T790M-positive Non-small Cell Lung Cancer Research Articles

Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial

ObjectivesThe aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy. Materials and methodsPhase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [EGFR T790 M mutation-positive patients]; 2B: 500 mg twice daily [EGFR T790 M mutation-positive]; 3: 800 mg once daily [EGFR T790 M mutation-negative]). In phase 2, EGFR T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2′). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters. ResultsOverall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6–67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6–9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%). ConclusionOlmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.

Abstract 3032: Acquired resistance to osimertinib in patients with de novo EGFRT790M-positive non-small cell lung cancer (NSCLC)

Abstract Background: Epidermal growth factor receptor (EGFR) T790M mutation is well known as primary and acquired resistance mechanisms to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). However, a de novo and clonal EGFR T790M mutation is rarely observed in 0.8-2% of patients with EGFR-mutant NSCLC. The 3rd generation EGFR TKIs including osimertinib are expected to be effective against de novo, clonal EGFRT790M-positive NSCLC. However, the efficacy and resistance mechanisms of osimertinib have been limited in patients with de novo and clonal EGFRT790M-positive NSCLC. Methods: The seven (1%) of 690 patients with EGFR-mutant NSCLC were identified as having de novo and clonal EGFRT790M mutations between December 2002 and July 2014 in Seoul National University Hospital. Three with de novo EGFRL858R/T790M mutation received osimertinib at a dose of 80mg or 160mg once daily (NCT01802632) and two showed acquired resistance to osimertinib. Fresh tumor samples were obtained before and after treatment with osimertinib and analyzed by whole-exome and -transcriptome sequencings as well as droplet digital polymerase chain reaction (ddPCR). MET amplification was determined by fluorescence in situhybridization (FISH) in formalin-fixed paraffin-embedded tumor tissues. Results: Three patients with de novo EGFRL858R/T790M mutation received osimertinib and two (LC1 and LC2) showed acquired resistance to osimertinib at 16 and 30 months, respectively (Table 1). As of November 2018, the LC3 patient received osimertinib without disease progression. Novel MTOR L1433S mutation within FAT domain that was not seen at initial tumors (ploidy 2.3) was clonally acquired at osimertinib-resistant tumors (ploidy 2.4) in the LC1 patient. In addition, a novel and clonal MGA V124D mutation within T-box was found at osimertinib-resistant tumors (ploidy 5.9) of the LC2 patient. MET copy number was 14 with high fpkm level (721.9) at osimertinib-resistant tumors in the LC2 patient. Average MET gene copies per nucleus by FISH were 2.74 at initial tumors and 5.25 at osimertinib-resistant tumors in LC2 patient, resulting in MET amplification as a resistance mechanism. Subclonal MGA V124D mutation was found at initial tumors of the LC2 patient using ddPCR. The Ba/F3 systems confirmed that novel mutants were oncogenic. Conclusions: Novel MTOR and MGA mutations were functional and clonally acquired as resistance mechanisms to osimertinib in patients with de novo EGFRL858R/T790M-mutant NSCLC. In addition, MET amplification contributed to acquired resistance to osimertinib. Taken together, acquired resistance mechanisms of osimertinib might be mainly mediated by alternative pathway activation in de novo EGFRT790M-positive NSCLC. Citation Format: Ha-Ram Park, Yusoo Lee, Tae Min Kim, Soyeon Kim, Chan-Young Ock, Miso Kim, Bhumsuk Keam, Yoon Kyung Jeon, Dong-Wan Kim, Dae Seog Heo. Acquired resistance to osimertinib in patients with de novo EGFRT790M-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3032.

Impact of clinical features on the efficacy of osimertinib therapy in patients with T790M-positive non-small cell lung cancer and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors.

Osimertinib exhibits good efficacy in patients with T790M-positive non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Compared with the clinical trials, in real-world clinical practice, osimertinib must be administered to older patients and those with poor Eastern Cooperative Oncology Group performance status (ECOG-PS). Therefore, we investigated the association between osimertinib efficacy/safety and PS score, age, and other clinical features in patients with T790M-positive NSCLC. We reviewed all patients with T790M-positive NSCLC and acquired resistance to initial EGFR-TKIs who were administered osimertinib between March 2016 and January 2018 at the Tokyo Metropolitan Cancer and Infectious Diseases Center in Komagome Hospital, Japan. In total, 31 patients, including 8 young (<65 years) and 23 elderly (≥65 years) patients, were included in the study. Of these, 10 (32.3%) patients had poor PS scores. The progression-free survival (PFS) was significantly shorter in young patients was than elderly patients [3.5 vs. 6.4 months, P=0.041; hazard ratio (HR), 2.41]. The overall survival (OS) of the young patients tended to be shorter than that of the elderly patients (5.3 vs. 19.4 months, P=0.067; HR, 2.58). The PFS (9.1 vs. 5.5 months; P=0.071; HR, 0.38) and the OS (not reached vs. 6.6 months, P=0.061; HR, 0.39) were shorter in patients with poor ECOG-PS than those with good ECOG-PS. The toxic effects of osimertinib were manageable. By multivariate analysis, both age and ECOG-PS were independent predictors of osimertinib efficacy. Poor ECOG-PS and younger age were associated with lower efficacy of osimertinib in T790M-positive NSCLC.

Impact of next-generation sequencing on clinical outcomes in advanced EGFR-mutant lung cancer patients after resistance to osimertinib.

e20726 Background: Osimertinib is used to treat EGFR-mutant non–small-cell lung cancer (NSCLC) with acquired T790M mutation. Next-generation sequencing (NGS) is helpful to understand mechanisms of resistance to osimertinib. However, whether NGS after resistance to osimertinib has an impact on clinical outcomes of patients treated with subsequent treatments has been elusive. Methods: We retrospectively identified advanced, EGFR-mutant T790M positive NSCLC patients treated with the 2nd or further-line osimertinib from January 27th, 2015 to January 31th, 2019 at our institute. Genetic profiles and clinical outcomes were analyzed. These patients were divided into 2 groups based on NGS data after resistance to osimertinib. Progression-free survival1 (PFS1) was calculated from the start of osimertinib to progression or death. PFS2 was calculated from the start of subsequent-line treatment to progression or death. Objective response rate (ORR) of subsequent-line treatments was evaluated by RECIST1.1. Results: Among 187 patients treated with osimertinib, 66 had NGS data and 27 had no NGS data after progression. Maintained EGFR T790M was detected in 23 patients (34.8%), and loss of T790M was seen in 43 patients (65.2%). Mutations of EGFR C797S were detected in 12 patients (18.1% overall; 52.2% of those with retained T790M), 11 in cis with a maintained T790M, 1 in trans with a maintained T790M. There was no significant difference in median PFS1 between the maintained T790M group and the loss of T790M group (10.8 vs. 7.0 months, P = 0.085).The NGS group was treated with TKIs according to the results of NGS strictly (n = 36), the non-NGS group received chemotherapy or best supportive care (n = 11).There was a significant difference in median PFS2 between the NGS and non-NGS groups (5.4 vs. 2.9 months, P = 0.043). The ORR of the NGS group was significantly superior to that of the non-NGS group (16.2% vs 11.1%, P &lt; 0.001). Conclusions: NGS after resistance to osimertinib might favor clinical outcomes of advanced EGFR-mutant NSCLC patients. Further more investigations are warranted.

Impact of EGFR genotype on the efficacy of osimertinib in EGFR tyrosine kinase inhibitor-resistant patients with non-small cell lung cancer: a prospective observational study.

Purpose: A T790M of the epidermal growth factor receptor (EGFR) is the most frequently encountered mutation conferring acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). The aim of this study was to assess the differential clinical outcomes of osimertinib therapy in NSCLC patients with T790M according to the type of activating EGFR mutation, ie, exon 19 deletion or L858R point mutation.Patients and methods: A prospective observational cohort study was conducted to evaluate the efficacy and safety of osimertinib in patients with a major EGFR mutation and T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy. The efficacy of osimertinib was evaluated according to the type of EGFR mutation.Results: A total of 51 patients were included in this study. An objective response was obtained in 29 patients, indicating an objective response rate of 58.8%. The response rate was 69.7% in patients with exon 19 deletion and 38.9% in patients with L858R point mutation, indicating a statistically significant difference (P=0.033). The median progression-free survival (PFS) and overall survival (OS) of the entire patient population were 7.8 and 15.5 months, respectively. The median PFS in the exon 19 deletion and L858R point mutation groups was 8.0 months and 5.2 months, respectively, indicating a statistically significant difference (P=0.045). Median OS in the exon 19 deletion and L858R point mutation groups was significantly different at 19.8 months and 12.9 months, respectively (P=0.0015). Multivariate analysis identified the exon 19 deletion as a favorable independent predictor of PFS and OS.Conclusion: Investigators should consider the proportions of sensitive EGFR mutation types as a stratification factor in designing or reviewing clinical studies involving osimertinib.

Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial.

BackgroundResistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367).MethodsPatients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50–350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing (NGS)-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis.FindingsThirty of 73 patients enrolled were eligible for resistance analysis. Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and three patients only provided tissue samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed: 15% (4/27) experienced EGFR T790M loss and 13% (4/30) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (37%), and considered a putative resistance mechanism in seven (23%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation.InterpretationOur findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort.FundThe National Key R&D Program of China (Grant No. 2016YFC1303800), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120).

Evaluation of osimertinib efficacy according to body surface area and body mass index in patients with non-small cell lung cancer harboring an EGFR mutation: A prospective observational study.

BackgroundOsimertinib is recommended for non‐small cell lung cancer (NSCLC) patients with EGFR mutation; however, it is unclear whether body size variables affect the efficacy of osimertinib in such patients. This study assessed the potential effect of body surface area (BSA) and body mass index (BMI) on osimertinib chemotherapy in patients with T790M‐positive advanced NSCLC who progress on prior EGFR‐tyrosine kinase inhibitors (TKIs).MethodsWe conducted a prospective observational cohort study. Median BSA and BMI were used as cut‐off values to evaluate the impact of body size variables on osimertinib chemotherapy.ResultsThe median BSA and BMI of 47 patients were 1.50 m2 and 21.5 kg/m2, respectively. Clinical outcomes did not significantly differ between the high and low BSA groups, with response rates of 59.1% and 56.0% (P = 0.83) and progression‐free survival (PFS) of 7.6 and 9.1 months (P = 0.69), respectively. Similarly, there were no significant differences between the high and low BMI groups relative to response rates, which were 60.8% and 54.1% (P = 0.64), respectively, and PFS, which was 7.6 months in both groups (P = 0.38). No significant differences were observed among toxicity profiles in relation to BSA or BMI. Multivariate analysis identified better performance status, young age, and EGFR exon 19 deletion as independent favorable predictors of PFS.ConclusionThe efficacy of osimertinib does not significantly vary relative to body size variables of patients with T790M‐positive NSCLC who progress on prior EGFR‐TKIs.

Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations

SummaryPurpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

Patterns of progression on osimertinib in EGFR T790M positive NSCLC: A Swiss cohort study

IntroductionOsimertinib is an EGFR tyrosine kinase inhibitor (TKI) with antitumor activity in non-small cell lung cancer (NSCLC) with EGFR T790 M mutations. The incidence of oligo-progression (PD) on osimertinib is unknown. MethodsWe retrospectively analyzed 50 pre-treated EGFR T790M-positive NSCLC patients treated with osimertinib at seven Swiss centers. Oligo-PD was defined as PD in ≤ 5 lesions. Mutational profiling of pre- and post-osimertinib tumor samples was performed. ResultsMedian age was 62 years (37–89), 64% were females, 86% had a PS ≤ 1, 54%/13% were never/current smokers. Median follow-up was 15.3 (IQR: 8.6–21.6) months. Overall response rate was 80%, median progression-free survival 12.1 months (95% CI 8.3–18.3), median overall survival 28 months (95% CI 20.2-not reached [NR]) and median treatment duration 18.8 months (95%CI 16-8-NR). PD occurred in 36 patients (72%). 73% had oligo-PD. Median osimertinib treatment duration in patients with oligo-PD was 19.6 vs. 7 months if systemic PD (p = 0.007). The number of progressive lesions in patients with oligo-PD was 1 (27%), 2 (35%) and 3–5 (39%). Sites of PD included lungs (56%), bones (44%), and brain (17%). Sixteen patients with oligo-PD continued treatment with osimertinib for a median of 6.7 months beyond PD. Thirteen received local ablative treatment (LAT). In pre- and post-PD tumor tissue multiple molecular alterations were detected. ConclusionIn patients with acquired resistance to osimertinib, we observed a high rate (73%) of oligo-PD. Outcomes of patients receiving LAT were favorable, supporting the concept of osimertinib treatment beyond progression in combination with LAT of progressing lesions.

The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer

Background: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367), and describe clinical strategies to overcome EGFR amplification-mediated resistance. Methods: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50-350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. Findings: Thirty-two of 73 patients enrolled were eligible for resistance analysis. A heterogeneous landscape of resistance mechanisms to abivertinib was observed with 14% (4/28) experiencing EGFR T790M loss and 13% (4/32) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (34%), and considered a putative resistance mechanism in seven (22%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. We demonstrated that abivertinib plus nimotuzumab or afatinib is effective and tolerable in overcoming EGFR amplification-mediated resistance to abivertinib. Interpretation: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort and may be overcome by combining abivertinib with an EGFR monoclonal antibody or afatinib. Funding: This work was supported by The National Key R&D Program of China (Grant No. 2016YFC1303800, to Q Zhou), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational 447 Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120, to YL WU). Medical writing support was provided by Siân Marshall PhD, SIANTIFIX Inc., Cambridge, UK, funded by ACEA Therapeutics Inc. Declaration of Interest: QZ declares grants from National Key R&D Program of China, speaker fees from AstraZeneca and Roche. Y-LW declares grants from Key Lab System Project of Guangdong Science and Technology Department, speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. XX is the CEO and stock owner of ACEA Therapeutics Inc. WT, FRL are employees of ACEA Therapeutics Inc. S-KC, J-YY, H-ZH, ZZ are employees of Burning Rock Biotech. Other authors declare no competing interests. Ethical Approval: This study was approved by the ethics committee at Guangdong General Hospital, and all patients provided written, informed consent. The study adhered to the principles of Declaration of Helsinki and the Good Clinical Practice guidelines.

The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer

The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer

A Modified Phase 1 Clinical Trial of Abivertinib (Ac0010), a Third-Generation EGFR Tyrosine Kinase Inhibitor, in Chinese Patients with EGFR-T790M-positive Non-Small Cell Lung Cancer

Background: Abivertinib is a novel, third-generation EGFR tyrosine kinase inhibitor. We investigated the safety and efficacy of abivertinib in Chinese patients with EGFR T790Mpositive non-small cell lung cancer (NSCLC) and determined the recommended Phase II dose (RP2D). Methods: This open-label, single-arm, dose-escalation study enrolled patients (18–75 years) with disease progression on prior EGFR TKIs from 8 centers in China. Patients received abivertinib 50–350 mg BID in sequential cohorts using a dose escalation/expansion protocol which determined dose-limiting toxicities (DLTs) in Cycle 1 and evaluated the clinical activity of abivertinib. RP2D (primary endpoint) was based on DLTs along with available safety, efficacy and pharmacokinetic data. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. This study is registered with ClinicalTrials.gov (NCT02330367). Findings: Between January 2015 and March 2018, 140 patients received abivertinib for a median (range) of 21·7 (1·3–148) weeks. Median relative dose intensity was 99%. Maximum tolerated dose was not reached with only 3 DLTs observed across all doses. RP2D was 300 mg BID based on a median (range) PFS of 6·9 (3·0, 9·0) months, ORR of 40% and broadly comparable safety profile to the 50–300 mg BID doses. Grade 3/4 treatment-related adverse events were more frequent with abivertinib 350 mg BID (4/6 patients, 67%) versus 300 mg BID (12/45, 27%) and lower doses. Minimal accumulation of abivertinib was observed at steady state across the studied doses and exposure rose proportionally with increasing dose. Interpretation: Abivertinib 150–300 mg BID represented the efficacious range while 350 mg BID dose had the least favorable safety profile, suggesting 300 mg BID as the RP2D. This novel study design which considered efficacy, pharmacokinetics, and safety beyond Cycle 1 in addition to DLTs may facilitate RP2D determination for drugs with favorable toxicity profiles. Clinical Trial Number: This study is registered with ClinicalTrials.gov (NCT02330367). Funding Statement: This study was funded by ACEA Therapeutics Inc. Declaration of Interests: W-HX is an employee of ACEA Pharmaceutical Research, Hangzhou, China. FL, LX and XX are employees of ACEA Therapeutics Inc. QZ declares speaker fees from AstraZeneca and Roche. LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. YLW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. X-QL, PH, J-YZ, LZ, T-TA, YC, JJ, Z-HC, and BG declare no competing interests. Ethics Approval Statement: The study was conducted according to the ethical principles established in the Declaration of Helsinki and was consistent with the Chinese Good Clinical Practice Guidelines. The study protocol was approved by the institutional review board or independent ethics committee at each study center.

Real-life efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer harboring EGFR T790M mutation

Objectives The efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR T790 M resistance mutation was demonstrated in clinical trials. However, data on efficacy of osimertinib in real world remain rare.Materials and methods This retrospective multicentric study analyzed T790M-positive advanced NSCLC patients enrolled in French early access program for osimertinib. Patients were pretreated with first- or second-generation EGFR tyrosine-kinase inhibitor and for a majority with chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation.Results 205 patients (mean age, 69.5 years; female, 68.8%; adenocarcinoma, 97.5%, never-smokers, 71.5%) were analyzed. Osimertinib was used in second and third line in 18.0% and 82.0% of patients, respectively. Median PFS was 12.4 (95% CI, 10.1–15.1) months. In patients with and without cerebral metastasis, PFS was 9.7 (7.7–13.5) and 15.1 (12.0–17.1) months (p = 0.21), respectively. PFS in second and third line or more was 12.6 (6.7–17.5) and 12.4 (9.7–15.3) months, respectively. Median PFS in patients with EGFR exon 19 deletion and exon 21 mutation was 13.5 (10.1–16.0) and 9.7 (7.4–13.2) months, respectively (p = 0.049). Median OS since osimertinib initiation was 20.5 (16.9–24.3) months: 23.1 (18.6–27.8) and 18.0 (12.2–22.2) months in patients without and with cerebral metastasis (p = 0.11); 17.5 (11.6–27.8) and 21.7 (17.3–24.3) months as second or third line of treatment or more (p = 0.46), respectively. Median OS in patients with EGFR exon 19 deletion and exon 21 mutation was 23.1 (18.6–25.7) and 15.3 (11.6–21.7) months, respectively (p = 0.03).Osimertinib dosage was modified in 8.0% of patients and definitively discontinued for adverse events in 5.9%. Fifty patients benefited from rebiopsy (persistence of T790 M mutation, 44.7%; C797S mutation, 21.1%; cMET amplification, 8.0%).Conclusion In pretreated patients with T790M-mutated advanced NSCLC, the efficacy of osimertinib appears similar in real-world setting to that of clinical trials.

511P - AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): Updated phase II results including overall survival (OS)

511P - AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): Updated phase II results including overall survival (OS)

Optial treatment and research prospect of T790M-positive non-small cell lung cancer

Optial treatment and research prospect of T790M-positive non-small cell lung cancer

P3.01-53 Comparison of the Treatment Efficacy of Osimertinib in Young and Elderly Patients with T790M-Positive NSCLC

Osimertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The AURA3 trial showed that osimertinib is superior to platinum doublet chemotherapy in T790M-positive non-small cell lung cancer (NSCLC) with acquired resistance to first or second generation EGFR-TKIs in patients, irrespective of age. In contrast, another study showed that first or second generation EGFR-TKIs may have poorer efficacy and prognosis in young subjects than in elderly patients with EGFR mutation-positive NSCLC. Thus, we aimed to determine whether osimertinib exerted similar effects on young and old patients with T790M-positive NSCLC. We retrospectively investigated T790M-positive NSCLC patients with acquired resistance to first or second generation EGFR-TKIs who were administered osimertinib therapy from May 2015 to January 2018 by referring to their charts in the Tokyo Metropolitan Cancer and Infectious disease Center, Komagome Hospital, Japan. We defined patients > 65 years old as elderly and those < 65 years old as young. We compared the clinical characters, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the two age groups. Total 31 patients with acquired resistance to first or second generation EGFR-TKIs were administered osimertinib. Twenty-three subjects belonged to the older age group, while 8 belonged to the younger age group. The median ages of the elderly and young patients were 75 years (range: 65–88 years) and 54 years (34–64) years, respectively. There were no significant differences in their clinical characteristics (sex, Eastern Cooperative Oncology Group Performance Status, smoking history, histology, type of de novo EGFR mutation, initial EGFR-TKI therapy, re-biopsy sample, central nervous system metastasis, and osimertinib line). The median PFS duration after initial EGFR-TKI treatment was greater in the elderly patients (17.2 vs. 10.5 months; hazard ratio; 2.86; 95% confidence interval [CI] , 1.03–7.97; P = 0.0022); the ORR of osimertinib in the elderly and young patients was 53.3% and 37.5%, respectively. The median follow up interval after osimertinib initiation was 10.1 months. The total median PFS duration was 5.6 months. The median PFS duration tended to be greater in elderly patients (3.5 vs. 9.1 months; hazard ratio; 1.90; 95% CI, 0.75–4.78; P = 0.17). The median OS duration after osimertinib initiation was significantly greater in elderly patients (5.3 months vs. NA; hazard ratio; 3.36; 95% CI, 1.11–10.1; P = 0.027). Osimertinib showed poorer efficacy in younger patients than in elderly patients with T790M positive NSCLC.

1461P - ASTRIS: A real world treatment study of osimertinib in patients (pts) with EGFR T790M-positive non-small cell lung cancer (NSCLC) - European subset

1461P - ASTRIS: A real world treatment study of osimertinib in patients (pts) with EGFR T790M-positive non-small cell lung cancer (NSCLC) - European subset

P2.13-13 Real-World Study of Osimertinib in EGFR T790M-Mutated Non-Small Cell Lung Cancer (NSCLC): ASTRIS Canadian Cohort Analysis

ASTRIS is an open-label, single-arm, multinational, real world study of osimertinib for patients with advanced/metastatic epidermal growth factor receptor-mutated (EGFRm) T790M-positive non-small cell lung cancer (NSCLC) who previously received therapy with an EGFR tyrosine kinase inhibitor (EGFR-TKI) (NCT02474355). Data cut-off (DCO) for the second interim analysis was 20 October 2017, with 3014 patients enrolled (full analysis set), including 99 patients in Canada. Adult patients with locally advanced/metastatic EGFRm NSCLC, not amenable to curative surgery/radiotherapy, with confirmation of T790M and prior EGFR-TKI therapy were enrolled. Patients were included with World Health Organization performance status of 0 to 2, as well as those with asymptomatic stable central nervous system (CNS) metastases. Patients received osimertinib 80 mg once daily until loss of clinical benefit. The primary efficacy outcome was overall survival (OS), with secondary outcomes of investigator-assessed response rate (RR), progression-free survival (PFS), and time to treatment discontinuation (TTD). From study start (14 January 2016) to DCO (20 October 2017), 99 patients were enrolled at 12 Canadian centres. Median age was 64 years (30-89 years). Patients were 68% female, 57% Asian, and had ECOG 0/1/2 of 22%/65%/13%. Twenty-five patients had CNS metastases at screening. Gefitinib was the most commonly used previous EGFR-TKI (gefitinib, erlotinib and afatinib were 80%, 14%, and 14%, respectively). Thirty-nine percent had previous chemotherapy; 6% previous immunotherapy; 46% previous radiotherapy. All patients had T790M: 75% tissue, 7% blood and 18% cytology. Biomarker testing methods varied, with the majority (61%) identified by Entrogen EGFR kit. At DCO, 45 patients had discontinued treatment. OS data were immature. Median PFS was 11.0 months (95% CI, 8.9-13.3). Median TTD was 14.9 months (95% CI, 11.2-not calculated). RR was 67.0% (95% CI, 56.7-76.2); sub-analyses showed RR of 69.9% (58.0-80.1), 66.7% (22.3, 95.7) and 55.6% (30.8, 78.5) for patients with T790M by tissue, blood and cytology, respectively. Serious adverse events (AEs) were reported for 18% of patients. AEs leading to dose modifications and discontinuations were reported for 12% and 5% of patients, respectively. The Canadian results from this real world study of osimertinib in advanced/metastatic EGFRm T790M-positive NSCLC, which includes heavily pretreated patients and various approaches to biomarker testing, were comparable to outcomes reported in the phase III study AURA3 (NCT02151981). These findings provide further support for osimertinib as standard of care for EGFRm T790M-positive NSCLC.

P3.01-93 Osimertinib-Related Hematological and Pulmonary Toxicities in Advanced NSCLC Patients: Combined Analysis of Phase III Trials

In both epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitizing and EGFR T790M resistance mutations in patients with advanced non-small-cell lung cancer (NSCLC), osimertinib, a third-generation and irreversible oral EGFR-TKI, has been shown to improve survival in studies. We performed a systematic review and meta-analysis of phase III randomized controlled trials (RCT) to determine the risk of hematological and pulmonary toxicities among patients with advanced NSCLC treated with osimertinib. We undertook a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention hematological and pulmonary toxicities as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). A total of 971 patients with advanced NSCLC from two phase III studies were eligible for analysis. The study arm used osimertinib while the control arm utilized either chemotherapy (carboplatin/cisplatin+ pemetrexed) or standard EGFR-TKIs (gefitinib or erlotinib). The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: anemia, 0.594 (95% CI: 0.433 – 0.814, p = 0.001); cough, 1.122 (95% CI: 0.829 – 1.520, p = 0.455); dyspnea, 1.143 (95% CI: 0.784 – 1.666; p = 0.487); and ILD, 2.378 (95% CI: 0.984 – 5.744; p = 0.054). The RR of high-grade adverse effects were as follows: anemia, 0.175 (95% CI: 0.072 – 0.425, p < 0.001); neutropenia, 0.293 (95% CI: 0.138 – 0.623; p = 0.001); thrombocytopenia, 0.183 (95% CI: 0.060 – 0.564, p = 0.003); pneumonia, 1.237 (95% CI: 0.442 – 3.459; p = 0.685); dyspnea, 0.895 (95% CI: 1.192 – 4.175; p = 0.888); and ILD, 1.238 (95% CI: 0.404 – 3.789; p = 0.708). Our meta-analysis demonstrated that patients on osimertinib experienced a significant decrease in the risk of hematological toxicities, compared to control arm. Moreover, no increase in the risk of pulmonary toxicities was noted in the osimertinib group.

P3.01-100 Risk of Gastrointestinal and Hepatic Toxicities in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Osimertinib

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) who harbors EGFR mutation. The presence of T790M point mutation, later, mediates the resistance to first-generation and second-generation EGFR-TKIs. Osimertinib, an oral third-generation EGFR-TKI, targets both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We undertook a systematic review and combined analysis of two phase III randomized controlled trials (RCT) to determine the risk of gastrointestinal and hepatic toxicities among patients with advanced NSCLC treated with osimertinib. We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention diarrhea, nausea, vomiting, stomatitis and elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Two phase III RCTs with a total of 971 patients with advanced NSCLC were included in the analysis. Studies compared osimertinib vs carboplatin/cisplatin + pemetrexed and osimertinib vs gefitinib/erlotinib. The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: diarrhea, 1.305 (95% CI: 1.128 – 1.509, p < 0.0001); nausea, 0.480 (95% CI: 0.378–0.611; p < 0.0001); vomiting, 0.783 (95% CI: 0.561–1.092; p = 0.149); stomatitis, 1.262 (95% CI: 0.980 – 1.626, p = 0.071); elevated AST, 0.397 (95% CI: 0.277–0.569; p < 0.0001); and elevated ALT, 0.312 (95% CI: 0.212–0.458; p < 0.0001). The RR of high-grade side effects were as follows: diarrhea, 0.912 (95% CI: 0.354 – 2.347, p = 0.849); vomiting, 0.135 (95% CI: 0.022 – 0.831; p = 0.031); stomatitis, 0.532 (95% CI: 0.124 – 2.293, p = 0.397); elevated AST, 0.296 (95% CI: 0.096 – 0.907; p = 0.033); and elevated ALT, 0.112 (95% CI: 0.034 – 0.372; p < 0.0001). Patients on osimertinib noted a significant increase in the risk of all-grade diarrhea. Nevertheless, the risk of developing any-grade nausea, all grades of elevated AST/ALT and high-grade vomiting, was significantly reduced in osimertinib arm, favoring osimertinib.