Receptor Tyrosine Kinase Inhibitor Research Articles

Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: a systematic review and meta-analysis

BackgroundNon-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with substantial differences in morphology, genetic profiles, clinical behavior, and prognosis. Optimal treatment for nccRCC remains unclear, largely extrapolated from evidence available for clear cell renal cell carcinoma (ccRCC). This study aimed to compare the efficacy of current mainstream drug treatments for nccRCC to provide clinical treatment guidance for advanced cases.MethodsWe systematically searched PubMed, Embase, and Cochrane databases for trials published up to January 2, 2024, including controlled and single-arm trials. Primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsWe selected six randomized controlled trials (RCTs) comparing mammalian target of rapamycin inhibitors (mTORi) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These trials included four first-line and two second-line studies, with a total of 398 advanced nccRCC patients. Pooled results showed that VEGFR-TKIs significantly improved PFS compared to mTORi in first-line treatment (relative risk [RR] = 1.387; 95% confidence interval [CI]: 1.04-1.85; p = 0.026). In a single-arm meta-analysis, we included 22 VEGFR-TKI trials, three mTORi trials, 12 immune checkpoint inhibitor (ICI) therapies, five chemotherapy trials, and 10 combination therapy trials. The pooled ORR ranged from 6% (95% CI: 0–16%) to 36% (95% CI: 27–44%), and the pooled DCR ranged from 54% (95% CI: 50–58%) to 81% (95% CI: 70–91%). Subgroup analysis of ICI showed a higher ORR in the PD-L1 positive group compared to the PD-L1 negative group (RR = 3.044; 95% CI: 1.623-5.709; p = 0.001).ConclusionThis systematic review and meta-analysis demonstrate that VEGFR-TKIs improve PFS in first-line treatment compared to mTORi. The single-arm meta-analysis suggest that combination therapies with different mechanisms result in better ORR and DCR. Furthermore, PD-L1 positive patients showed significantly better therapeutic responses with ICI treatment than PD-L1 negative patients.

Plasma metabolomics profiling of EGFR-mutant NSCLC patients treated with third-generation EGFR-TKI

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies.

Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: a phase II trial

Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927). Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits. An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Abstract A011: Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801

Abstract The AXL receptor (AXL) is a transmembrane protein that is highly expressed in a variety of tumors and correlates with poor prognosis in cancer patients. AXL is expressed in cancer, immune, and stromal cells and has been implicated in the development of resistance to chemotherapy, targeted therapies, and immunotherapies. Activation of AXL by either its ligand, growth arrest specific protein 6 (GAS6), or ligand-independent homo- and hetero-dimerization facilitates AXL phosphorylation and initiates signaling cascades that promote cancer cell proliferation, survival, and an immunosuppressive microenvironment. Historically, most small-molecule inhibitors capable of suppressing AXL signaling are unselective and inhibit several other related kinases. Administration of a truly selective AXL inhibitor would be expected to be free of the off-target toxicity of other kinase inhibitors; this, in turn, might allow the unmasking of the full therapeutic benefit associated with robust AXL inhibition. To this end, we initiated a medicinal chemistry campaign with additional goals of discovering a potent and orally bioavailable inhibitor. Through iterative SAR-guided design we discovered AB801, a reversible AXL inhibitor. Importantly, AB801 exhibits excellent selectivity against MERTK, TYRO3 (closely related tyrosine kinases) and the overall kinome. AB801 exhibits a double-digit picomolar inhibitory constant and retains significant activity in cell-based assays performed in 100% human serum. In vitro, AB801 increases sensitivity to standard of care (SOC) therapeutics such as chemotherapy and results in increased DNA damage, leading to cancer cell death. AB801 treatment also sensitizes tumors to immune checkpoint blockade by increasing immune cell activation. Significant anti-tumor efficacy is observed in combination with SOC therapies in multiple in vivo models. When compared against existing AXL inhibitors such as bemcentinib, AB801 shows large improvements in both potency and selectivity. A placebo-controlled phase 1 study (NCT06004921) to assess the safety and pharmacokinetics of AB801 in healthy volunteers was recently completed; AB801 was well tolerated at all tested doses and exhibited a dose-proportionate increase in exposure. Currently, AB801 is in clinical evaluation in patients with advanced cancer (NCT06120075). Citation Format: Dillon H. Miles, Corinne N. Foley, Shiwei Qu, Dillon H. Miles, Srinivas Paladugu, Ehesan U. Sharif, Joice Thomas, Pradeep Nareddy, Guiling Zhao, Rebecca Grange, Manmohan R. Leleti, Jay P. Powers, Stefan Garrido-Shaqfeh, Ada Chen, Hema Singh, Yue Tong Lee, Xiaoning Zhao, David Green, Hsin-Ting Huang, Lixia Jin, Jhansi Leslie, Logan Chinn, Susan L Paprcka, Ester Fernandez-Salas. Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A011.

Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial

Lenvatinib, a multi-kinase inhibitor, has been approved as first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression (EGFRhigh). We present here the results of a single-arm, open-label, exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib (NCT04642547; n = 30). Only patients with EGFRhigh HCC and progressive disease after lenvatinib treatment were recruited in the study. The most frequent adverse events of all grades were fatigue (27 patients; 90%), followed by rash (25 patients; 83.3%), diarrhea (24 patients; 80%), and anorexia (12 patients; 40%). Among 30 patients, 9 (30%) achieved a confirmed partial response and 14 (46.7%) had stable disease according to mRECIST criteria. Based on RECIST1.1, 5 (16.7%) achieved a confirmed partial response and 18 (60%) had stable disease. The estimated median progression free survival (PFS) and overall survival (OS) time were 4.4 months (95% CI: 2.5 to 5.9) and13.7 months (95% CI: 9.0 to NA), respectively. The objective response rate (ORR) of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC (cabozantinib ORR of 4%; regorafenib ORR of 11%). Given that this combination was well-tolerated, a further clinical study of this combination is warranted.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

Lung cancer has emerged as a highly aggressive malignancy posing a significant global health hazard, with a particular concern for the rising incidence and mortality of gene-altered non-small cell lung cancer (NSCLC). As the prevalence of NSCLC rises, the investigation and selection of tumor treatment techniques are gaining significance. The treatment of individuals with genetic mutations in advanced NSCLC has emphasized the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Early and subsequent generations of EGFR-TKIs have demonstrated clinical efficacy in NSCLC patients carrying select genetic alterations. Osimertinib, a third-generation EGFR-TKI, has been sanctioned as the standard first-line therapy and is also utilized as a second-line option for individuals who develop the T790M resistance mutation following prior EGFR-TKI treatment. Approximately 10 to 30 percent of patients diagnosed with NSCLC exhibit EGFR mutations. This leads to abnormal activation of cancer genes and inactivation of tumor suppressor genes, resulting in poor prognosis for patients. This paper aims to analyze the development and resistance processes of EGFR inhibitors, thereby enhancing the comprehension of the resistance pathways to EGFR-TKIs.

In silico design, modelling and molecular mechanisms of Axl receptor tyrosine kinase inhibitors

A kinase domain from receptor tyrosine kinases (RTKs) regulate intracellular communications to control cellular metabolic activities. Some of the malignant cells have upregulated and overexpressed RTKs which are responsible for angiogenesis in many metastatic cancers. Axl RTK is present in most of the eukaryotic cells and all metastatic cancer cells have overexpressed Axl tyrosine kinase to trigger uncontrolled growth and angiogenesis in the malignant cells. The upregulated kinases can be inhibited in its active and inactive states in the presence of small organic molecule inhibitors. Kinase inhibitors have been discovered to arrest the signal transduction pathways in the malignant cells as a therapy and cure for cancer. In this work, small molecule databases were screened using the pharmacophore features of a macrocyclic inhibitor (7YS) taken as reference from the crystal structure of Axl kinase domain. Pharmacophore based virtual screening of small molecule libraries (CHEMBL32, ChemDiv, Chemspace, Mcule, MolProt, PubChem and Zinc), followed by molecular docking, molecular dynamics simulations, binding energies from MM-PBSA calculations and trajectory analysis as principal component analysis were studied. The molecular basis for the binding of macrocyclic inhibitor, ATP and seven screened hit molecules bound at Axl kinase domain in two different modes at catalytic and regulatory sites was analyzed.

