Real-World Testing Practices,Treatment Patterns and Clinical Outcomes in Patients from Central Eastern Europe with EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Retrospective Chart Review Study (REFLECT)

The targeted therapy with tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor mutation (EGFRm) in advanced non-small cell lung cancer (NSCLC) changed the treatment paradigm. REFLECT study ({"type":"clinical-trial","attrs":{"text":"NCT04031898","term_id":"NCT04031898"}}NCT04031898) explored EGFR/T790M testing and treatment patterns in EGFRm NSCLC patients receiving first- or second-generation (1G/2G) EGFR TKIs as front-line (1L) in eight countries. Pooled data from Central Eastern Europe (CEE) countries from this study (Bulgaria, Poland, Romania, Slovenia) are presented here. This physician-led chart review study was conducted in patients with confirmed-EGFRm NSCLC initiating 1L 1G/2G EGFR TKIs between 2015–2018. The CEE cohort included 389 patients receiving 1L erlotinib (37%), afatinib (34%), and gefitinib (29%). Overall, 320 (82%) patients discontinued 1L, and 298 (77%) progression events were registered. Median progression free survival on 1L TKIs was 14.0 (95% CI: 12.6–15.6) months. Median overall survival from 1L start was 26.6 (95% CI: 24.1–29.0) months. Attrition rate between 1L and next line was 30%. Among patients with 1L progression, 200 (67%) were tested for T790M and 58% were positive. This first CEE analysis of treatments and outcomes in EGFRm NSCLC patients highlights the importance of using the most efficacious therapies currently available in 1L to reduce attrition and improve patient outcomes.     

Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG)

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non–small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data.Patients and MethodsIn this retrospective, global, multi-center study ({"type":"clinical-trial","attrs":{"text":"NCT04179890","term_id":"NCT04179890"}}NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or “other” mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS).ResultsOverall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years.ConclusionIn a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.     

Phase I Trial of a Third Generation EGFR Mutant-Selective Inhibitor (D-0316) in Patients with Advanced Non-Small Cell Lung Cancer

BackgroundD-0316 is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR T790M mutation that progressed after prior treatment with the first- or second-generation EGFR-TKI.MethodsThis phase I, open-label, multicenter clinical trial evaluated daily oral D-0316 administration in dose-escalation (25 to 150 mg; 17 patients) and dose-expansion (50, 100 mg; 67 patients) cohorts for safety, tolerability, anti-tumor activity, and pharmacokinetics.ResultsD-0316 was well tolerated at daily doses of 25 to 150 mg and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events (AEs) were platelet count decreased, electrocardiogram QT corrected interval prolonged, anemia, rash, low white blood cell count, hypertriglyceridemia, high cholesterol, headache, pruritus, cough, and aspartate transaminase (AST) or alanine transaminase (ALT) increased. Most of AEs were grade 1 or 2. In the 50 and 100 mg group, the overall response rate (ORR) was 33.3% and 45.5%, the disease control rate (DCR) was 86.7% and 93.9%, and the median PFS was 8.3 and 9.6 months, respectively. D-0316 exposure increased in proportion to dose from 25 to 150 mg. The recommended phase II dose (RP2D) was 100 mg.ConclusionD-0316 is safe, tolerable, and effective for patients with locally advanced/metastatic NSCLC with the EGFR T790M mutation who previously received EGFR-TKI.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT03452150","term_id":"NCT03452150"}}NCT03452150.     

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2–IA3 EGFR-Mutated NSCLC: ADAURA2

IntroductionOsimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non–small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2–IA3 EGFRm NSCLC, following complete tumor resection.Patients and MethodsADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated.ResultsStudy enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.     

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

IntroductionThis integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy.MethodsAdults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR.ResultsA total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1–66.4). Median progression-free survival was 11.1 months (95% CI: 5.5–16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%–100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss.ConclusionsLazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.     

Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre

AimsPresently, three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved against oncogene addicted EGFR-mutant non-small cell lung cancer (NSCLC). Patients with actionable EGFR mutations invariably develop resistance. This resistance can be intrinsic (primary) or acquired (secondary).Materials and methodsThis was a retrospective study carried out between January 2016 and April 2021 analysing 486 samples of NSCLC for primary and secondary resistance to first- (erlotinib, gefitinb), second- (afatinib) and/or third-generation (osimertinib) TKIs in EGFR-mutant NSCLCs by next generation sequencing (NGS). Tissue NGS was carried out using the Thermofischer Ion Torrent? Oncomine? Focus 52 gene assay; liquid biopsy NGS was carried out using the Oncomine Lung Cell-Free Total Nucleic Acid assay. All cases were previously tested for a single EGFR gene with the Therascreen® EGFR RGQ PCR kit.ResultsThe results were divided into four groups: (i) group 1: primary resistance to first- and/or second-generation TKIs. This group, with 21 cases, showed EGFR exon 20 insertions, dual, complex mutations and variant of unknown significance, de novo MET gene amplification besides other mutations. (ii) Group 2: primary resistance to third-generation TKIs. This group showed two cases, with one showing dual EGFR mutation (L858R and E709A) and EGFR gene amplification. (iii) Group 3: secondary resistance to first- and second-generation TKIs. This group had 27 cases, which were previously reported negative for EGFR T790M by single gene testing. Significant findings were MET gene amplification in four cases, with one also showing MET exon 14 skipping mutation. Three cases showed small cell change and one showed loss of primary mutation. (iv) Group 4: secondary resistance to third-generation TKIs. The latter group was further subgrouped into group 4A: secondary resistance to osimertinib (third-generation TKI) when offered as second-line therapy after first- and second-generation TKIs on detection of T790M mutation. This group had 15 cases. EGFR T790M mutation was lost in 10 (10/15; 67%) cases and was retained in five cases. Patients with T790M loss experienced early resistance (6.9 months versus 12.6 months mean, P = 0.0024) compared with cases that retained T790M. Two cases gained MET amplification as the resistance mechanisms. Other mutations that were found when EGFR T790M was lost were in FGFR3, KRAS, PIK3CA, CTNNB1, BRAF genes. One case had EML4-ALK translocation. Two cases showed driver EGFR deletion 19, retained T790M and C797S mutation in Cis form. Group 4B: secondary resistance to osimertinib (when given as first-line therapy) in EGFR-mutant NSCLC. This group had three cases. The duration of osimertinib treatment ranged from 11 to 17 months. Two patients showed additional C797S mutation along with primary EGFR mutation.ConclusionThis study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs.     

Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor

Introduction

The genomic alterations driving resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) are not well established, and collecting tissue biopsy samples poses potential complications from invasive procedures. Cell-free circulating DNA (cfDNA) testing provides a noninvasive approach to identify potentially targetable mechanisms of resistance. Here we utilized a 70-gene cfDNA next-generation sequencing test to interrogate pretreatment and progression samples from 77 EGFR-mutated non-small cell lung cancer (NSCLC) patients treated with a third-generation EGFR TKI.

Real-World Pattern of Treatment and Clinical Outcomes of EGFR-Mutant Non-Small Cell Lung Cancer in a Single Academic Centre in Quebec

The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62–13.44) months for first-line treatment, and 4.4 (95% CI: 1.47–7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9–30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5–27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.     

Therapeutic approaches for T790M mutation positive non-small-cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50–60% of cases to the T790M resistance mutation.

Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance.

Expert commentary: Osimertinib is the current treatment option for T790M mutation positive NSCLC after progression to first or second-generation EGFR TKIs, with activity also on brain metastasis. However, the scenario is in continuous evolution and results from clinical trials are awaited in first-line setting and in combination strategies.     

Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFRT790M-Mutant NSCLC

IntroductionEGFR^T790M mostly exists subclonally and is acquired as the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, because de novo EGFR^T790M-mutant NSCLC is rare, little is known on acquired resistance mechanisms to third-generation EGFR TKIs.MethodsAcquired resistance mechanisms were analyzed using tumor and plasma samples before and after third-generation EGFR TKI treatment in four patients with de novo EGFR^T790M-mutant NSCLC. Genetic alterations were analyzed by whole-exome sequencing, targeted sequencing, fluorescence in situ hybridization, and droplet digital PCR. MTOR^L1433S, confirmed for oncogenicity using the Ba/F3 system, was reproduced in H1975 cell lines using CRISPR/Cas9-RNP.ResultsOf seven patients with NSCLC with de novo EGFR^T790M/L858R mutation, four (LC1–4) who received third-generation EGFR TKIs acquired resistance after achieving a partial response (median = 27 mo, range: 17–48 mo). Novel MTOR^L1433S and EGFR^C797S/L798I mutations in cis, MET amplification, and EGFR^C797S mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs. The MTOR^L1433S mutation was oncogenic in Ba/F3 models and revealed resistance to osimertinib through AKT signaling activation in NCI-H1975 cells harboring the MTOR^L1433S mutation edited by CRISPR/Cas9 (half-maximal inhibitory concentration, 800 ± 67 nM). Osimertinib in combination with mTOR inhibitors abrogated acquired resistance to osimertinib.ConclusionsActivation of bypass pathways and the EGFR^C797S or EGFR^C797S/L798I mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs in patients with NSCLC with de novo EGFR^T790M mutation. In addition, MTOR^L1433S- and EGFR^L858R/T790M-mutant NSCLC cells were sensitive to osimertinib plus mTOR inhibitors.     

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

Single-agent osimertinib is the standard of care for the first-line treatment of advancedEGFR+ NSCLC and remained the only marketed third-generation EGFR tyrosine kinase inhibitor (TKI) until March 2020 when almonertinib (HS-10296) was approved in the People’s Republic of China for the treatment of advanced EGFR T790M+ NSCLC based on a phase 2 expansion study of a phase 1/2 trial. In this review, we profiled many of the third-generation EGFR TKIs in late-stage clinical development (e.g., almonertinib, lazertinib, alflutinib¹, rezivertinib, ASK120069, SH-1028, D-0316, and abivertinib) based on their interim results from phase 1 and phase 2 trials, and included the designs of the phase 3 trials and their chemical structures when publicly available. We also listed other third-generation EGFR TKIs in pipeline development based on the search of clinical trial registration websites. In addition, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, mavelertinib), including phase 3 results of rociletinib and naquotinib. We further profiled combination clinical trial design of the third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704), and ACROSS2 (NCT04500717) that if positive can potentially usher in the next standard of care for advanced EGFR+ NSCLC.     

Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing

BackgroundEGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naïve patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear.Patients and methodsThe frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs.ResultsTo define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%–35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months.ConclusionsDe novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.     

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy.

Materials and Methods

Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded.

Results and Conclusion

PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control.     

CD73 Inhibitor Oleclumab Plus Osimertinib in Previously Treated Patients With Advanced T790M-Negative EGFR-Mutated NSCLC: A Brief Report

IntroductionCD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC.MethodsPatients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 [DL1]) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1.ResultsBy July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing; three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses); response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose.ConclusionsOleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC.     

Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Although T790M mutation is considered to be the major mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC), its clinical implication remains undetermined.

Methods

Post-progression tumor specimens were prospectively collected for T790M mutation analysis in NSCLC patients with acquired resistance to initial EGFR TKIs. Clinical features were compared between patients with and without T790M.

Results

Out of 70 cases, 36 (51%) were identified to have T790M mutation in the rebiopsy specimen. There was no difference in the pattern of disease progression, progression-free survival for initial TKIs (12.8 and 11.3 months), post-progression survival (14.7 and 14.1 months), or overall survival (43.5 and 36.8 months) in patients with and without T790M. In total, 34 patients received afatinib after post-progression biopsy as a subsequent treatment, and the response rate was 18%. The median progression-free survival for afatinib was 3.7 months for the entire group, and 3.2 and 4.6 months for the groups with and without T790M, respectively (P = 0.33).

Conclusions

The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TKIs.     

Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization

RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT ({"type":"clinical-trial","attrs":{"text":"NCT02489903","term_id":"NCT02489903"}}NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types – non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors – prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to ‘episensitize’ tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival.Key Words: Partial response, Platinum doublets, Refractory EGFR, Non-small cell lung cancer, RRx-001     

Safety,Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter,Open-label,Phase 1 Trial

IntroductionAlmonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy.MethodsThis phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated.ResultsA total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42–63) and 92% (95% CI: 84–96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5–not reached) months.ConclusionsAlmonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.     

Comprehensive Analysis of EGFR-Mutant Abundance and Its Effect on Efficacy of EGFR TKIs in Advanced NSCLC with EGFR Mutations

IntroductionA qualitative detection method for EGFR mutations is not sufficient to guide precise targeted therapy in clinical practice. The aim of this study was to explore the relationship between the abundance of EGFR mutations and efficacy of EGFR tyrosine kinase inhibitors (TKIs).MethodsWe used the amplification refractory mutation system (ARMS) method optimized with competitive blockers and specific mutation quantitation (ARMS+) to quantitatively evaluate the abundance of EGFR mutations in 201 patients with advanced NSCLC. A cutoff value of the abundance of EGFR mutations was determined by receiver operating characteristic analysis in a training group and validated in a validation group.ResultsThe abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of 19DEL was significantly higher than that of L858R, with cutoff values for 19DEL and L858R of 4.9% and 9.5%, respectively. The median progression-free survival in the high group was significantly longer than that in the low group (19DEL, 15.0 versus 2.0 months [p < 0.001] and L858R, 12.3 versus 2.0 months [p < 0.001]) in the training set. Similar results were also observed in the validation set. Nine of 13 patients harboring T790M mutation achieved a partial response to EGFR TKIs. Most (seven of nine) were identified to have a low abundance of T790M mutation. The abundance of EGFR mutations appeared to be more significantly associated with the copy number of EGFR mutations from circulating tumor DNA in 19DEL group.ConclusionThe abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of EGFR^T790M mutation may have an adverse impact on progression-free survival rather than on objective response rate in patients with advanced EGFR-mutant NSCLC treated with EGFR TKIs.     

<Emphasis Type="Italic">BIM</Emphasis> Deletion Polymorphism Confers Resistance to Osimertinib in <Emphasis Type="Italic">EGFR</Emphasis> T790M Lung Cancer: a Case Report and Literature Review

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has shown significant clinical efficacy against the EGFR T790M mutation in non-small cell lung cancer (NSCLC) patients. However, resistance inevitably occurs, and the mechanisms leading to treatment failure need to be further investigated. The B-cell lymphoma 2 (BCL-2)-like 11 (BIM) deletion polymorphism, which occurs at a frequency of 21% in East Asians but is absent in African and European populations, has been associated with resistance to first-generation EGFR TKIs, such as gefitinib and erlotinib; and is a poor prognostic factor for NSCLC patients with EGFR mutations. Nevertheless, the significance of this BIM deletion polymorphism in the resistance to osimertinib has not been reported. Here, we show for the first time that a NSCLC patient harboring the EGFR L858R/T790M mutations, as well as the BIM deletion polymorphism, exhibited poor clinical outcomes with osimertinib treatment. This result suggests that the BIM deletion polymorphism might have prognostic value for determining NSCLC patient outcomes following osimertinib treatment.     

Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancers Dependent on the Epidermal Growth Factor Receptor Pathway

Most advanced Non–Small-cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6–12 months), most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and “oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR-mutated patients with TKI resistance, and in vitro, this mutation negates the hypersensitivity of activating EGFR mutations. Sensitive detection methods have identified a proportion of TKI-naive tumors that carry T790M, and these resistant clones may be selected after exposure to gefitinib or erlotinib. Other secondary resistance mutations (D761Y, L747S, T854A) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however, in half of the cases with this “oncogene kinase switch" mechanism the T790M is coexistent. It is possible that other kinases (such as insulin-like growth factor-1 receptor [IGF-1R]) might also be selected to bypass EGFR pathways in resistant tumors. The growing preclinical data in EGFR-mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (neratinib, XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R inhibitors in combination with EGFR TKIs, and heat shock protein 90 inhibitors. Ongoing preclinical and clinical research in EGFR-mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations.