EGFR T790M-positive Non-small Cell Lung Research Articles

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

PP217 Dynamics of disease progression during treatment with osimertinib in patients with EGFR T790M-positive non-small cell lung cancer

PP217 Dynamics of disease progression during treatment with osimertinib in patients with EGFR T790M-positive non-small cell lung cancer

Retrospective Analysis of Real-World Management of EGFR-Mutated Advanced NSCLC, After First-Line EGFR-TKI Treatment: US Treatment Patterns, Attrition, and Survival Data.

Background and ObjectivesEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard-of-care first-line (1L) treatment for EGFR mutation-positive advanced/metastatic non-small cell lung cancer. In 2015, osimertinib, a third-generation EGFR-TKI, received US accelerated approval for second-line (2L) EGFR T790M-positive non-small cell lung cancer treatment. The objective of this US study was to characterize treatment patterns, attrition, and survival in EGFR mutation-positive non-small cell lung cancer, after 1L first-/second-generation EGFR-TKI treatment.MethodsWe retrospectively analyzed 1029 patients diagnosed with stage IIIB/IV non-small cell lung cancer from 1 January, 2011 to 31 December, 2018 using the US electronic medical record CancerLinQ Discovery® database. Demographic/disease characteristics, EGFR mutations, treatments, and death dates were collected.ResultsFrom 1 January, 2011 to 31 December, 2014 (< 2015 cohort), 519 patients received 1L EGFR-TKIs and 510 between 1 January, 2015 and 31 December, 2018 (≥ 2015 cohort). Median follow-up from advanced diagnosis was 19.8 months (interquartile range: 9.9–33.4 months). Twenty-eight percent of patients (288/1029) died without receiving 2L, and 52% (539/1029) initiated 2L with 35% (186/539) receiving osimertinib; in the < 2015 and ≥ 2015 cohorts, the same proportion initiated 2L (52%; 272/519 vs 267/510, respectively). Median overall survival from advanced diagnosis for patients initially diagnosed with stage I–IIIA disease was 43.3 months (95% confidence interval 30.9–73.7), vs 26.4 months (95% confidence interval 24.4–28.1) for stage IIIB–IV; all-cause mortality hazard ratio: 1.56 (95% confidence interval 1.2–2.0; p = 0.001).ConclusionsWe identified disease stage, performance status, and central nervous system metastasis as survival predictors, highlighting the importance of optimal 1L treatment selection. Over a quarter of patients died before initiating 2L; half progressed after 1L and received 2L, of whom a third received 2L osimertinib.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-022-00302-w.

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6months, whereas patients with a complete or partial response or stable disease for > 6months were considered as having acquired resistance. We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib. CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.

ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial\u2013mesenchymal transition

BackgroundID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear.MethodsWe established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial–mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry.ResultsIn our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib.ConclusionsOur study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.

147P PD-L1 expression influenced by osimertinib treatment in advanced EGFR T790M-positive non-small cell lung cancer patients

Background: Anti-PD-1/L1 antibodies could be an optional therapy for EGFR-TKI-resistant non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, little is known about PD-L1 expression in advanced NSCLC patients with the T790M-positive EGFR mutation, as well as the changes induced by osimertinib treatment.

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.

Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).

9091 Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.

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.

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)

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

Acquired resistance to AZD9291 as an upfront treatment is dependent on ERK signaling in a preclinical model.

AZD9291 (osimertinib) is approved for standard care in patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) after prior EGFR TKI progression. Furthermore, AZD9291 is now being evaluated as a first-line treatment for NSCLC patients with activation EGFR mutations. Based on previous experiments, resistance to AZD9291 as a first-line treatment may also emerge. Thus, identification and understanding of resistance mechanisms to AZD9291 as a first-line treatment can help direct development of future therapies. AZD9291-resistant cells (PC9/AZDR) were established using EGFR inhibitor-naïve PC9 cells. Resistance mechanisms were analyzed using next-generation sequencing (NGS) and a proteome profiler array. Resistance to AZD9291 developed through aberrant activation of ERK signaling by an EGFR-independent mechanism. The combination of a MEK inhibitor with AZD9291 restored the sensitivity of PC9/AZDR cells in vitro and in vivo. PC9/AZDR cells also showed increased MET expression and an HRAS G13R mutation. In addition, maspin expression was higher after AZD9291 treatment in PC9/AZDR cells. Sustained ERK activation confers resistance to AZD9291 as a first-line therapy. Thus, co-targeting EGFR and MEK may be an effective strategy to overcome resistance to AZD9291.

P3.02-041 EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer

P3.02-041 EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer

P3.01-006 Osimertinib in Pretreated EGFR T790M-Positive Non-Small Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis

P3.01-006 Osimertinib in Pretreated EGFR T790M-Positive Non-Small Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis

1348P - Overall survival (OS) in patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) treated with osimertinib: Results from two phase II studies

1348P - Overall survival (OS) in patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) treated with osimertinib: Results from two phase II studies