T790M-positive Non-small Cell Lung Cancer Research Articles

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9months; estimated survival rates at 12, 24, and 36months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.

Real-world osimertinib pretreatment experience in patients with epidermal growth factor receptor T790M mutation-positive locally advanced or metastatic non-small cell lung cancer.

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.

Development and validation of a deep learning-based model to predict response and survival of T790M mutant non-small cell lung cancer patients in early clinical phase trials using electronic medical record and pharmacokinetic data.

Epidermal growth factor receptor (EGFR) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR-mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS). CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively. CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non-Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA.

Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutation-positive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6. In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33-0.68; P < 0.0001]. In patients with Week 3 clearance versus non-clearance (n = 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3-12.6) versus 5.7 (4.1-9.7) with osimertinib and 6.2 (4.0-9.7) versus 4.2 (4.0-5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41-0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5-16.5) with osimertinib and 10.8 (9.7-11.1) versus 7.0 (5.6-8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance. Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.

Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study

PurposeASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non–small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study.MethodsAdults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0–2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety.ResultsA total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53–0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1–12.5) and 13.9 months (95% CI 13.1–15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively.ConclusionOsimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified.Clinical trial numberNCT02474355.

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

Patterns of treatment failure and subsequent treatment in non-small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies. We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed. Eighty-four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo-progressive disease (PD) and central nervous system (CNS)-sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM-free (46/49, 93.9%), and 60% of patients (21/35) with pre-existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M-loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M-loss (progression-free survival, 5.4 vs. 16.5 months, p = 0.02; overall survival, not reached, p = 0.03). PD during osimertinib treatment occurred preferentially in the thorax and pre-existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for EGFR-mutated NSCLC with BM.

A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC: the final ASTRIS data.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).

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

Clinical Outcomes of Patients with Epidermal Growth Factor Receptor–Mutated Non-Small-Cell Lung Cancer with Leptomeningeal Metastasis in the Modern Target Therapy Era

Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. The median OSLM was 16.0 months and the 3-year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P= 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P= 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

EGFR-TKI re-administration after osimertinib failure in T790M mutation loss cases with re-biopsy.

Data on the re-administration of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) after osimertinib failure in patients with T790M-positive non-small cell lung cancer (NSCLC) is limited. EGFR-TKI re-administration efficacy may vary between patients with T790M loss and those with T790M persistent with re-biopsy after osimertinib treatment. Patients who received EGFR-TKI re-administration (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) after osimertinib failure were identified from our database. T790M mutation status before EGFR-TKI re-administration was analyzed via repeat biopsy. We retrospectively evaluated the efficacy of EGFR-TKI re-administration, especially differences according to the T790M mutation status, via repeat biopsy. Until June 2020, 28 patients received EGFR-TKI re-administration and 17 underwent repeat biopsy after osimertinib failure. Patients were divided into three groups, including the T790M loss group, where active mutation persisted and T790M was lost (13/17); T790M remaining group, where both the active mutation and T790M persisted (3/17); and active mutation loss group where both the active mutation and T790M were lost (1/17). The overall response rate (ORR) of EGFR-TKI re-administration in the T790M loss group was 31% and the disease control rate (DCR) was 54%, which were higher than the ORR of 21% and DCR of 43% in the entire patient population. ORR and DCR of the not re-biopsy group were low (9% and 27%, respectively). The therapeutic effect of EGFR-TKI re-administration in patients with T790M-positive NSCLC after osimertinib failure is limited. EGFR-TKI re-administration may be considered in cases of T790M loss after repeat biopsy.

EP08.02-127 Resistance Mechanisms to Osimertinib in Advanced EGFR-mutated NSCLC: A Single Institution Prospective Cohort Study

Osimertinib is a recommended first-line treatment for advanced EGFR-mutated (deletion in exon 19 and exon 21 L858R) and EGFR-TKI pretreated T790M-positive non-small cell lung cancer. Resistance to osimertinib inevitably developed after a period of treatment and this study aims to evaluate the mechanisms of resistance.

Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations.

Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR’s kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. Graphical abstract

Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer.

Simple SummaryOsimertinib is a third-generation EGFR tyrosine kinase inhibitor and the standard of care therapy for non-small cell lung cancer patients harboring EGFR-activating mutations. However, even for patients treated with osimertinib, resistance inevitably occurs leading to disease progression. Here, we utilized two osimertinib-resistant cell lines and investigated their RNA profiles. We found that Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) were upregulated and associated with resistance in osimertinib-resistant cells as well as in liquid biopsies from patients with disease progression following osimertinib treatment. Moreover, we found RAB32 and THBS1 to be mechanistically linked to activation of the focal adhesion pathway where combination of osimertinib with a FAK inhibitor resulted in a synergistic suppression of viability of osimertinib-resistant cells. Our findings propose a potential therapeutic strategy for overcoming acquired resistance to osimertinib in non-small cell lung cancer.Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients.

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.

Efficacy of osimertinib in epidermal growth factor receptor-mutated non-small-cell lung cancer patients with pleural effusion

BackgroundOsimertinib is a standard first-line treatment for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although malignant pleural effusion (PE) is a common clinical problem in NSCLC, information about the efficacy of osimertinib in patients with PE is limited, especially regarding its efficacy in EGFR T790M-negative patients with PE remains unclear.MethodsWe retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who were treated with osimertinib in our institution between May 2016 and December 2020.ResultsA total of 63 patients with EGFR mutated NSCLC were treated with osimertinib; 33 (12 with PE) had no EGFR T790M mutation, while 30 (12 with PE) had EGFR T790M mutation. In EGFR T790M-negative NSCLC, the progression-free survival (PFS) of the patients with PE was comparable to that of the patients without PE (median PFS 19.8 vs. 19.8 months, p = 0.693). In EGFR T790M- positive NSCLC, the PFS and overall survival (OS) of the patients with PE were significantly shorter than those of the patients without PE (median PFS 16.8 vs. 8.3 months, p = 0.003; median OS 44.9 vs. 14.2 months, p = 0.007). In the multivariate analysis, the presence of PE was independently associated with shorter PFS and OS in EGFR T790M-positive NSCLC patients, but not EGFR T790M-negative patients.ConclusionsThese data suggest the efficacy of osimertinib may differ between EGFR T790M-positive and -negative NSCLC patients with PE.

Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC.MethodsWe combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial.ResultsVarious miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib.ConclusionsOur results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.

An Analysis of 5-Level Version of EQ-5D Adjusting for Treatment Switching: The Case of Patients With Epidermal Growth Factor Receptor T790M-Positive Nonsmall Cell Lung Cancer Treated With Osimertinib

ObjectivesTreatment switching from control to treatment after disease progression is common in oncology trials. Analyses of survival data typically adjust for this bias, but such adjustments are rarely performed in analyses of patient-reported outcomes. This analysis aimed to examine the impact of adjusting for treatment switching on estimated treatment effects on 5-level version of EQ-5D (EQ-5D-5L) utilities and quality-adjusted life-years (QALYs). The AURA3 trial (NCT02151981) was a randomized controlled trial comparing osimertinib with platinum-based doublet chemotherapy (standard care) in patients with locally advanced or metastatic epidermal growth factor receptor mutant- and T790M-positive nonsmall cell lung cancer whose disease has progressed with previous epidermal growth factor receptor tyrosine kinase inhibitor therapy. MethodsDescriptive analyses were used to compare treatment arms. The primary analysis used a 2-stage least squares instrumental variable regression to estimate treatment effect adjusting for treatment crossover. Time to deterioration, defined from baseline to minimally important deterioration in EQ-5D-5L utility, was assessed using a rank preserving structural failure time model. ResultsIntention-to-treat analysis of imputed data showed incremental QALYs for osimertinib of 0.23 at 60 weeks. Accounting for treatment switching increased this to 0.52 in the primary analysis and to 0.63 QALYs in sensitivity analysis at 150 weeks. Time to deterioration analysis showed longer health-related quality of life maintenance with osimertinib, of 12.76 weeks, although this was at the borderline of statistical significance (acceleration factor, ψ = −0.275; 95% confidence interval −0.50 to 0.00). ConclusionsThis analysis demonstrates methods to adjust for treatment switching in the analysis of EQ-5D-5L from clinical trials. Failure to account for crossover substantially underestimated the QALY gain for osimertinib.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1–2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1–45.6%). The best overall response was 25.0% (95% confidence interval: 9.8–46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4–58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7–17.5) for the former and 4.4 months (95% confidence interval: 3.0–N.E.) for the latter, with no statistically significant difference (P = 0.74).

Immunotherapy-based combination strategies for treatment of EGFR-TKI-resistant non-small-cell lung cancer.

The rapid development of molecular targeted therapybrings hope to patients with advanced non-small-cell lung cancer (NSCLC). However, drug resistance inevitably occurs during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation EGFR-TKI, shows a favorable prognosis in T790M-positive NSCLC. Unfortunately, acquired resistance is still a challenge for both patients and clinicians. There is still no consensus on the optimal treatment. PD-1 and its ligand receptor 1 (PD-L1) inhibitors have yielded great progress, especially in patients with no actionable mutations. In this review, the authors take stock of the relationship between EGFR mutations and PD-L1 expression and summarize the important clinical studies on immunotherapy-inhibitor-based treatment in patients withEGFR-TKI-resistant NSCLC.