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

YAP/TAZ Inhibitor-Based Drug Delivery System for Selective Tumor Accumulation and Cancer Combination Therapy.

The YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two important transcriptional coactivators that are often aberrantly activated in cancer cells. Their dysregulation promotes cancer development and can confer resistance to anticancer therapies. Therefore, the pharmacological inhibition of YAP/TAZ presents a promising approach for treating tumors with heightened YAP/TAZ activity. However, the clinical use of a known YAP/TAZ inhibitor, niflumic acid (NA), is limited by its poor in vivo half-life. To improve its bioavailability, we developed a series of NA-based prodrug polymers and investigated the impact of NA monomer units on the physicochemical properties of their self-assembled nanoparticles. The optimal pNA polymer was selected as a prodrug micellar nanocarrier to load hydrophobic receptor tyrosine kinase inhibitors (RTKIs) for combination therapy. The nanocarrier selectively accumulated in the tumor and synergistically inhibited tumor growth with the cargo RTKIs, particularly Dasatinib, introducing a nanocombination therapy enhanced breast cancer treatment.

CXCR1+ neutrophil infiltration orchestrates response to third-generation EGFR-TKI in EGFR mutant non-small-cell lung cancer

Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1+ neutrophils infiltration (P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1+ neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1+ neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1+ neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1+ neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1+ neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

Cardiac Events and Survival in Patients With EGFR-Mutant Non–Small Cell Lung Cancer Treated With Osimertinib

Although it has been reported that osimertinib mesylate provides better survival benefits compared with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), it remains unclear whether osimertinib is associated with more cancer therapy-related cardiac events (CTRCEs) compared with other EGFR TKIs, as does the extent of the association these adverse effects may have with overall survival. This issue is particularly critical due to the high prevalence of EGFR variants within Asian populations, including that of Taiwan. To compare CTRCEs and their association with survival in patients treated with osimertinib vs other EGFR TKIs. This cohort study was conducted at the National Cheng Kung University Hospital, a college hospital and tertiary academic referral center in Taiwan. The median follow-up duration was 23.2 (IQR, 15.2-31.5) months. A total of 401 patients with EGFR-mutant non-small cell lung cancer (NSCLC) beginning treatment with EGFR TKIs from September 1, 2019, to July 31, 2022, were retrospectively analyzed. CTRCEs included newly emerging arrhythmias, valvular heart diseases (moderate and more), myocardial infarction, and heart failure and were analyzed after adjusting for age, sex, smoking, alcohol consumption, body mass index, cardiovascular comorbidities, thoracic radiotherapy, and cardiovascular medications. Follow-up was completed January 31, 2024. Osimertinib. The Cox proportional hazards model was used to estimate CTRCEs in patients treated with osimertinib or other EGFR TKIs. Considering that death can lower the incidence of CTRCEs, the competing risk method was used to calculate CTRCEs after adjusting for potential confounders. Multivariable Cox proportional hazard regression analysis for overall survival was used to explore whether CTRCEs were independently associated with overall survival. Among the 401 patients (253 [63.1%] female; mean [SD] age, 69.2 [11.3] years), 195 (48.6%) treated with osimertinib were matched with 206 (51.4%) treated with other EGFR TKIs. Occurrence of CTRCEs in patients receiving osimertinib was significantly higher compared with patients treated with other EGFR TKIs (29 [14.9%] vs 9 [4.4%]; hazard ratio [HR], 3.37; 95% CI, 1.56-7.26; P = .002). After adjustment for relevant cardiovascular risk factors, the HR of CTRCEs was significantly higher in the group treated with osimertinib (adjusted subdistribution HR, 4.00; 95% CI, 1.81-8.85; P < .001). In addition, CTRCEs were independently associated with overall survival (HR, 4.02; 95% CI, 2.44-6.63; P < .001). In this cohort study of patients with EGFR-mutant NSCLC, osimertinib was associated with a higher incidence of CTRCEs compared with other EGFR TKIs; CTRCEs were independently associated with overall survival. These findings highlight the need for ongoing cardiac monitoring in these patients, regardless of preexisting cardiac risk factors.

Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.

FN-1501 Inhibits Diffuse Large B-Cell Lymphoma Tumor Growth by Inducing Cell Cycle Arrest and Apoptosis.

Due to its high degree of aggressiveness, diffuse large B-cell lymphoma (DLBCL) presents a treatment challenge because 30% to 50% of patients experience resistance or relapse following standard chemotherapy. FN-1501 is an effective inhibitor of cyclin-dependent kinases and Fms-like receptor tyrosine kinase 3. This study aimed to examine the anti-tumor impact of FN-1501 on DLBCL and clarify its molecular mechanism. This study used the cell counting kit-8 assay to evaluate cell proliferation, along with western blotting and flow cytometry to analyze cell cycle progression and apoptosis influenced by FN-1501 in vitro. Afterward, the effectiveness of FN-1501 was evaluated in vivo utilizing the xenograft tumor model. In addition, we identified the potential signaling pathways and performed rescue studies using western blotting and flow cytometry. We found that FN-1501 inhibited cell proliferation and induced cell cycle arrest and apoptosis in DLBCL cells in vitro. Its anti-proliferative effects were shown to be time- and dose-dependent. The effect on cell cycle progression resulted in G1/S phase arrest, and the apoptosis induction was found to be caspase-dependent. FN-1501 treatment also reduced tumor volumes and weights and was associated with a prolonged progressionfree survival in vivo. Mechanistically, the MAPK and PI3K/AKT/mTOR pathways were significantly inhibited by FN-1501. Additional pathway inhibitors examination reinforced that FN-1501 may regulate cell cycle arrest and apoptosis through these pathways. FN-1501 shows promising anti-tumor activity against DLBCL in vivo and in vitro, suggesting its potential as a new therapeutic option for patients with refractory or relapsed DLBCL.

Entrectinib versus crizotinib in Asian patients with ROS1-positive non-small cell lung cancer: A matching-adjusted indirect comparison

ObjectivesEntrectinib and crizotinib are the only ROS proto-oncogene 1 receptor (ROS1) tyrosine kinase inhibitors available for most Asian patients. Their efficacy has neither been compared directly in clinical trials in patients with ROS1-positive non-small cell lung cancer (NSCLC), nor indirectly in Asian populations. Thus, we aimed to provide comparative evidence of the efficacy and safety of entrectinib and crizotinib for Asian patients with advanced or metastatic ROS1-positive NSCLC. Materials and MethodsEfficacy, including overall survival (OS) and progression-free survival (PFS), and safety were evaluated using an unanchored matching-adjusted indirect comparison (MAIC). Individual patient data (IPD) from entrectinib trials (ALKA-372–001/EudraCT 2012–000148-88, STARTRK-1/NCT02097810, and STARTRK-2/NCT02568267; dosage, ≥600 mg once daily; enrollment cutoff, 02 July 2020; data cutoff, 02 August 2021) and aggregate data with simulated pseudo-IPD from a crizotinib trial (OxOnc/NCT01945021; dosage, 250 mg twice daily) were analyzed. Key eligibility criteria from the crizotinib trial were applied to IPD from the entrectinib trials. Baseline characteristics were match-adjusted between arms using propensity score weighting. ResultsFifty-two and 127 patients from the entrectinib and crizotinib trials, respectively, were available for evaluation. Median OS was not reached (NR; weighted; 95 % confidence interval [CI] 28.3–NR) in the entrectinib arm and 44.2 months (95 % CI 32.0–NR) in the crizotinib arm (hazard ratio [HR], 0.662; 95 % CI 0.32–1.37). The respective median PFS was 39.4 months (weighted; 95 % CI 10.4–46.8) and 15.9 months (95 % CI 12.9–24.0) (HR, 0.688; 95 % CI 0.37–1.27). Most AEs were Grade 1–2; both drugs were generally well tolerated. Neutropenia was the most common Grade 3 or 4 treatment-related adverse event for both entrectinib and crizotinib. ConclusionsThe outcomes in this MAIC study including Asian patients with ROS1-positive NSCLC showed a trend for greater clinical benefit with entrectinib versus crizotinib. These findings may contribute to better-informed treatment decisions.

