectable stage-III NSCLC, regardless of EGFR mutation status, and has demonstrated clinical benefit. However, improved treatment options for stage II/III are needed. Recent studies indicate that EGFR-TKI therapy could potentially achieve tumour size reduction and clearance of micrometastases in the neoadjuvant setting; treatment effect can be assessed in resected specimens. Osimertinib is a third-generation, CNS-active EGFR-TKI, with superior efficacy to comparator EGFR-TKI in treatment-naïve EGFR mutation-positive (EGFRm) advanced NSCLC. In the Phase III ADAURA study (NCT02511106), osimertinib showed statistically significant DFS improvement (hazard ratio: 0.20 [99.12% confidence interval 0.14, 0.30; p<0.001) in resected stage IB—IIIA EGFRm NSCLC following adjuvant chemotherapy, when indicated. A recent study (NCT03433469) found neoadjuvant osimertinib was well tolerated in patients with Stage I—IIIA NSCLC. Efficacy and tolerability of osimertinib in advanced and adjuvant settings support its investigation as neoadjuvant treatment in resectable disease. NeoADAURA (NCT04351555) is a Phase III, controlled, randomised study assessing efficacy and safety of osimertinib (with/without chemotherapy) versus chemotherapy plus placebo as neoadjuvant treatment in resectable stage II—IIIB EGFRm NSCLC. Trial Design: Eligible patients: ≥18 years (≥20 years, Japan), ECOG PS 0/1, primary non-squamous stage II—IIIB (IASLC Cancer Staging Manual v8) NSCLC and confirmed EGFRm (Ex19del/L858R), deemed completely resectable. Prior treatment with systemic anti-cancer therapy for NSCLC is not allowed. Approximately 351 patients will be randomised 1:1:1 (Figure) to receive platinum-based chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5 or cisplatin 75 mg/m2) plus placebo (Arm 1; double-blind), platinum-based chemotherapy plus osimertinib 80 mg once-daily (Arm 2; double-blind) or osimertinib 80 mg once-daily alone (Arm 3; open-label). Patients will be stratified by disease stage (II/III), race (non-Asian/Chinese/other Asian) and EGFR mutation (Ex19del/L858R). Following three cycles of chemotherapy (Arms 1 and 2) or nine weeks of osimertinib (Arm 3), patients will undergo complete surgical resection of primary NSCLC. Treatment with osimertinib or placebo may continue until surgery, unless unacceptable toxicity/withdrawn consent/other discontinuation criterion. Post-surgery, patients will receive optimal care (investigator-defined); this may include adjuvant osimertinib treatment for three years (maximum)/until disease recurrence or unmanageable toxicity. The primary endpoint is MPR, (≤10% residual cancer cells in surgical specimen post-surgery) centrally assessed. Secondary endpoints include pCR, EFS, downstaging, DFS, OS and safety. MPR and EFS will be tested using hierarchal testing procedure at MPR primary analysis. osimertinib, Stage II—IIIB NSCLC, Neoadjuvant

Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050)

ObjectivesTo compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. Materials and methodsIn this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. ResultsOf 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391–0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9–18.4] vs. 9.3 months [95 % CI: 9.2–11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578–0.996; median 37.7 months [95 % CI: 30.2–44.7] vs. 29.1 months [95 % CI: 25.6–36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively. ConclusionFirst-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.

Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.

Clinical trial and real-world data in non-small-cell lung cancer indicate that 10-60% of patients that progressed on first- or second-generation EGFR-targeting tyrosine kinase inhibitors (TKI) do not receive systemic second-line therapy. In our article, we discuss efficacy, safety and treatment duration with different EGFR-TKIs and stress the need for delivery of the most efficacious therapy in the first-line. We also provide our perspective on analysis of circulating tumor DNA and the role of EGFR-TKI in combined therapies. Finally, we review new therapeutic options to overcome resistance to EGFR-TKI. We believe that overall treatment duration and access to different medications in subsequent lines of therapy should be considered when planning the optimal treatment strategy.

