TKI Osimertinib Research Articles

Clearing of circulating tumour DNA predicts clinical response to osimertinib in EGFR mutated lung cancer patients

ObjectivesTyrosine kinase inhibitors (TKIs) are first line treatment choices for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, responses vary among patients, therefore good biomarkers predicting better responses are required. EGFR mutations are detected in the blood from patients as circulating tumour DNA (ctDNA). Studies have shown that clearing ctDNA during first line TKI treatment predicts outcomes for first and second generation TKI treatments. We aimed to investigate the effects on outcome measures of ctDNA clearing in subsequent treatment lines to treatment with the third generation TKI osimertinib. MethodsIn total, 225 patients were included in a prospective, multicentre study, where consecutive blood samples were monitored for EGFR mutations during systemic treatment lines, using the Cobas® EGFR mutation test v2. This study focused on EGFR mutations in ctDNA of 82 systemically pre-treated patients receiving osimertinib. ResultsClearing all EGFR mutations from the blood after osimertinib treatment, significantly predicted progression-free survival, objective response rates and disease control rates. Primary sensitising EGFR mutations were found in ctDNA in 70 % of patients, and were accompanied by the T790 M mutation in nearly two thirds of cases. The T790 M mutation was cleared in all cases, while the accompanying sensitising mutations did not necessarily clear. However, T790 M clearing without simultaneously clearing of the primary sensitising mutation did not predict clinical responses. Neither the detection of T790 M before osimertinib treatment, nor the presence of EGFR mutations at the time of osimertinib initiation predicted clinical outcomes. ConclusionThe clearing of EGFR mutations in ctDNA after osimertinib treatment initiation in patients with advanced NSCLC is useful as a positive predictor of clinical outcome.

Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improved clinical outcome compared to chemotherapy in EGFR mutated advanced non-small cell lung cancer (NSCLC) patients. Nonetheless, acquired resistance develops within 10-14 months and 20-30% of EGFR-mutated patients do not respond to EGFR-TKI. In order to delay or overcome acquired resistance to EGFR-TKIs, combination therapies of EGFR-TKIs with chemotherapy has been investigated with conflicting results. Early studies failed to show a survival benefit because of a lack of patient selection, but more recently clinical studies in EGFR mutated patients have shown promising results. This review summarizes preclinical and clinical studies of combination of EGFR-TKIs, including the third-generation TKI osimertinib, with chemotherapy in first- and second-line settings, using concurrent or intercalated treatment strategies. In the new era of third-generation EGFR-TKIs, new studies of this combination strategy are warranted.

P2.14-30 Predictive Value of ctDNA in Patients with EGFR Positive NSCLC Receiving 3rd Generation TKI

The third generation TKI (osimertinib) according to AURA III trial results achieved longer PFS compared to standard platinum based chemotherapy in patient’s resistant to 1-2 generation TKIs due to T790M mutation (8.5 vs 4.2 months). The evolution of resistance profile during thins therapy can be analyzed based on ctDNA. In this study patients with metastatic EGFR mutated NSCLC, with a confirmed disease progression during treatment with 1/2 generation TKIs, T790M positive which included patients received osimertinib 80 mg daily. Before the treatment and then every 2 months, whole blood was taken, for qualitative assessment of ctDNA dynamics by RT-PCR. The aim of the study was to assess the relationship between the disappearance of T790M + ctDNA and the time to progression on osimertinib. From August 2016 to December 2018 22 patients with T790M positive progression were identified. 18/22 (81.9%) were women, 4/22 (18.1%) - men. The mean age was 61.2 years (50-75). Only 1/22 had a smoking history >30 pack/years. Primary activating mutations in EGFR gene were ex19del, L858R and G719S + S768I in 16, 5 and 1 patients respectively. Median PFS on the first line TKI was 21.7 months (CI 95%, 10.8 – 53.3). In 59.1% (13/22) progressive disease was characterized by the appearance of new metastases and in 40.9% (9/22) by the growth of previously identified metastases. 22 patients were evaluable for response. PR and SD were achieved in 11/20 (50%) and 10/20 (45/5%) respectively. Median PFS was in a whole group 16.7 months (CI 95%, 11.4 - 22.0). T790M in ctDNA was negative after 2 months of osimertinib treatment in 12/22 patients. Median PFS was 18.9 months (CI 95%, 14.8–19.7) in patients with undetectable T790M in ctDNA after 2 month of therapy compared to 8.0 months (CI 95%, 4.2 – 11.8) in patients remaining ctDNA T790M positive. No clinical factors were associated with the disappearance of ctDNA by statistical analysis. The disappearance of T790M + ctDNA after 2 months osimertinib therapy is predictive of greater PFS in patients with EGFR mutation positive NSCLC, receving of 2nd line.

Abstract 1055: Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors

Abstract Tyrosine Kinase Inhibitor (TKI) of Epidermal Growth Factor Receptor (EGFR) is a first-line therapy for non-small cell carcinoma lung cancer patients with EGFR mutations, but patients often develop resistance to such a target therapy. Recently several PD-1 and PD-L1 inhibitors were approved for treating NSCLC, however, it remains unclear whether EGFR mutant NSCLC would benefit from PD-1/PD-L1 treatment. PD-1 response in cancer patients is closely associated with oncogenic mutation status, tumor microenvironment, PD-L1 expression and tumor mutation burden (TMB); however, the lack of pre-clinical models limited the investigation of the checkpoint inhibitors in EGFR mutant tumors. Here we use human PBMC reconstitution system for immune-humanization, and established a series of IO-Xenograft models (IO-CDX and IO-PDX) with cancer cell lines (IO-CDX) or patient-derived tissues (IO-PDX) that contain various EGFR mutations, including EGFR 19 del, L858R, T790M, and EGFR over-expression, amplification and fusion. We treated these models with either EGFR TKI (erlotinib, afatinib or osimertinib) or nivolumab, a PD-1 inhibitor. The predictive biomarkers including PD-L1 expression and TMB were analyzed by whole exom sequencing (WES) and FACS for tumor infiltrating lymphocytes (TILs), respectively. We found that 3 TKI-resistant PDX models bearing EGFR T790M mutation exhibited lower TILs than those bearing EGFR wild type or exon 19del mutation. Of the 8 IO-CDX or IO-PDX humanized models we have examined, those exhibiting higher TILs achieved better responses to nivolumab treatment. The 3 most sensitive models are EGFR amplification (wt), EGFR over-expression (wt) and EGFR exon 19del. In contrast, the EGFR T790M model from H1975 cell line was observed with hyper-progressive disease after nivolumab treatment. We will also discuss the contribution of PD-L1 expression and TMB to nivolumab in other models. In summary, these well-established IO-CDX and IO-PDX models can provide a human-resembling immune system for of immune therapeutics and combination with targeted therapies, and help to facilitate the understanding of relationship among tumor microenvironment, driver oncogenic mutations and drug response. Citation Format: Xuzhen Tang, Li Yang, Hui Qi, Xianzhi Zhai, Fuyang Wang, Xiangnan Qiang, Jie Xu, Xiaoran Qin, Qingyang Gu, Shaoyu Yan, Qunsheng Ji. Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors [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 1055.

Abstract 3999: Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform

Abstract Purpose: Patients with advanced lung adenocarcinoma often lack large clinical specimens required for molecular testing which limits next therapeutic options. Patient-derived cells (PDC) from malignant effusions can predict patient drug responses and provide a valuable tool for studying drug resistance mechanisms. In this study, we created an Advanced Lung Adenocarcinoma Cell Bank (ALACB) consisting of 28 unique PDCs established from patients who progressed on various tyrosine kinase inhibitor TKIs including 3rd generation EGFR TKI osimertinib. Experimental design: Patient malignant effusion samples were tested for malignancy, processed, observed by light microscopy, and cultured with appropriate media and supplements. The criteria for established PDCs include the following: sharing the same driver mutation as the patient; free of stromal fibroblasts confirmed by FACS staining; recapitulating patient’s drug response; and can be cryopreserved and re-grown. Established PDCs were further authenticated by STR profiling and microplasma testing to maintain cell quality. We were able to perform various in vitro assays and next generation sequencing for detailed analysis of individual PDC. Results: We were able to successfully establish 28 PDCs incorporating unique patient characteristics. Among the total 146 samples, we observed a success rate of 30% only accounting 95 malignancy positive samples. Established PDCs consists of 20 EGFR mutation positive cell lines, 3 with ALK rearrangements, 6 with ROS1 rearrangements, 1 with BRAF K601E mutation and 1 with KRAS G12D mutation. Seven PDCs were established from patients who progressed on osimertinib, two from olmutinib (HM61713), and others from 1st and 2nd generation EGFR TKI such as gefitininb and erlotinib. We were able to newly generate 3 PDCs harboring a T790M mutation with an activating EGFR mutation. Moreover, we are one of the few labs to successfully establish an EGFR del19/T790M/C797S triple mutant PDC showing resistance to osimertinib treatment in vitro. Other established PDCs harbored rare EGFR mutations including exon 20 insertion, L861Q and G719X/S768I. PDC with EGFR G719X/S768I compound mutation showed high sensitivity to afatinib but was resistant to gefitininb and osimertinib treatment. Three ALK-positive PDCs were derived from crizotinib-resistant, alectinib-resistant and ceritinib-resistant tumors. Furthermore, of 6 ROS1 fusion positive PDCs, 3 were derived from TKI-naïve tumors, and 3 from crizotinib-resistant tumors. Conclusions: Successfully established PDCs reflecting patient genomic profiles and drug response is a valuable resource for biological assays, generating in vitro drug-resistant models, and evaluating novel drugs and therapeutic targets. Further advances in drug development combined with a library of cell bank will facilitate lung cancer translational research. Citation Format: Hyeong-Seok Joo, Dong Hwi Kim, Seok-Young Kim, Ji-Yeon Lee, Mi-Ran Yun, Han-Na Kang, Byoung Chul Cho, Hye Ryun Kim. Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform [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 3999.

Treatment response to osimertinib in a patient with leptomeningeal metastasis from lung adenocarcinoma following failure of gefitinib and erlotinib: A case report.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in the treatment of advanced non-small-cell lung cancer (NSCLC) with leptomeningeal metastases (LM); however, a proportion of the patients with resistant tumors do not benefit from EGFR-TKI treatment. In the present study the case of a female patient with advanced lung adenocarcinoma harboring the EGFR L858R mutation (encoded in exon 21) who developed intracranial metastases following treatment with erlotinib after gefitinib failure is reported. The patient achieved a partial response (PR) after four cycles of chemotherapy with pemetrexed/cisplatin. However, after 4 months, LM were detected. The patient was treated with osimertinib, a third-generation EGFR-TKI, but the LM continued to progress and the patient eventually succumbed to the disease (overall survival, 6 months). Therefore, LM in patients without the EGFR T790M mutation (encoded in exon 20) appear to be resistant to treatment with the third-generation TKI osimertinib, which may be associated with human epidermal growth factor receptor 2 amplification. Further clinical trials are required to confirm our results.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors, T790M, and clinical trials.

Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (nsclcs) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as upfront therapy for EGFR-mutated advanced nsclc and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases. Multiple drivers of tki resistance have now been identified, and many new drugs are in development. With respect to this rapidly evolving field, our review highlights the current status of treatment options for patients with EGFR-mutated advanced nsclc, focusing especially on identified causes of resistance, challenges, and clinical trials aiming to improve outcomes in this patient population.

Evidence-Based Best Practices for EGFR T790M Testing in Lung Cancer in Canada

Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as first-line systemic therapy for patients with non-small-cell lung cancer (nsclc) having mutations in the EGFR gene. Resistance to tkis eventually occurs in all nsclc patients treated with such drugs. In patients with resistance to tkis caused by the EGFR T790M mutation, the third-generation tki osimertinib is now the standard of care. For optimal patient management, accurate EGFR T790M testing is required. A multidisciplinary working group of pathologists, laboratory medicine specialists, medical oncologists, a respirologist, and a thoracic radiologist from across Canada was convened to discuss best practices for EGFR T790M mutation testing in Canada. The group made recommendations in the areas of the testing algorithm and the pre-analytic, analytic, and post-analytic aspects of clinical testing for both tissue testing and liquid biopsy circulating tumour dna testing. The recommendations aim to improve EGFR T790M testing in Canada and to thereby improve patient care.

EGFR Primary T790M and L858R Double Mutation Confers Clinical Benefit to Erlotinib and Resistance to Osimertinib in One Lung Adenocarcinoma Patient: A Case Report

Introduction: EGFR TKI has been widely studied in both research and clinic. However, only few limited studies focus on EGFR primary resistance rather than acquired mutation. Usually, EGFR T790M mutation is resistant to first generation TKI (erlotinib, gefitinib) and sensitive to third generation TKI Osimertinib. Here, we report an EGFR primary T790M and L858R double mutation patient confers clinical benefit to Erlotinib and resistance to Osimertinib. Case presentation: Here we present a 70-year-old woman with lung adenocarcinoma harboredprimary T790M and L858R EGFR double mutation and underwent multiple lines of treatments. She benefited from the first-generation of EGFR TKI Erlotinib, and later quickly developed resistance to the third-generation TKI Osimertinib after disease progression, then followed a few rounds of chemotherapies. Multiple resistant EGFR mutations were detected, indicating frequent complex tumor heterogeneity in later stage patients caused by subclone evolution. Colonies with distinct Osimertinib resistance mutations included well known EGFR mutations L792V, L718V/R, G796S/A, and novel EGFR G729V and D1014V mutations, which are predicted to be acquired osimertinib resistance mutations by 3D-structural remodeling. Conclusion: Our study revealed that EGFR primary T790M accompany with L858R mutation could benefit from erlotinib, and has stable disease for 7 months. The patient also benefited from chemotherapy for three months after resistance to osimertinib. ctDNA–based assay is a valuable tool for late stage cancer diagnosis, monitoring and intervention.

Impact on OS of 2nd and 3rd generation TKI in EGFR mt+ and ALK+ patients: Results of the NOWEL network.

e20560 Background: Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with proven mutations. Targeted therapies achieve a higher ORR, PFS, OS and a better quality of life than chemotherapy in mt+ patients. With the advent of 2nd and 3rd generation TKI´s effective in 1st generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers. Methods: 1383 patients from the three cancer centers diagnosed with NSCLC stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Results: 880/1383 (64%) consecutive patients with non-squamous cell NSCLC from the cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The EGFR mutation rate was 16.6% (141/880), and the ALK-translocation rate 3.8% (24/635). Median OS in EGFR mt+ patients was 31 (n = 78) vs. 32 (n = 38) vs. 16 (n = 14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 25 (n = 17) months in center 1 and 11 (n = 5) months in center 2 (p < 0.05). Use of 3rd generation TKI Osimertinib (n = 17) lead to a significantly higher OS (n = 17, median OS 67 mo) than the use of only 1st and 2nd generation TKI (n = 113, median OS 24 mo, p < 0.000). Similarly, use of 2nd and 3rd generation ALKi impacted significantly on median OS: Crizotinib alone n = 7, 17 months, Crizotinib followed by Ceritinib and/or Brigatinib (n = 9) median OS not reached, p < 0.001. Conclusions: Smalldifferences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting.

Current Status and Prospect of T790M Mutation in Non-small Cell Lung Cancer

目前，针对表皮生长因子受体（epidermal growth factor receptor, EGFR）突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）公认的一线治疗方案是以EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）为主的靶向治疗，尽管一代、二代TKIs带来的靶向治疗可为患者带来更长的无进展生存（progression-free survival, PFS），及更好的耐受，但其远期治疗不可避免会出现耐药。其中，50%以上的获得性耐药与T790M突变有关，因此美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）推出的最新指南已经提出三代TKI（Osimertinib，奥西替尼）可用于一线TKI治疗进展同时检出T790M突变的患者。但就在三代TKI为我们带来令人鼓舞的可长达13个月的中位PFS及延续着后EGFR-TKIs治疗时代的同时，也面临着严峻的挑战，如怎样实现T790M的检测及动态监测、对已有三代TKI的研究进展、出现三代TKI耐药的机制及后续治疗等，本文将围绕以上各热点问题展开综述。

P2.03b-022 Outcome in Molecularly Defined NSCLC within the NOWEL Network: The Influence of Sequential 2nd and 3rd Generation TKI in EGFR mt+ and ALK+ pts: Topic: Biomarkers

Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with a proved mutation. Targeted therapies achieve a better quality of life, a higher PFS and ORR and in some cases increased OS. The aim of the study was therefore to systematically analyze retrospective data from three cancer centers in the north of Germany. The study compares these three cancer centers in reference to the test rate and the therapeutic success of targeted therapy. 1383 patients from the three cancer centers diagnosed with non-small lung cancer stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Clinical characteristics including smoking status were available for more than 92% of the patients. 880 consecutive patients from the three cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The overall mutation testing rate was 63.6% (880/1383). EGFR mutations were found in 18.4% (86/467)/ 13.1% (38/289)/ 11.3% (14/124) in the Pius-Hospital, Bremen-Ost or Hamburg Harburg respectively, ALK in 3.9% (18/467)/ 1.7% (5/289)/1.6% (2/124) yielding an overall EGFR M+ rate of 15.7% (138/880) and overall ALK M+ rate of 2.9% (25/880). Median OS was 43 (n=86) vs. 25 (n=38) vs. 16 (n=14) months (Pius vs. Bremen vs. Hamburg) (p<0.035). PFS on the 1st line TKI therapy was 25 (n=77) vs. 22 (n=31) vs. 10 (n=13) months respectively. Pts receiving 3rd generation TKI (Osimertinib n=12) had a significantly longer OS than pts not receiving 3rd gen. TKI (n=134). PFS on 3rd gen TKI was significantly longer than for other therapies (p<0.020). Median OS in ALK mutated patients was 31 (n=18) vs. 17 (n=5) vs. 10 (n=2) months (Pius vs. Bremen vs. Hamburg). Median OS of pts treated with Crizo alone (n=14) was 18 months, pts treated sequentially with Crizo and Ceritinib (n=6) 31 months, median OS without Crizotinib (n=4) was 17 months. The results illustrate differences between the three Lung Cancer Centers in the north of Germany. Significant differences in OS were observed, depending on the center and a significant difference in PFS between the therapy with Osimertinib and other therapies could be established. The differences mentioned could depend on the selection of the patients and their clinical characteristics. The clinical characteristics should be observed in detail.