Revolutionizing NSCLC Treatment: Immunotherapy Strategies for EGFR-TKIs Resistance.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment choice for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. EGFR-TKIs have made significant progress in the treatment of advanced NSCLC patients, but drug resistance issues still inevitably arise. The mechanism of drug resistance and subsequent treatment has been current research challenge and priority. Immune checkpoint inhibitors (ICIs) are a new choice for late-stage NSCLC patients without druggable molecular alterations. Currently, several studies have applied ICIs therapy for NSCLC patients with EGFR-TKIs resistance and explored the potential efficacy of ICIs. This review elaborates on the current status of immunotherapy after EGFR-TKIs resistance, including ICIs monotherapy, combined with EGFR-TKIs, chemotherapy, antiangiogenic drugs, and other therapies.

Optimizing epidermal growth factor receptor-tyrosine kinase inhibitor treatment in lung cancer: a systematic review and meta-analysis of the influence of gastric acid suppressants.

The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized advanced non-small cell lung cancer (NSCLC) treatment. However, their efficacy can be compromised by concurrent use of gastric acid suppressants (GASs), such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). This study aimed to update the evidence on the impact of GASs on the overall survival (OS) and progression-free survival (PFS) in patients on EGFR-TKI treatment. A systematic review and meta-analysis were conducted using data from PubMed, Embase, Cochrane Library, Web of Science, Scopus, KoreaMed, and preprint repositories. Data from 13 retrospective studies, involving 10,814 patients, were analyzed. Overall, 34.6% of the patients used GASs, with most being Asian females and non-smokers. Most patients had EGFR-mutated adenocarcinoma, reflecting typical EGFR-TKI usage scenarios. Concurrent use of GASs was significantly associated with reduced OS [hazard ratio (HR) =1.34, 95% confidence interval (CI): 1.26-1.42], and PFS (HR =1.52, 95% CI: 1.25-1.86). In subgroup analysis, PPIs had a more negative impact on OS (HR =1.64, 95% CI: 1.51-1.79) than did H2RAs (HR =1.11, 95% CI: 0.95-1.31). Longer overlap times of GASs correlated with a higher trend in HRs for OS. However, the results for PFS were not significant in both subgroup analyses. Concurrent use of GASs with EGFR-TKIs is linked to poorer OS and PFS in patients with advanced NSCLC. Careful consideration is advised when prescribing GASs, including adjusting administration timing, minimizing overlap duration, or opting for H2RAs over PPIs. Further research is needed to optimize treatment protocols, specifically addressing the duration of overlap time, to improve patient outcomes.

Aplastic anemia associated with osimertinib: Analysis of the FDA adverse event reporting system.

Aplastic anemia (AA) is a life-threatening disease, and drug-induced AA is rare. Recently, studies on cases that possibly developed AA following osimertinib treatment have been conducted. This study evaluated the association of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including osimertinib, with AA and characterized such registered patients using a large spontaneous adverse event reporting database. Data from the Food and Drug Administration's Adverse Event Reporting System spanning from the first quarter of 2015 to the second quarter of 2023 were used. Disproportionality analyses with reporting odds ratio (ROR) and information component (IC) were performed for signal detection. Furthermore, we described a case series of patients who experienced AA during osimertinib treatment. A signal was detected with osimertinib (ROR: 4.16, 95% confidence interval (CI): 2.54 - 6.80; IC: 1.80, 95% CI: 1.10 - 2.51); however, no signals were detected with other EGFR-TKIs. 16 individuals treated with osimertinib had AA, of whom 14 (87.5%) were registered as suspected drugs. The median age of these individuals was 70.5 years (interquartile range (IQR), 64.8 - 78.3 years), with varying time to onset (IQR, 4 - 210 days) and outcomes, including 3 (18.8%) deaths. Our analyses generated a safety signal for the association between osimertinib and AA. Further studies are required to understand and confirm the role of osimertinib administration in the development of AA.

Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

EGFR-TKIs or EGFR-TKIs combination treatments for untreated advanced EGFR-mutated NSCLC: a network meta-analysis

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC.MethodsWe searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach.ResultsWe identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events.ConclusionThese results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates.