Oral Tyrosine Kinase Inhibitor Research Articles

Solid Self Nano-Emulsifying Drug Delivery System of Dasatinib: Optimization, In-vitro, Ex-vivo and In-vivo assessment.

Aim: Dasatinib (DST) is an oral tyrosine kinase inhibitor with poor aqueous solubility. To outwit this issue, a solid self-nano emulsifying drug delivery system (S-SNEDDS) of DST was formulated.Methods: I-optimal mixture design was used for optimization of DST-loaded SNEDDS using Linalool, Cremophor RH40 and Transcutol P. S-SNEDDS underwent physicochemical characterization, in-vitro release and ex-vivo permeation, cell-based assays and pharmacokinetic study.Results: DST-S-SNEDDS showed globule size and PDI of 141.53±5.371nm and 0.282±0.020, respectively. DST-S-SNEDDS revealed significantly lower IC50 (1.825μg/mL) than free DST (7.298μg/mL) in MDA-MB-231. In-vivo pharmacokinetic study revealed 1.94-fold increment in AUC0-t for the DST-S-SNEDDS group than free DST.Conclusion: S-SNEDDS could be promising approach for improving bioavailability and efficacy of DST.

CML-396 Safety, Tolerability, Pharmacokinetics, and the Effect of Food on TERN-701, an Oral Allosteric BCR-ABL Tyrosine Kinase Inhibitor, in Healthy Participants

CML-396 Safety, Tolerability, Pharmacokinetics, and the Effect of Food on TERN-701, an Oral Allosteric BCR-ABL Tyrosine Kinase Inhibitor, in Healthy Participants

Efficacy and safety of transarterial chemoembolization alone compared to its combination with anlotinib among patients with intermediate or advanced stage hepatocellular carcinoma: a phase II randomized controlled trial.

Anlotinib hydrochloride is a potent oral multitargeted tyrosine kinase inhibitor that targets VEGFR1-3, FGFR1-4, and PDGFR α/β, demonstrating significant antiangiogenic activity. Transcatheter arterial chemoembolization (TACE) is considered the effective treatment for intermediate/advanced hepatocellular carcinoma (HCC), which remains a major global health challenge. This study evaluated the relative efficacy and safety of combining anlotinib with TACE against the standard TACE monotherapy among patients with intermediate or advanced HCC. This phase II randomized controlled trial included 38 patients diagnosed with intermediate or advanced HCC. Patients were randomly assigned to receive either TACE in combination with anlotinib or TACE alone. The primary endpoint of the study was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. This trial aimed to determine whether the addition of anlotinib could extend PFS and improve other clinical outcomes compared to TACE alone. The median PFS for patients treated with TACE and anlotinib was significantly longer at 11.04 months compared to 6.87 months in the TACE-alone group [hazard ratio (HR) 0.46; P=0.02], indicating a robust enhancement in disease management. Although the median OS was not reached at the time of analysis, early trends suggest potential improvement. Both treatment groups had comparable ORR and DCR, demonstrating effective disease control. The safety profile of the combined treatment was manageable, with side effects similar in nature to those observed with TACE alone but not significantly more severe, thus maintaining patient quality of life. The addition of anlotinib to TACE appears to provide a safe and effective therapeutic benefit for patients with intermediate or advanced-stage HCC. However, longer follow-up is needed for a more comprehensive efficacy assessment. ClinicalTrials.gov NCT04066543.

Safety, Tolerability, Pharmacokinetics, and the Effect of Food on TERN-701, an Oral Allosteric BCR-ABL Tyrosine Kinase Inhibitor, in Healthy Participants

Safety, Tolerability, Pharmacokinetics, and the Effect of Food on TERN-701, an Oral Allosteric BCR-ABL Tyrosine Kinase Inhibitor, in Healthy Participants

Advances and future directions in ROS1 fusion-positive lung cancer.

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

Lorlatinib experience in a patient with ALK + non-small cell lung cancer on hemodialysis: A case report.

Lorlatinib is a potent third-generation anaplastic lymphoma kinase/c-ros oncogene 1 (ALK)/ROS1 oral tyrosine kinase inhibitor that has broad coverage of acquired resistance mutations and is currently indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ALK-positive. In this case, we aimed to present the safety and effectiveness of lorlatinib use in a patient diagnosed with ALK-positive metastatic NSCLC who underwent hemodialysis 3 days a week. A 76-year-old female patient has been undergoing regular hemodialysis for about 2 years. A brain magnetic resonance imaging (MRI) was taken due to headache and a mass was detected. She was diagnosed with lung adenocarcinoma as a result of excisional biopsy. Positron emission tomography/ computed tomography (PET/CT) showed a mass in the hilar region of the left lung and multiple lymphadenopathy in the mediastinum. In February 2023, 100 mg lorlatinib was started daily. There was no significant regression in PET-CT and no brain MRI residue during follow-up. The patient has been continuing lorlatinib for approximately 1 year with almost complete response, with no side effects other than hypercholesterolemia. We presented our experience using lorlatinib in a patient with metastatic ALK + NSCLC undergoing hemodialysis. Although the dosage of lorlatinib in hemodialysis patients is still controversial, our case report indicates that 100 mg lorlatinib was safe in this patient.

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.

TPS219 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773 .

Post-marketing safety surveillance of fostamatinib: an observational, pharmacovigilance study leveraging FAERS database

ABSTRACT Objective Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use. Methods The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days. Conclusion Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Nanoparticle-based targeted therapy through EGFR tyrosine kinase inhibitors and their recent advances in lung cancer therapy

The emergence and subsequent advancement of nanotechnology in recent years have greatly benefited the healthcare sector, particularly in the treatment of cancer. As per study, major fatalities are related to the lung cancer. For many years, oral tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor (EGFR) family of receptors have been used in the clinic to treat human malignancies, although they observed some very serious adverse effects in the treatment of lung cancer, especially in non-small cell lung cancer (NSCLC). Despite EGFR-TKIs’ exceptional qualities as small-molecule targeted medications, their applicability is nevertheless limited by their poor solubility, inconsistent oral bioavailability, high daily dose needs, high plasma albumin binding propensity, and initial/acquired drug resistance. Article’s purpose is to investigate EGFR-TKI’s effects on lung cancer and get around some of its drawbacks, nanotechnology will be an innovative strategy. An effective tool to increase the effectiveness of these pharmaceuticals is nanotechnology by methods other than oral. This article signifies that a range of nanomedicine delivery systems have been developed to effectively distribute EGFR-TKIs with improved drug release kinetics and tissue-targeting capacity. This review article intends to present information regarding lung cancer and EGFR relation, mechanism of recently approved EGFR-TKI’s targeted therapy, an updated landscape of EGFR-TKIs and their clinical status over lung cancer, advantages and disadvantages of nanotechnology, and new breakthroughs in nano-delivery which mentioned as a significantly better over traditional drug chemotherapy and delivery.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

NFS-11. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

Abstract BACKGROUND Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS). METHODS Eligible participants were age &amp;gt;5 years with a clinical diagnosis of neurofibromatosis type 2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL). RESULTS Twelve participants were enrolled and eight completed 12 cycles, including two pediatric patients. Two patients were non-evaluable due to coming off study prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for non-compliance. Due to slowing accrual, the study closed prior to meeting planned enrollment of 17 evaluable patients. Ten patients were evaluable for the primary endpoint, defined as ≥20% decrease in VS volume, with two volumetric responses observed; both were reached after three cycles and sustained during treatment. Best volumetric response was −53.9% after nine cycles. Hearing response was evaluable in nine participants, with three hearing responses observed, one of which was sustained during treatment. All participants experienced drug-related toxicities, the most common were diarrhea, hematuria and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment in all participants. CONCLUSIONS Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. The convenience of oral administration appears to be offset, however, by increased toxicity and lower response rates compared to VEGF-A targeted therapy with bevacizumab.

Clinical efficacy of pyrotinib combined with stereotactic radiosurgery in HER2-positive breast cancer brain metastases.

e13017 Background: Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system(CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. Methods: This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guangdong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. Results: 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). Conclusions: Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.

The feasibility and tolerability of anlotinib plus PD-1 blockades among patients with previously immunotherapy treated advanced esophageal squamous cell carcinoma (ESCC): Update results of a retrospective exploratory study.

e16006 Background: Immunotherapy (ICI) demonstrated promising efficacy for patients with advanced ESCC in both second-line and first-line treatment clinically. Therefore, whether the patients might benefit from the PD-1 blockades-related regimens when they failed after the previous ICI remained to be identified and the feasibility of PD-1 blockades rechallenge in ESCC was warranted to be explored. As a novel oral multi-targeted tyrosine kinase inhibitor (TKI) for tumor angiogenesis and proliferation, anlotinib was an efficacious second-line monotherapy for ESCC in China and the combination of anlotinib plus PD-1 blockades might be a promising strategy for patients with previously ICI treated advanced ESCC. Methods: This multicenter, retrospective study was planned to include 110 patients with previously ICI treated advanced ESCC from 9 hospitals in China who were treated with anlotinib plus PD-1 blockades in clinical practice from July 2018 to November 2022 consecutively. The Outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Results: At the date of data-cutoff (May 12 2023), 110 eligible patients were available to be analyzed. Characteristics were as follows: median age of 64 years, male/female 74.5%/25.5%, ECOG PS 0/1/2 22.7%/75.5%/1.8%, clinical stage II/III/IV 0.9%/20.9%/78.2%. All the patients had received ICIs and 10.9% patients were treated with TKIs previously. 39.1% patients had received first-line therapy, 41.8% patients had received second-line, 19.1% patients had received third or above line previously. Prognostic outcomes exhibited that the median OS was 11.1 months (95%CI: 8.6-13.7), 12-month OS rate, 24-month OS rate were 47.6% and 30.8%, separately. Additionally, the median PFS was 5.6 months (95%CI: 4.4-6.8). In 110 patients, ORR was 19.1% (95%CI: 12.2%-27.7%), DCR 69.1% (95%CI: 59.6%-77.6%). Safety profile of anlotinib plus PD-1 blockades indicated that the treatment related adverse events (TRAEs) were 89.1%. The most common TRAEs were anaemia (62.7%), hypothyroidism (25.5%), hypoalbuminemia (21.8%), lymphocytopenia (20%), leukopenia (19.1%). Conclusions: Anlotinib plus PD-1 blockades demonstrated encouraging efficacy and tolerable adverse reactions among patients with advanced ESCC who had received immunotherapy previously and the feasibility of PD-1 blockades rechallenge in ESCC was promising to be elucidated. Clinical trial information: ChiCTR2300070777.

Pyrotinib in HER2-altered advanced salivary gland carcinomas: Analysis of two cohorts from an exploratory study.

6108 Background: The HER2 altered in a subset of salivary gland cancers (SGCs). Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting HER1, HER2, and HER4. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-amplified/overexpressed/mutated advanced SGCs, including recurrent/metastatic(R/M) and locally advanced (LA) patients with high-risk of recurrence. Methods: R/M and high-risk LA SGCs with HER2-alteration were enrolled. Pyrotinib (400 mg) was given orally once daily. In LA cohort, pyrotinib were given as adjuvant therapy after standard surgery and postoperative radiation. Results: Between August 2019 and August 2023, 18 patients were enrolled (10 in R/M cohort and 8 in LA cohort). In R/M cohort, the median age was 58.5 years, and all patients were grade III. The ORR was 90%, including 2 CRs, 7 PRs and 1PD; median DOR was 5.7 months (range: 3.1-13.7) and median PFS was 7.6 months (range: 2.7-16.8). In LA cohort, the median age was 59.0 years, and all patients but one were grade III. All patients but one had T4 disease; 5 patients had N3 and 2 had N2b disease; 5 patients had ENE and 5 patients had positive margin. With a median follow up 21.3 months, only 3 patients experienced recurrence, and one patient died due to non-tumor reasons. The estimated 2-years PFS and 2-years OS were 75% and 100%. The most common adverse event was diarrhea, which occurred in 11/18 (61.1%) patients and 3/18 (16.7%) were grade III. Conclusions: Pyrotinib showed promising antitumor activity in recurrent/metastatic HER2-altered SGCs, and had a potential to prolong survival outcome as adjuvant treatment in LA patients setting, which needs further randomized studies. Clinical trial information: NCT05087706 .

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (EGFR) mutations.

TPS8670 Background: Patients with NSCLC harboring uncommon EGFR mutations, including ex20ins, have limited treatment options. Zipalertinib (CLN-081/TAS6417) is an oral tyrosine kinase inhibitor of EGFR with broad activity against EGFRmutations (including ex20ins) and increased selectivity for ex20ins versus wild-type EGFR. Zipalertinib has shown preclinical activity against a wide spectrum of EGFR ex20ins mutations and other uncommon EGFR mutations. In a phase 1/2a study (REZILIENT1), encouraging antitumor activity and an acceptable safety profile were observed in heavily pretreated patients with EGFRex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation from the U.S. Food and Drug Administration. The aim of REZILIENT2 is to evaluate the efficacy and safety of zipalertinib in patients with NSCLC harboring EGFRex20ins and other uncommon single or compound EGFR mutations, including patients with brain metastases and leptomeningeal disease (LMD). Methods: In this global, phase 2b, open-label, multicohort study (NCT05967689), adult patients with locally advanced or metastatic NSCLC will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation: A) patients with EGFR ex20ins mutations who have progressed on or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins (administered together or separately) for advanced disease; B) patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease; C) patients with ex20ins or other uncommon single or compound EGFR mutations and active central nervous system metastases (including LMD) who may or may not have received prior treatment for advanced disease; and D) patients harboring other uncommon non-ex20ins single or compound EGFR mutations who have progressed on or after standard systemic therapy. Patients will receive zipalertinib at a starting dose of 100 mg orally twice daily, which will continue on a 21-day cycle until progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumours, version 1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (cohort C), safety and tolerability, and pharmacokinetics. Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023. Clinical trial information: NCT05967689 .

Efficacy and safety of fruquintinib across different subgroups of patients with previously treated metastatic colorectal cancer: A meta-analysis.

e15589 Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p &lt; 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p &lt; 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p &lt; 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p &lt; 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p &lt; 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p &lt; 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]

In vitro inhibitory effects of selumetinib on activity of human UDP-glucuronosyltransferases and prediction of in vivo drug-drug interactions

Selumetinib is an oral, effective, and selective tyrosine kinase inhibitor targeting mitogen-activated protein kinase 1 and 2 (MEK1/2), which is clinically active in multiple tumor types, such as neurofibromatosis type 1 (NF1), melanoma, gliomas and non-small cell lung cancer (NSCLC). The purpose of this article was to assess the effects of selumetinib on the activities of twelve human UDP-glucosyltransferases (UGTs) including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17, and its potential for inducing clinical drug-drug interactions (DDIs). The results demonstrated that selumetinib potently inhibited the activity of UGT2B7 through the mechanism of mixed inhibition with the inhibition constant value of 5.79 ± 0.65 μM. Furthermore, the plasma concentration of UGT2B7 substrate as the co-administered drug was predicted to be increased by at least 84 % when patients took selumetinib 75 mg twice daily, suggesting a high potential to induce clinical DDIs. Selumetinib exhibited weak inhibitory effects on other human UGTs and was unlikely to trigger off UGTs-mediated DDIs except for UGT2B7. Therefore, the combination of selumetinib with the substrate drug of UGT2B7 requires additional attention to avoid adverse events in clinical treatment.

Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) frequently harbors mutations in the epidermal growth factor receptor (EGFR), with exon 20 insertions comprising 1-10% of these mutations. EGFR exon 20 insertions are less responsive to conventional tyrosine kinase inhibitors (TKIs), leading to the development of targeted agents. This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Amivantamab, a bispecific antibody-targeting EGFR and c-MET, demonstrates significant efficacy, particularly when combined with chemotherapy. Mobocertinib, a TKI, selectively targets EGFR exon 20 mutations but faces limitations in efficacy. Poziotinib, another oral TKI, shows mixed results due to mutation-specific responses. Zipalertinib and Sunvozertinib have emerged as potent TKIs with promising clinical data. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling.

Abstract PO3-06-07: Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial

Abstract Background: Antiangiogenic drugs have demonstrated synergistic effect with anti-PD-1 antibody in advanced triple negative breast cancer (TNBC). Anlotinib is an oral multi-target tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Preclinical studies showed that metronomic chemotherapy inhibited angiogenesis and enhanced the efficacy of immunotherapy in TNBC via modulation of the tumor immune microenvironment. We hereby conducted a single-arm, multicenter, phase II trial to investigate the efficacy and safety of sintilimab (anti-PD-1 antibody) plus anlotinib and metronomic chemotherapy as a potential novel therapeutic strategy in advanced TNBC and explore potential biomarkers. Methods: Forty-four cases were planning to be included in this trial. The eligible patients who had received no more than two lines of chemotherapy for metastatic disease were enrolled and received sintilimab (200 mg iv q3w) and anlotinib (12 mg po d1-14 q3w) plus capecitabine (500 mg po, tid) or vinorelbine (40 mg po, tiw) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR) and secondary endpoints are disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Results: As of April 2023, a total of 44 patients were enrolled, and 42 patients were evaluable for efficacy. 3 patients (7.1%) achieved complete response (CR). 6 patients (14.3%) achieved partial response (PR). 25 patients (59.5%) achieved stable disease (SD).The ORR is 21.4% (95%CI 0.103-0.368) and DCR is 81.0% (95%CI 0.810-0.659). The median PFS was 5.06 months (95%CI 2.051-8.069). The most common grade 1 or 2 adverse events (AEs) include elevated thyroid stimulating hormone (52.38%, 22/42), elevated bilirubin (23.81%, 10/42), hand-foot syndrome (22.22%, 8/42), leukopenia (16.67%,7/42), nausea (14.29%, 6/42). Grade 3 AEs include elevated bilirubin (2.38%, 1/42), hypertension (2.38%, 1/42) and herpes zoster (2.38%, 1/42). No grade 4 or 5 AEs occurred. Conclusions: Our date showed that sintilimab in combination with anlotinib plus metronomic chemotherapy have shown favorable efficacy and acceptable safety profile in patients with advanced TNBC. Clinical trial information: ChiCTR2100044725 Citation Format: huihui Li, Dongdong Zhou, Zeshun Yv, Yuqian Liao, Jie Huang, Shujuan Sun, fangchao zheng, Baojiang Li, Shu Fang, Ling Qiang, Guohua Ren, Bing Bu, Pengfei Qiu, Xinzhao Wang, Chao Li, Fangli Cao, Qian Shao, Dali Han, Lihua Song, Baoxuan Zhang, Bingjie Fan, Liang Xu, Xuemei Xie, Xianguang Zhao, Lanping Liu, Wanlong Li, Zhenbo Wang, Changmin Liu, Hui Fu, Xiao Sun, Zhiqiang Shi, Fengxiang Li. Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-07.