Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Therapy Research Articles

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. AK112 is the first-in-class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. This study aimed to evaluate the efficacy and safety of AK112 combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). This open-label, multicenter, phase II clinical trial was conducted in 11 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, and an estimated life expectancy of at least 3 months. The participants were categorized into three cohorts based on prior therapy and functional genomic alterations. Patients in cohort 1 were previously untreated advanced NSCLC, had no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene modifications, and received AK112 combined with pemetrexed (500mg/m2) for non-squamous (non-sq)-NSCLC or paclitaxel (175mg/m2) for sq-NSCLC plus carboplatin (area under the curve of 5mg/mL per min) for four cycles, followed by AK112 with pemetrexed for non-sq-NSCLC and AK112 alone for sq-NSCLC as maintenance therapy. The participants in cohort 2 had advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy, and received pemetrexed plus AK112 and carboplatin for four cycles, followed by pemetrexed plus AK112 as maintenance therapy. The participants in cohort 3 had advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/programmed death-ligand 1 (PD-L1) treatments and received AK112 plus docetaxel (75mg/m2). Two dosages of AK112 (10 or 20mg/kg) were examined in each cohort, and the drug was administered intravenously on day 1 of each 3-week treatment cycle. The primary endpoints were the investigator-assessed objective response rate (ORR) and safety. This study was registered with ClinicalTrials.gov (NCT04736823). Eighty-three patients were enrolled from February 2021 to August 2022 and received the study treatment. Cohorts 1, 2, and 3 had 44, 19, and 20 patients, respectively. The confirmed ORR was 53.5% (23/43) [95% CI, 36.9-67.1], 68.4% (13/19) [95% CI, 43.4-87.4], and 40.0% (8/20) [95% CI, 19.1-63.9] in cohorts 1, 2, and 3, respectively. In cohort 1, the median PFS was not reached, and the 12-month PFS rate was 59.1%. In cohorts 2 and 3, the median PFS were 8.5 [95% CI, 5.5-NE] and 7.5 [95% CI, 2.3-NE] months, and the 12-month PFS rates were 35.5% and 44.5%, respectively. The most common grade ≥3 treatment-related adverse events were decreased white blood cell count [7 (8.4%)], neutropenia [5 (6.0%)], thrombocytopenia [2 (2.4%)], anemia [4 (4.8%)], and myelosuppression [2 (2.4%)]. AK112 plus platinum-doublet showed promising antitumor activity and safety not only in first-line treatment of advanced NSCLC patients without driver mutation but also in patients with EGFR-functional mutation who failed previous EGFR-TKI therapy and advanced NSCLC patients who failed prior systemic platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatments, suggesting a valuable potential new treatment option for this patient population. Akeso Biopharma, Inc., Zhongshan, China, and National Natural Science Foundation of China.

Comparation of EGFR-TKI (EGFR tyrosine kinase inhibitors) combination therapy and osimertinib for untreated EGFR-mutated advanced non-small cell lung cancers: A systematic review and network meta-analysis.

EGFR-TKI (tyrosine kinase inhibitor) monotherapy has become the first-line treatment option for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Prolonging the survival time, improving the progression-free survival of front-line treatment, and delaying the occurrence of drug resistance. At present, combination therapy is being widely used. Evaluate the therapeutic effect of TKI joint and Osimertinib drug therapy for positive patients with gene positive. Articles that met the inclusion criteria were searched through electronic databases. treatment emergent adverse events were summarized, and progression-free survival (PFS) and overall survival (OS) were calculated. Appropriate networks for different outcomes were created to incorporate all the evidence. Bayesian network-based multitreatment was used to compare the efficacy and specific toxicity of all treatment regimens. Fourteen eligible studies involving 2325 patients were included. Of these, 7 studies compared EGFR-TKI plus chemotherapy with EGFR-TKI alone, and 6 studies compared EGFR-TKI plus antiangiogenic therapy with EGFR-TKI alone. One study compared Osimertinib and GP, ER, EB, and GCP were more effective than SOC in PFS analysis; however, there was no significant difference between osimertinib and the other 4 combination regimens. The cumulative probabilities of being the most efficacious treatments were (PFS, OS, treatment emergent adverse events): O (73%, 16%, 0%, 0%), GCP (14%, 64%, 10%, 16%), GP (2%, 17%,8%), and EB (3%, 3%, 8%), ER (5%, NA, 4%);GA(1%, NA, 69%). Osimertinib has the lowest side effects and provides better PFS first-line treatment in advanced EGFR-mutated NSCLC.GCP is the best regimen for OS, but its toxicity limits its application, and it may be the first choice for patients with higher survival requirements.

Pemetrexed induces ROS generation and cellular senescence by attenuating TS-mediated thymidylate metabolism to reverse gefitinib resistance in NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR mutations, while drug resistance makes exploring resistance mechanisms and seeking effective therapeutic strategies urgent endeavours. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, we found a positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. The examination of gene sets from 140 NSCLC patients received EGFR-TKI therapy demonstrated a negative correlation between high TS expression and the efficacy of EGFR-TKI therapy. 24 tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The NSCLC cell PC9 and HCC827 sensitive to gefitinib and relatively resistant PC9/GR and HCC827/GR cells were used to demonstrate the knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation, DNA damage and cellular senescence, thereby hampering cancer progression and restoring sensitivity to gefitinib. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This study suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKI and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and therapeutic value.

Clinical features and prognosis of lung cancer in patients with connective tissue diseases: a retrospective cohort study.

Studies have demonstrated a close association between connective tissue diseases (CTDs) and lung cancer (LC). Evidence supports that poor survival may be associated with the presence of CTDs in patients with LC. This retrospective cohort study investigated 29 patients with LC with CTDs, and 116 patients with LC without CTDs were enrolled as case-matched control cohorts. Medical records, therapeutic efficacy of cancer, and outcomes were analyzed. The median duration from the diagnosis of CTDs to LC was 17 years. The Eastern Cooperative Oncology Group (ECOG) performance score for LC-CTD patients was worse than that for matched non-CTD LC patients. The median progression-free survival (mPFS) and overall survival (mOS) of first-line chemotherapy did not differ between patients with lung adenocarcinoma (AC) with and without CTDs. A significant difference was observed in mPFS [4 months vs. 17 months; hazard ratio (HR), 9.987; p = 0.004] and mOS (6 months vs. 35 months; HR, 26.009; p < 0.001) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment between patients with AC with and without CTDs. The presence of CTD, sex, ECOG performance status, and tumor-node-metastasis clinical stage were the independent prognostic factors in all patients with non-small cell LC (NSCLC). ECOG performance status was determined to be an independent prognostic factor in patients with LC-CTD. In patients with NSCLC with CTD (n = 26), sex (male) and worse ECOG score were the independent poor prognostic factors. CTDs were associated with poor survival in patients with LC. The therapeutic efficacy of first-line EGFR-TKI therapy was significantly worse in patients with lung AC with CTDs than in those without CTDs. ECOG performance status was determined as an independent prognostic factor for patients with LC and CTDs.

EGFR tyrosine kinase inhibitors (TKIs) versus durvalumab (durva) following concurrent chemoradiation (CRT) in unresectable EGFR-mutant non-small-cell lung cancer (NSCLC).

8567 Background: Adjuvant osimertinib (osi) improves disease-free survival (DFS) in patients (pts) with resected, early-stage, EGFR-mutant (EGFRmut) NSCLC, yet the benefit of osi after CRT in pts with unresectable locally advanced NSCLC is unknown. Post-hoc analysis of the PACIFIC trial showed a lack of survival benefit with consolidation durva versus placebo in pts with EGFRmut NSCLC. Comparisons between consolidation durva and EGFR TKIs in unresectable EGFRmut NSCLC following CRT are lacking. Methods: We conducted a multi-institutional retrospective analysis of pts with stage III unresectable EGFRmut NSCLC (exon19 deletion, exon21 L858R), who received EGFR TKI or durva after ≥ 2 cycles of platinum-based chemotherapy plus definitive radiation therapy between 2015-2022. Baseline characteristics including age, sex, smoking history, PD-L1 status, and outcomes on DFS, overall survival (OS), and safety were collected. Multivariable (MVA) cox regression analysis was used for statistical analysis. Treatment-related adverse events (trAE) were defined using CTCAE 5.0. Results: Seventeen pts from 12 institutions received an EGFR TKI (osi, n=15; erlotinib, n=2), and 13 pts received consolidation durva. Median follow-up was 23 months. Median age of all pts was 61 years (IQR:52-72) and 76.7% were female. Most pts in both groups had never-smoked and had adenocarcinoma. All pts received ≥ 60 Gy of radiation with concurrent chemotherapy. PD-L1 expression was ≥ 50% in 1/10 (10%) pts treated with durva vs 6/13 (46.2%) treated with TKI, p=0.09. Median duration on treatment for EGFR TKI and durva was 12.2 months and 4.8 months, respectively. Pts treated with EGFR TKI had significantly longer 24-month DFS versus pts treated with durva after adjusting for stage (3A vs 3B vs 3C) (Table). Any grade tRAE occurred in 58.8% (10/17) of pts treated with EGFR TKI vs 38.5% (5/13) with durva. Grade &gt; 3 tRAE occurred in 15.4% (1 pneumonitis and 1 AST/ALT elevation) of pts treated with durva but in none of pts treated with EGFR TKI. Three pts within each arm came off treatment due to toxicity (EGFR TKI: 1 pneumonitis and 2 dermatitis; durva: 1 of each pneumonitis, Type 1 diabetes, AST/ALT elevation). Conclusions: EGFR TKI therapy after definitive CRT was associated with significantly longer DFS compared to durva in this retrospective study of pts with stage III unresectable EGFRmut NSCLC, without unanticipated safety signals. Follow-up is ongoing and OS outcomes will be evaluated subsequently. Further investigation is warranted to define the optimal therapy for locally advanced EGFRmut NSCLC. [Table: see text]

Molecular risk factors for locoregional recurrence in resected non-small cell lung cancer.

Locoregional recurrence is of high risk and is associated with a poor prognosis in terms of OS for non-small cell lung cancer (NSCLC). Local control is essential for radical cure of NSCLC. Previous studies have investigated the clinicopathological risk factors for locoregional recurrence, but the genomic biomarkers associated with locoregional recurrence have been inadequately studied. A total of 118 patients who underwent tumor resection with mutation-detected tumor specimens were included. Tumor samples at surgery and pretreatment/postoperative blood samples were collected for mutational profiling. Among 48 patients with disease recurrence, 46% developed locoregional recurrence (LR) and 75% developed distant metastasis (DM). The 3-year actuarial risk of LR and DM was 25% and 43%, respectively. The first sites of failure were locoregional only (29%), locoregional and distant (10%), and distant only (61%). Patients with LR showed significantly higher ctDNA level than those with only DM at the time of initial recurrence. On multivariate analysis of baseline risk factors, the presence of allele frequency heterogeneity and baseline ctDNA shedding were found to be independently associated with a higher risk of LR. Patients with disruptive TP53 mutations had significantly lower LR-free survival as compared to patients with wild-type TP53 or nondisruptive mutations. EGFR mutations showed a favorable prognostic value for LR and is not induced by EGFR tyrosine kinase inhibitor therapy. Both disruptive TP53 mutation and EGFR mutation remained the significant prognostic factor after adjustment for histological type, pathologic nodal stage and adjuvant therapy. Nearly half of disease recurrences after surgery for NSCC involved locoregional sites. We identified genomic biomarkers from baseline tumor and ctDNA samples which showed promising prognostic value for LR only. This can help identify patients who had a higher risk of locoregional recurrence regardless of the risk of distant metastasis.

Patient Characteristics, Testing and Treatment Patterns, and Outcomes in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multinational, Real-World Study.

Treatment landscape for advanced/metastatic NSCLC (aNSCLC) has evolved considerably over the past few decades with the advent of targeted therapies for epidermal growth factor receptor-mutated (EGFRm+) aNSCLC treatment. This study described real-world patient and disease characteristics, treatment and practice patterns, and clinical, economic, and patient-reported outcomes (PROs) in patients with EGFRm+ aNSCLC. Data were derived from the Adelphi NSCLC Disease Specific Programme™ (DSP™), a point-in-time survey conducted between July and December 2020. The survey included oncologists and pulmonologists, and their consulting patients (with physician-confirmed EGFRm+ aNSCLC) from nine countries: the US, Brazil, theUK, Italy, France, Spain, Germany, Japan, and Taiwan. All analyses were descriptive. Overall, 542 physicians reported data for 2857 patients (mean age 65.6years), and most patients were female (56.0%), white (61.0%), and had stageIV disease at initial diagnosis (76.0%), and adenocarcinoma histology (89.0%). Most patients received EGFR-tyrosine kinase inhibitors (TKI) therapy in first- (91.0%), second- (74.0%), and third-line (67.0%). The most common tumor samples and methods for EGFR detection were EGFR-specific mutation detection tests (44.0%) and core needle biopsy (56.0%). Median time to next treatment was 14.0 (IQR 8.0-22.0) months and disease progression was the main physician-reported reason for early discontinuation. The most common physician-reported disease symptoms were cough (51.0%), fatigue (37.0%), and dyspnea (33.0%). In patients assessed for PROs, mean EQ-5D-5L index and FACT-L health utility scores were 0.71 and 83.5, respectively. On average, patients lost 10.6h of work/week for approximately 29.2weeks due to EGFRm+ aNSCLC. This real-world multinational dataset showed that most patients with EGFRm+ aNSCLC were treated per the country relevant clinical guidelines, with progression as the main reason for early treatment discontinuation. For the included countries, these findings may offer a useful benchmark for decision makers to determine future allocation of healthcare resources for patients with EGFRm+ aNSCLC.

Survival Rate of Lung Adenocarcinoma Patients Receiving EGFR - Tyrosine Kinase Inhibitor Targeted Therapy

Globally, lung cancer is by far the leading cause of death by cancer-which contribute to 2.094 million death-with the highest toll from cancer being 1.8 million. Currently, lung cancer therapy has developed from chemotherapy to targeted therapy, such as Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI). This study aimed to assess the survival rate of adenocarcinoma cell lung cancer patients who received EGFR-TKI therapy at the Pulmonary Clinic of Dr. Saiful Anwar General Hospital Malang. This study was a retrospective study using patient medical records between 2017 and 2020. The data were processed and analyzed using the Chi-Square test. The number of samples was 117 patients consisting of 63 patients receiving Gefitinib therapy, 36 patients receiving Afatinib therapy, and 18 patients receiving Erlotinib therapy. There were no significant differences between variables of age, sex, smoking history, stage, and exon mutations with 1-year survival. Gefitinib therapy has a higher average survival time than Afatinib and Erlotinib. However, the 1-year survival rate (YSR) was highest on Afatinib. The Middle Survival (MS) of the three regimens is almost the same, about 300 days. Statistical data showed no relationship between survival and the treatment regimen given (p=0.187). The most common side effect of TKI is skin rash. This research should be carried out with a larger sample to minimize bias.

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

Multiregional radiomics of brain metastasis can predict response to EGFR-TKI in metastatic NSCLC.

To develop radiomics signatures from multiparametric magnetic resonance imaging (MRI) scans to detect epidermal growth factor receptor (EGFR) mutations and predict the response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). We included 230 NSCLC patients with BM treated at our hospital between January 2017 and December 2021 and 80 patients treated at another hospital between July 2014 and October 2021 to form the primary and external validation cohorts, respectively. All patients underwent contrast-enhanced T1-weighted (T1C) and T2-weighted (T2W) MRI, and radiomics features were extracted from both the tumor active area (TAA) and peritumoral edema area (POA) for each patient. The least absolute shrinkage and selection operator (LASSO) was used to identify the most predictive features. Radiomics signatures (RSs) were constructed using logistic regression analysis. For predicting the EGFR mutation status, the created RS-EGFR-TAA and RS-EGFR- POA showed similar performance. By combination of TAA and POA, the multi-region combined RS (RS-EGFR-Com) achieved the highest prediction performance, with AUCs of 0.896, 0.856, and 0.889 in the primary training, internal validation, and external validation cohort, respectively. For predicting response to EGFR-TKI, the multi-region combined RS (RS-TKI-Com) generated the highest AUCs in the primary training (AUC = 0.817), internal validation (AUC = 0.788), and external validation (AUC = 0.808) cohort, respectively. Our findings suggested values of multiregional radiomics of BM for predicting EGFR mutations and response to EGFR-TKI. TheapplicationofradiomicanalysisofmultiparametricbrainMRIhasproventobeapromisingtooltostratifywhichpatientscanbenefitfromEGFR-TKItherapyandtofacilitatetheprecisetherapeuticsofNSCLCpatientswithbrainmetastases. • Multiregional radiomics can improve efficacy in predicting therapeutic response to EGFR-TKI therapy in NSCLC patients with brain metastasis. • The tumor active area (TAA) and peritumoral edemaarea (POA) may hold complementary information related to the therapeutic response to EGFR-TKI. • The developed multi-region combined radiomics signature achieved the best predictive performance and may be considered as a potential tool for predicting response to EGFR-TKI.

STAT3 and STAT6 polymorphisms predict the severity of adverse reactions in Chinese NSCLC patients receiving EGFR-TKIs therapy

A total of 162 non-small cell lung cancer (NSCLC) patients were divided into discovery (N = 68) and validation (N = 94) groups. Nine Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway-related single nucleotide polymorphisms were selected to explore the potential associations between genetic polymorphisms and adverse drug reactions (ADRs). The TT genotype of STAT6 rs324011 was significantly associated with severe ADRs in the recessive genetic model (TT vs. CC + CT, OR = 13.5, 95% CI = 2.12–86.09, p = 0.006 in the discovery group; OR = 8.41, 95% CI = 1.95–36.19, p = 0.004 in the validation group). The T allele was associated with a higher incidence of severe ADRs than was the C allele of rs324011 (OR = 3.67, 95% CI = 1.46–9.19, p = 0.006 in the discovery group; OR = 3.17, 95% CI = 1.44–6.99, p = 0.004 in the validation group). Patients with the CC genotype in STAT3 rs1053023 (and rs1053005) or the TT genotype of STAT6 rs324011 were likely to experience severe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) related ADRs.

Tackling Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer.

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.

Making the Best Use of Available Weapons for the Inevitable Rivalry-Resistance to EGFR-TKIs

The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the treatment of advanced-stage non-small cell lung cancer (NSCLC). Detected in more than 50% of late-stage lung adenocarcinoma in Asian patients, the EGFR mutation was regarded as a golden mutation for Asians. However, resistance to TKIs seems inevitable and severely hinders patients from getting further benefits from treatment. Even though resistance caused by EGFR T790M could be effectively managed by third-generation EGFR-TKIs currently, resistance to third-generation EGFR-TKIs is still a troublesome issue faced by both clinicians and patients. Various efforts have been made to maximize the benefits of patients from EGFR-TKIs therapy. Thus, new requirements and challenges have been posed to clinicians of this era. In this review, we summarized the clinical evidence on the efficacy of third-generation EGFR-TKIs in patients with EGFR-mutated NSCLC. Then, we discussed advancements in sequential treatment aiming to delay the onset of resistance. Moreover, the resistance mechanisms and features were depicted to help us better understand our enemies. Lastly, we put forward future strategies, including recent approaches involving the utilization of antibody drug conjugates against resistance and research directions about shaping the evolution of NSCLC as a core idea in the management of NSCLC.

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice.

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.

Abstract 859: Simulations of tumor heterogeneity impact on treatment response using a mechanistic model of EGFR-mutant lung adenocarcinoma

Abstract Introduction Epidermal growth factor receptor (EGFR) mutations occur in about 40% of Asian and 13-25% of Western patients with lung adenocarcinoma (LUAD) [1,2]. EGFR tyrosine kinase inhibitors (TKIs) have been developed to target tumors with an EGFR driver mutation. However such tumors also harbor additional mutations and genotypic alterations, which contribute to the variability in treatment response. Overall, intratumor heterogeneity is a dynamic source of therapeutic resistance. Here, we assessed the impact of tumor mutational profile on inter-patient treatment response variability by using a mechanistic model of late stage EGFR-mutant LUAD [3]. Methods We developed in the jinko platform a knowledge-based model of late stage EGFR-mutant LUAD, whose parameters each hold a pathophysiology-related meaning. Indeed, causality between disease-related biological phenomena is inherent to the mechanistic knowledge-based model, easing the biological interpretation of the impact of parameter values on model outcomes, which is highly valuable in the context of uncommon populations. To explore the impact of tumor heterogeneity, tumors are implemented with distinct subpopulations of cancer cells, called subclones. Each subclone is defined by a set of mutations and a corresponding proliferating phenotype. A virtual population representative of real world EGFR-mutant LUAD patients was developed to reproduce the variability observed between and within patients’ tumors for the modeled mutations. A physiologically-based pharmacokinetics model of a TKI drug, integrating a mechanistic modeling of the drug’s mechanism of action, is connected to the disease model. Results After simulating a clinical trial on a virtual population in the jinko platform using the developed model, we were able to follow the proliferating phenotype of each cancer subclone over time, as well as the overall evolution of the tumor size of each patient. The model reproduced the emergence of treatment-resistant subclones on EGFR TKI therapy. Modeling tumor size evolution throughout the clinical trial enabled computing the patients’ time to progression as clinical outcome, based on the RECIST 1.1 criteria, and generating corresponding survival curves. Stratification of virtual patients according to their tumor mutations allowed us to pinpoint key mutations that negatively impacted treatment response. Conclusion Modeling and simulation can help understanding how intratumor heterogeneity affects cancer evolution and drives resistance to treatment. Clinical trial simulations using knowledge-based models of disease and treatment provide relevant additional tools to help clinicians in exploring new hypotheses, providing treatment guidance and supporting therapeutic innovation.

Abstract 2300: Non-invasive liquid biopsy assay for the detection of ASCL1 expression in CTCs of patients with lung cancer

Abstract Background: Lung cancer (LC) is the deadliest cancer worldwide, with small cell LC (SCLC) and neuroendocrine (NE) LC being the most aggressive and lethal forms. The transcription factor, achaete-scute homolog 1 (ASCL1), regulates neuronal and NE cell development, and is a hallmark of the ASCL1(+) SCLC subtype. Further, investigating subtype has become increasingly important as new drug candidates emerge for SCLC that may be efficacious in only some patients. ASCL1 by IHC tissue biopsy is highly specific, detecting patients who have transformed from NSCLC to SCLC and have acquired resistance to EGFR tyrosine kinase inhibitor therapy in NSCLC. Quantification of ASCL1 on circulating tumor cells (CTCs) is a blood-based, non-invasive alternative to tissue biopsy that provides functional protein-level expression data to monitor lung cancer patients across the disease continuum, informing patient treatment. Methods: A 4-color immunofluorescence (IF) assay was developed to detect ASCL1 expression in CTCs from routine blood samples, comprising detection of nucleated cells (DAPI), cytokeratin positive CTCs, CD45(+) white blood cells (WBC), and ASCL1(+) cells. During validation, cancer cell lines (SHP-77 [ASCL(+)] and U2-OS [ASCL1(-)]) were spiked into normal blood at a ratio of 1:10,000 (CLC/WBC) and plated onto coated glass slides. Slides were stained, imaged, and CTC candidates were identified with a proprietary imaging algorithm. The threshold of ASCL1 positivity (316 MFI) included 99% of all ASCL1(-), U2-OS cells. Assay specificity, sensitivity, overall accuracy, and subcellular localization of biomarker expression were assessed. The ability of the assay to quantify ASCL1 expression in CTCs was confirmed using 31 samples from 11 Extensive Stage SCLC patients. Results: The ASCL1 CTC assay achieved an overall accuracy of 0.992 (95% CI 0.081, 0.993), and an analytical specificity and sensitivity of 0.990 and 0.995, respectively. The assay displayed a positive predictive value and a negative predictive value of 0.979 and 0.998, respectively, determined by evaluating ASCL1 expression in SHP-77 (N=4062) and U2-OS (N=8645). ASCL1 expression was detected in the nucleus of all SHP-77 and majority of SCLC patient CTCs. Of the 11 Extensive Stage SCLC patients tested, 9 (82%) showed at least one conventional CTC (0.02 - 9.63 CTCs/mL), and all 9 (100%) had at least 1 ASCL1(+) CTC (0.06 - 5.5 CTCs/mL). Conclusion: This blood based ASCL1 assay is a highly specific and sensitive approach to monitor ASCL1 expression on CTCs isolated from the blood of lung cancer patients. Citation Format: Luisa Fernandez, Andrew Kunihiro, Mark Frilles, Alisa Tubbs, Jason Christiansen, David Bourdon. Non-invasive liquid biopsy assay for the detection of ASCL1 expression in CTCs of patients with lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2300.

Adjuvant EGFR-TKI therapy in resected EGFR-mutation positive non-small cell lung cancer: A real-world study.

Although several clinical studies have laid the foundation for the adjuvant application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), some questions remain unresolved. This real-world study aimed to address questions such as the effect of adjuvant chemotherapy prior to adjuvant EGFR-TKI therapy on survival outcomes, and the duration of adjuvant EGFR-TKI therapy, etc. Between October 2005 and October 2020, 227 consecutive patients with non-small cell lung cancer (NSCLC) who underwent complete pulmonary resections were included in this retrospective study. Patients received postoperative adjuvant chemotherapy followed by EGFR-TKI or adjuvant EGFR-TKI monotherapy. The disease-free survival (DFS) and overall survival (OS) were evaluated. Of the total 227 patients, 55 (24.2%) patients underwent 3-4 cycles of chemotherapy prior to receiving adjuvant EGFR-TKI therapy. The 5-year DFS rate was 67.8%, while the 5-year OS rate was 76.4%. The stages were significantly associated with both DFS (P<0.001) and OS (P<0.001), while no significant differences were observed in the DFS (P=0.093) and OS (P=0.399) between the adjuvant chemotherapy followed by EGFR-TKI and adjuvant EGFR-TKI monotherapy groups. A longer duration of EGFR-TKI therapy was associated with better DFS (P<0.001) and OS (P<0.001) benefit. Additionally, pTNM stage and duration of EGFR-TKI therapy were considered independent prognostic factors for long-term survival (All P<0.05). This study supports the use of EGFR-TKI as a postoperative adjuvant treatment for patients with stage II-IIIA EGFR-mutation positive NSCLC. Additionally, patients with stage I who had pathological risk factors were also suitable for receiving adjuvant EGFR-TKI therapy. Postoperative EGFR-TKI based, chemotherapy-free adjuvant regimen may be a potential therapeutic option for patients with EGFR-mutation positive NSCLC.

Treatment Patterns, Testing Practices, and Outcomes in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer in Poland: A Descriptive Analysis of National, Multicenter, Real-World Data from the REFLECT Study.

Non-small-cell lung cancer (NSCLC) represents 85% of new cases of lung cancer. Over the past two decades, treatment of patients with NSCLC has evolved from the empiric use of chemotherapy to more advanced targeted therapy dedicated to patients with an epidermal growth factor receptor (EGFR) mutation. The multinational REFLECT study analyzed treatment patterns, outcomes, and testing practices among patients with EGFR-mutated advanced NSCLC receiving first-line EGFR tyrosine kinase inhibitor (TKI) therapy across Europe and Israel. The aim of this study is to describe the Polish population of patients from the REFLECT study, focusing on treatment patterns and T790M mutation testing practice. A descriptive, retrospective, non-interventional, medical record-based analysis was performed on the Polish population of patients with locally advanced or metastatic NSCLC with EGFR mutations from the REFLECT study (NCT04031898). A medical chart review with data collection was conducted from May to December 2019.The study involved 110 patients. Afatinib was used as the first-line EGFR-TKI therapy in 45 (40.9%) patients, erlotinib in 41 (37.3%), and gefitinib in 24 (21.8%) patients. The first-line EGFR-TKI therapy was discontinued in 90 (81.8%) patients. The median progression-free survival (PFS) on first-line EGFR-TKI therapy was 12.9 months (95% CI 10.3-15.4). A total of 54 patients started second-line therapy, of whom osimertinib was administered to 31 (57.4%). Among 85 patients progressing on first-line EGFR-TKI therapy, 58 (68.2%) were tested for the T790M mutation. Positive results for the T790M mutation were obtained from 31 (53.4%) tested patients, all of whom received osimertinib in the next lines of therapy. The median overall survival (OS) from the start of first-line EGFR-TKI therapy was 26.2 months (95% CI 18.0-29.7). Among patients with brain metastases, the median OS from the first diagnosis of brain metastases was 15.5 months (95% CI 9.9-18.0). The results of the Polish population from the REFLECT study highlight the need for effective treatment of patients with advanced EGFR-mutated NSCLC. Nearly one-third of patients with disease progression after first-line EGFR-TKI therapy were not tested for the T790M mutation and did not have the opportunity to receive effective treatment. The presence of brain metastases was a negative prognostic factor.

Healthcare coverage affects survival of EGFR-mutant Thai lung cancer patients.

Despite significant benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with EGFR-mutated NSCLC, access remains limited in Thailand and elsewhere. Retrospective analysis of patients with locally advanced/recurrent NSCLC and known EGFR mutation (EGFRm) status treated at Ramathibodi Hospital (2012-2017). Prognostic factors for overall survival (OS), including treatment type and healthcare coverage, were analyzed using Cox regression. Of 750 patients, 56.3% were EGFRm-positive. After first-line therapy (n=646), 29.4% received no subsequent (second-line) treatment. EGFR-TKI-treated EGFRm-positive patients survived significantly longer than EGFRm-negative patients without EGFR-TKIs (median OS [mOS] 36.4 vs. 11.9 months; hazard ratio HR=0.38 [95%CI 0.32-0.46], P<0.001). Cox regression indicated significantly longer OS in patients with comprehensive healthcare coverage that included reimbursement of EGFR-TKIs, versus basic coverage (mOS 27.2 vs. 18.3 months; adjusted HR=0.73 [95%CI 0.59-0.90]). Compared with best supportive care (BSC; reference), EGFR-TKI-treated patients survived significantly longer (mOS 36.5 months; adjusted HR (aHR)=0.26 [95%CI 0.19-0.34]), and versus chemotherapy alone (14.5 months; aHR=0.60 [95%CI 0.47-0.78]). In EGFRm-positive patients (n=422), relative survival benefit of EGFR-TKI treatment remained highly significant (aHR[EGFR-TKI]=0.19 [95%CI 0.12-0.29]; aHR(chemotherapy only)=0.50 [95%CI 0.30-0.85]; reference:BSC), indicating that healthcare coverage (reimbursement) affected treatment choice and survival. Our analysis describes EGFRm prevalence and survival benefit of EGFR-TKI therapy for EGFRm-positive NSCLC patients treated from 2012-2017, one of the largest such Thai datasets. Together with research by others, these findings contributed evidence supporting the decision to broaden erlotinib access on healthcare schemes in Thailand from 2021, demonstrating the value of local real-world outcome data for healthcare policy decision-making.

Clinical impact of tetracyclines and/or proton pump inhibitors on the efficacy of epidermal growth factor receptor inhibitors in non-small cell lung cancer: a retrospective cohort study

BackgroundThis retrospective cohort study examined the impact of tetracyclines (TCs) and proton pump inhibitors (PPIs) alone or in combination on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC treated with gefitinib or erlotinib for at least 1 week between January 2009 and October 2021 were enrolled and divided into four groups based on the presence/absence of TC and/or PPI in the therapeutic regimen: TC-/PPI-, TC + /PPI-, TC-/PPI + , TC + /PPI + . Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.ResultsThe estimated median PFS and OS of 347 included patients with NSCLC were 8.57 (95% confidence interval [CI]: 7.66–9.48) months and 13.10 (95% CI: 11.03–15.17) months, respectively. Co-administration of EGFR-TKIs with PPIs decreased the PFS and OS, while that with TCs improved the PFS and OS. However, the concomitant use of EGFR-TKIs, TCs, and PPIs yielded survival rates similar to that of EGFR-TKI therapy alone.ConclusionsThe administration of EGFR-TKIs with other drugs poses a challenge in managing patients with NSCLC. Therefore, reassessing the indications and necessity of TC or PPI therapy is essential for patients receiving erlotinib or gefitinib. The benefits and risks of possible discontinuation due to the clinical relevance of this interaction should be considered.