1532P - Afatinib followed by osimertinib in patients with EGFR mutation-positive (EGFRm+) advanced NSCLC: Updated data from the GioTag real-world study

BackgroundAfatinib is effective in EGFRm+ NSCLC; however, resistance develops over time, most commonly due to emergence of the T790M mutation. Osimertinib has shown efficacy in the treatment of T790M-positive NSCLC after progression on a first-line TKI. Further information on sequencing outcomes is needed to optimize treatment outcomes. MethodsThis observational study is the first to evaluate real-world outcomes of sequential afatinib followed by osimertinib. Data were retrospectively collected from patients with EGFRm+(Del19, L858R) advanced NSCLC and acquired T790M after first-line afatinib. Patients must have completed afatinib and started osimertinib ≥10 months prior to enrollment. Those with active brain metastases were excluded. The primary outcome was time to treatment failure (TTF) from initiation of afatinib until discontinuation of osimertinib. Results204 patients were included; 24.5/67.6% were Asian/non-Asian, 73.5/26.0% were Del19/L858R+, and 83.7% started on afatinib 40mg. The study included patients with poor prognosis features who are often excluded from clinical trials; 31 (15.2%) patients had ECOG PS≥2 and 21 (10.3%) had stable brain metastases. As of May 2018, overall median TTF was 27.6 months (90% CI: 25.9, 31.3). Median time on afatinib and osimertinib was 11.9 months (90% CI: 10.9, 12.2) and 14.3 months (90% CI: 12.8, 15.9), respectively. The 2-year OS rate was 78.9%. TTF was generally consistent across subgroups, but was longer in Asian patients (n=50; median 46.7 months; 90% CI: 26.8, NR) and those with Del19+ disease (n=150; median 30.3 months; 90% CI: 27.6, 44.5). Results were similar in patients who started on the approved 40mg dose of afatinib; median TTF was 27.6 months (90% CI: 26.3, 31.3) overall and 46.7 months (90% CI: 36.4, 46.7) in Asian Del19+ patients. OS and updated TTF data will be presented. ConclusionsFirst-line afatinib followed by osimertinib is feasible in a broad, real-world patient population with EGFRm+ NSCLC and acquired T790M mutation. The benefit of sequential afatinib followed by osimertinib was observed across all patient subgroups, particularly in those with Del19+ disease and Asian patients. Clinical trial identificationNCT03370770. Editorial acknowledgementFiona Scott of GeoMed, an Ashfield company, part of UDG Healthcare plc; funded by Boehringer Ingelheim. Legal entity responsible for the studyBoehringer Ingelheim. FundingBoehringer Ingelheim. DisclosureM.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): Novartis. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme. D. Hao: Advisory / Consultancy, Research grant / Funding (self), Research funding/consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self), Research funding/consultancy: AstraZeneca. R. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AZ; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BI; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Ignyta; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan. J.C. Yang: Honoraria (self): BI; Honoraria (self): Eli Lilly; Honoraria (self): Bayer; Honoraria (self): Roche/Genentech; Honoraria (self): Chugai; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Ono Pharma; Advisory / Consultancy: Astellas; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharma; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Hansoh Pharma; Advisory / Consultancy: Takeda Pharma; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: G1 Therapeutics. B. Halmos: Advisory / Consultancy, Research grant / Funding (self): AZ; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): BI; Advisory / Consultancy: Genentech; Advisory / Consultancy: Spectrum; Advisory / Consultancy: Ignyta; Advisory / Consultancy, Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Mirati; Research grant / Funding (self): AbbVie; Research grant / Funding (self): GSK; Advisory / Consultancy: Foundation Medicine. L. Wang: Full / Part-time employment: Boehringer Ingelheim. A. Golembesky: Full / Part-time employment: Boehringer Ingelheim. A. Märten: Full / Part-time employment: Boehringer Ingelheim. T. Cufer: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Chinese Herbal Medicine Combined With EGFR-TKI in EGFR Mutation-Positive Advanced Pulmonary Adenocarcinoma (CATLA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20–16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97–12.45 months; hazard ratio, 0.68; 95% CI, 0.51–0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1–2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01745302.

Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial.

9020 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third generation EGFR-TKI, showed superior efficacy to comparator EGFR-TKIs as first line treatment for EGFR mutation-positive (EGFRm) advanced NSCLC. In an exploratory analysis, we investigated clinical outcomes associated with detection of plasma EGFRm at 3 or 6 weeks (wks) after start of treatment. Methods: Treatment-naïve patients (pts) with EGFRm (ex19del or L858R) locally advanced or metastatic NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily (QD) or comparator EGFR-TKIs (gefitinib 250 mg QD or erlotinib 150 mg QD). Plasma EGFR mutation analysis was conducted at baseline (BL), wks 3 and 6 by droplet digital PCR. Clearance was defined as undetectable levels of EGFRm in ctDNA at wks 3/6, where they were detectable at BL. Progression-free survival (PFS) was investigated based on early clearance of EGFRm. Results: In total 489/556 (88%) pts (osimertinib: 244/279; comparator: 245/277) had evaluable ctDNA at BL and wks 3/6. Of these, 342/489 (70%; osimertinib: 168/244; comparator: 174/245) had detectable BL EGFRm and were included in this analysis. See table. Conclusions: Clearance of plasma EGFRm after 3/6 wks of EGFR-TKI therapy was associated with a numerical improvement in PFS. The efficacy of osimertinib was superior to comparator EGFR-TKIs regardless of clearance status. Clinical trial information: NCT02296125. [Table: see text]

133P - A study evaluating the different treatment modalities for EGFR mutation positive advanced NSCLC patients that acquire c-MET amplification after EGFR TKI therapy resistant

133P - A study evaluating the different treatment modalities for EGFR mutation positive advanced NSCLC patients that acquire c-MET amplification after EGFR TKI therapy resistant

CLO19-033: Afatinib Followed by Osimertinib in EGFR Mutation-Positive (EGFRm+) Advanced NSCLC: Subgroup Analyses of the GioTag Study by ECOG PS, Age, and Ethnicity

Background: EGFR TKIs have shown first-line efficacy in EGFRm+ NSCLC but acquired resistance is inevitable; with afatinib, this is predominantly through the emergence of T790M. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options. The GioTag study (NCT03370770) is the first to assess outcomes of real-world patients (Pts) who received first-line afatinib followed by osimertinib; for pts with EGFRm+ NSCLC and acquired T790M this sequence resulted in a median time on treatment (ToT) of 27.6 months, which did not include chemotherapy. We present subgroup analyses of pts from the GioTag study who are under-represented in randomized controlled trials (RCTs) and assess the impact of afatinib treatment on ECOG PS. Methods: The GioTag study is an observational, multicenter study. Data were collected retrospectively (Dec 2017–May 2018). Pts had EGFRm+ (Del19/L858R) advanced NSCLC and acquired T790M after first-line afatinib. Pts completed afatinib and started osimertinib treatment ≥10 months before data entry to avoid early censoring and ensure mature data collection. Patient subgroups were defined based on baseline characteristics (eg, ECOG PS, age, ethnicity). The primary outcome was ToT from afatinib initiation to osimertinib discontinuation. Results: A total of 204 pts were included in the GioTag study: 15.2% had ECOG PS ≥2; 7.4% were aged ≥75 years; 8.8% were African-American. Pts generally considered to have a poor prognosis derived clinical benefit from the afatinib–osimertinib sequence: median ToT for pts with ECOG PS ≥2 (n=31) was 22.2 months (90%CI 16.0–27.0; vs pts with ECOG PS 0/1 [n=153; 31.3 months; 27.6–44.5] P&lt;.001); and for pts aged ≥75 years (n=15), ToT was 19.9 months (9.7–not evaluable [NE]; vs pts aged &lt;75 years [n=189; 28.1 months; 26.6–31.3] P=.382). In African-American pts, median ToT was 27.6 months (90%CI 24.7–NE). Of 180 pts with available data, 75.0% had no change or an improvement in ECOG PS from the start of afatinib to the start of osimertinib treatment; 24.4% of pts had a deterioration in ECOG PS by 1 step and 0.6% of pts had a deterioration by 2 steps. Conclusions: First-line afatinib followed by osimertinib is a feasible therapeutic strategy in pts with EGFRm+ NSCLC and acquired T790M, including those who are often under-represented in RCTs. Clinical benefit (measured by ToT) was seen among pts with poor prognosis (ECOG PS ≥2), pts aged ≥75 years, and African-American pts.

Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study

Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study

Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study

The GioTag study aimed to assess outcomes in real-world patients who received first-line afatinib followed by osimertinb.

OA03 Afatinib Followed by Osimertinib in Real-World Patients with EGFR Mutation-Positive Advanced NSCLC: The Giotag Study

OA03 Afatinib Followed by Osimertinib in Real-World Patients with EGFR Mutation-Positive Advanced NSCLC: The Giotag Study

Impact of afatinib dose modification on safety and effectiveness in patients with EGFR mutation-positive advanced NSCLC: Results from a global real-world study (RealGiDo)

ObjectivesIn the LUX-Lung clinical trials of afatinib in EGFR mutation-positive NSCLC, tolerability-guided dose adjustment reduced the incidence and severity of adverse events while maintaining efficacy. The RealGiDo study evaluated the impact of afatinib dose adjustment in a real-world setting. Materials and methodsThis non-interventional, observational study used medical records of EGFR mutation-positive NSCLC patients treated with first-line afatinib. Primary outcomes were adverse drug reaction (ADR) incidence and severity, time to treatment failure (TTF), and time to progression (TTP), relative to LUX-Lung 3 (LL3). Results228 patients were enrolled from 13 countries. Baseline characteristics were in line with LL3 but with more Del19 patients (78.1% vs. 49.0%) and fewer Asian patients (43.9% vs. 72.2%); 11.8% had ECOG performance status 2–3. A total of 71 (31.1%) received a modified starting dose of ≤30 mg. Of patients who started with 40 mg, 67.1% underwent dose reductions, 86.5% of which were in the first 6 months. Dose reductions were mainly due to ADRs and were more common in female, East Asian, and low body-weight patients. There were no new safety signals and fewer ≥grade 3 ADRs (28.4% vs. 48.9%) and serious adverse events (5.2% vs. 14.0%) than in LL3. Median TTF and TTP were 18.7 and 20.8 months, respectively, and were not impacted by reduced starting dose or dose modification. ConclusionReal-world data show that afatinib dose adjustments reduced the frequency and intensity of ADRs without compromising effectiveness, highlighting the benefit of tailoring afatinib dose to optimise treatment outcomes and supporting clinical decision-making.The study is registered at clinicaltrials.gov (NCT02751879).

LBA7 - Afatinib followed by osimertinib in patients with EGFR mutation-positive advanced NSCLC: A real-world study (GioTag)

LBA7 - Afatinib followed by osimertinib in patients with EGFR mutation-positive advanced NSCLC: A real-world study (GioTag)

P1.01-28 Impact of Afatinib Dosing on Safety and Efficacy Real-World in Patients with EGFR Mutation-Positive Advanced NSCLC

P1.01-28 Impact of Afatinib Dosing on Safety and Efficacy Real-World in Patients with EGFR Mutation-Positive Advanced NSCLC

MA08.01 A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma

Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC. The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene). Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded. Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases.

CtDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study

IntroductionTo offer patients with EGFR mutation–positive advanced NSCLC appropriate EGFR tyrosine kinase inhibitor treatment, mutation testing of tumor samples is required. However, tissue/cytologic samples are not always available or evaluable. The large, noninterventional diagnostic ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for EGFR mutation testing. MethodsASSESS was conducted in 56 centers (in Europe and Japan). Eligible patients (with newly diagnosed locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytologic and plasma samples. DNA extracted from tissue/cytologic samples was subjected to EGFR mutation testing using local practices; designated laboratories performed DNA extraction/mutation testing of blood samples. The primary end point was level of concordance of EGFR mutation status between matched tissue/cytologic and plasma samples. ResultsOf 1311 patients enrolled, 1288 were eligible. Concordance of mutation status in 1162 matched samples was 89% (sensitivity 46%, specificity 97%, positive predictive value 78%, and negative predictive value 90%). A group of 25 patients with apparent false-positive plasma results was overrepresented for cytologic samples, use of less sensitive tissue testing methodologies, and smoking habits associated with high EGFR mutation frequency, indicative of false-negative tumor results. In cases in which plasma and tumor samples were tested with identical highly sensitive methods, positive predictive value/sensitivity were generally improved. ConclusionsThese real-world data suggest that ctDNA is a feasible sample for EGFR mutation analysis. It is important to conduct mutation testing of both tumor and plasma samples in specialized laboratories, using robust/sensitive methods to ensure that patients receive appropriate treatments that target the molecular features of their disease.

Abstract 2262: Thioredoxin reductase 1: the key member in metabolism affects PFS of 1st line erlotinib to advanced non-small cell lung cancer harboring EGFR mutation-positive

Abstract Background: Deregulating cellular energetics is one promising hallmark of cancer and Thioredoxin reductases 1 (TrxR1) plays a key role in cell metabolism [1-4]. It was found in our previous study that the activity of TrxR1 in serum is significantly higher in cancer patients than volunteers (based on 1122 cancer patients VS 84 volunteers), and over expression of TrxR1 correlates with poor prognosis in metastatic EGFR wild-type non-small-cell lung cancer patients treated with standard 1st line platinum doublets [5]. Yet the role of TrxR1 remained unclear in metastatic non-small-cell lung cancer harboring EGFR sensitive mutation treated with standard 1st line erlotinib. Aim: to explore the prognostic role of TrxR1 in metastatic non-small-cell lung cancer harboring EGFR sensitive mutation treated with 1st line erlotinib. Methods: We have built several cohorts to explore the clinical significance of TrxR1. In this prospective observational study, 37 metastatic non-small-cell patients harboring EGFR 19 deletion or L858 mutation were recruited from cohorts of NCT01980212, NCT01991418 and NCT02098954. EGFR mutation status was test by ARMS. The activity of serum TrxR1 was measured by ELISA assay after receiving one month first line standard EGFR-TKI (erlotinib). The cut off value was set as 12. Survival data were collected and analyzed to TrxR1 levels. Results: Until Nov.2015, all of the 37 patients are alive. Progression free survival (PFS) was not mature yet. Follow-up data and dynamic changes of TrxR1 were in process. Among the 17 patients who progressed, survival data analysis showed that the lower TrxR1 activity group was with significantly longer PFS compared to the higher group (15.2m vs 7.0m, p = 0.029)to both mutation types, also to the exon19del subtype(17.0m vs 13.0m, p = 0.19) and to the exon 21L858R subtype(11.5m vs 4.5m, p = 0.096). Conclusions: High activity of TrxR1 may suggest an independent role of poor prognosis in EGFR mutation-positive advanced NSCLC treated with 1st line erlotinib, including both exon19del and L858R mutation subtypes, which helps to illustrate the different results of erlotinib treatment. Possibly, those with high TrxR1 should be given a complex of EGFR-TKI plus TrxR1 inhibition. Several inhibitors are under developed in various tumors and hopefully our study could contribute to improve the current standard treatment of lung cancer. [1]Douglas Hanahan et al; Cell. 2011 Mar 4;144(5):646-74. [2]Lincoln DT et al; Anti-cancer Res. 2003, 23(3B):2425-33. [3]Turunen N, et al; APM IS. 2004, 112(2):123-32. [4]Fan C, et al;. Cell Death Dis. 2014 Apr 24;5:e1191. [5]Yongchang Zhang et al; Thirteenth Annual International Conference on Frontiers in Cancer Prevention Research, Poster Session B Citation Format: Yongchang Zhang. Thioredoxin reductase 1: the key member in metabolism affects PFS of 1st line erlotinib to advanced non-small cell lung cancer harboring EGFR mutation-positive. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2262.