Third-generation Tyrosine Kinase Inhibitors Research Articles

Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance.

Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of BCR::ABL1 are the most extensively studied mechanism of TKI resistance in CML, but BCR::ABL1-independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML.

Safety profile of lorlatinib: correction of adverse events

Lorlatinib is a new third-generation tyrosine kinase (TKI) inhibitor of ALK/ROS1, which has antitumour activity against most of the known mutations of resistance to crizotinib and second-generation TKI, as well as high intracranial efficacy. The safety of lorlatinib was evaluated in a multi-cohort phase I study involving 295 patients receiving the recommended dose of lorlatinib 100 mg once a day. Adverse events of lorlatinib were mainly mild to moderate severity. The most frequent complications – hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%) and side effects from the central nervous system (39.7%), were reversible and well controlled by dose modification and concomitant therapy, as evidenced by the low frequency of discontinuation of therapy due to adverse reactions. The majority of patients (81.0%) required the appointment of at least one hypolipidemic drug. When prescribing concomitant therapy, the possibility of drug interaction with lorlatinib, whose metabolism is carried out with the participation of specific CYP450 enzymes, should also be taken into account. Based on the presented results, an expert consensus opinion was developed on the correction of the main adverse reactions, including hyperlipidemia, complications from the central nervous system, weight gain, edema, peripheral neuropathy and others. No new adverse events were reported in the CROWN Phase III study conducted later. Lorlatinib has a characteristic toxicity profile, which must be taken into account for successful long-term targeted therapy while maintaining a good quality of life for patients. In the Russian Federation, the drug is approved for use in a wide clinical practice both for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) in the first line, and after progression to second-generation TKI. The article presents recommendations for the correction of the main adverse events of lorlatinib, as well as their own experience in managing patients.

Safety of lorlatinib in ALK-positivenon-small-cell lung cancer and management of central nervous system adverse events.

The use of tyrosine kinase inhibitors has made a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Recently, lorlatinib, a third-generation tyrosine kinase inhibitor, has demonstrated significant systemic and intracranial activity in both first-line and subsequent-line therapy in ALK-positive NSCLC patients. In this review, general characteristics of lorlatinib, its efficacy in the treatment of ALK-positive NSCLC patients and the safety of lorlatinib, particularly addressing central nervous system adverse events, are discussed. Management of central nervous system adverse events, which seem to be specific to lorlatinib therapy, is outlined.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Clinical Utility of Mobocertinib in the Treatment of NSCLC - Patient Selection and Reported Outcomes.

Mobocertinib is an oral tyrosine kinase inhibitor (TKI) that selectively targets epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations. It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. This is accomplished via a carboxylated isopropyl ester moiety at the C5-position of mobocertinib's central pyrimidine core. In Phase 1/2 dose-escalation and dose-expansion studies, mobocertinib was found to have an investigator-confirmed overall response rate (ORR) of 56% (9/16; 95% CI: 30-80%) and 25% (3/12; 95% CI: 5-57%) in patients without and with baseline brain metastasis, respectively. Median investigator-assessed progression-free survival (mPFS) was 10.2 months (95% CI: 5.6 - not reached) and 3.7 months (95% CI: 1.8-15.9) in patients without and with baseline brain metastasis, respectively. A third phase evaluated patients who had received pre-treatment with platinum-based chemotherapy (PPP) and included an extension cohort (EXCLAIM cohort) which evaluated patients treated previously with 1 or 2 lines of therapy. An Independent Review Committee (IRC) found both cohorts to have similar outcomes in terms of ORR, median time to response, mPFS, and disease progression or death. The treatment-emergent adverse events (TEAE) related to mobocertinib are similar to other EGFR inhibitors and are predominately gastrointestinal (eg diarrhea, nausea, vomiting) and cutaneous (eg rash). In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.

System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells

BackgroundBCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PurposeTo study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. MethodsCytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\\ Sca-1+ \\C-kit+) self-renewal. ResultsTreatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. ConclusionFrom the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

Continuation of Third-Generation Tyrosine Kinase Inhibitors in Second-Line Trials for EGFR-Mutated Non-Small-Cell Lung Cancer: Regulatory Considerations.

Continuation of Third-Generation Tyrosine Kinase Inhibitors in Second-Line Trials for EGFR-Mutated Non-Small-Cell Lung Cancer: Regulatory Considerations.

Chronic myeloid leukemia, tyrosine kinase inhibitors and cardiovascular system.

Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Use of a systems-biology informed machine learning model to predict drug response using clinically available NGS data.

3136 Background: Tremendous progress towards understanding the molecular underpinnings of cancer has ushered in an era of precision medicine, where actionable biomarkers inform rational design of novel drugs, repurposing of existing medications or new combination therapies, agnostic of tumor type. However less than 20% of cancer patients match to therapies using existing predictive biomarkers. There is therefore an acute need for new methods to expand the population of patients who could benefit from existing drugs and improve patient selection and design of clinical trials evaluating new or repurposed drugs. Methods: We developed systems biology-informed AI methods trained on vast multi-omics and multi-modal datasets from DepMap, TCGA and other publicly available sources, to uncover latent vulnerabilities existing in tumors. These vulnerabilities map to pharmacological sensitivities and can be assigned to individual patients using clinically available molecular data. To evaluate our model, we focused on predicting sensitivities to a third-generation tyrosine kinase inhibitor (TKI), which we assessed in non-small cell lung cancer (NSCLC) cell lines, patient derived xenografts (PDXs) and a clinicogenomics cohort from AACR Project GENIE (n=2004 patients, n=273 patients treated with TKI of interest). Where applicable, whole exome data used as input for validation model predictions were filtered to ~300 genes included on commercial NGS panels to reflect data available in RWD cohorts. Results: Our model accurately predicts response to the TKI across diverse cancer cell lines with high accuracy (r2= 0.768; rho= 0.83; mean absolute error = 0.065). Using NSCLC cancer cell lines and PDX model systems heterogeneous for this TKI’s current FDA molecular label (but within the scope of the drug’s current cancer indication), we were able to further validate our model’s predictions, show they were not dependent on obvious molecular confounders, and demonstrate a potential label expansion opportunity for this drug beyond the current narrow molecular label. While all NSCLC patients from AACR Project GENIE treated with this TKI were “on label”, NSCLC patients our model predicted to be sensitive to the TKI had a 4-month increased median PFS compared to patients predicted to be less sensitive (Log-rank test p-value< 0.05; HR= 1.64; 1.23-2.22, 95% CI). The PFS partition was not due to obvious clinical confounders such as stage (p= 0.91), age (p=0.86), sex (p=0.63), smoking status (p=0.57) or on-target mutations (p=0.70). Biological networks associated with each prediction provide rich context and highlight a putative rational drug combination strategy for this drug. Conclusions: We have developed an ML model that uses clinically obtainable NGS data to accurately predict increased sensitivity to a third-generation TKI validated in NSCLC cell lines, PDX models and a RWD patient cohort.

The Maverick trial: A phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).

TPS5106 Background: Abivertinib is a potent, small molecule third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), Bruton tyrosine kinase (BTK) receptor, and bone marrow tyrosine kinase gene on chromosome X (BMX). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor, and also BMX. The adrenal-permissive HSD3B1(1245C) allele, which is present in upwards of 50% of men with prostate cancer, encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from extragonadal precursor steroids and promotes poor clinical outcomes. 3βHSD1 must be phosphorylated by BMX for androgen biosynthesis. Preclinical studies suggest BMX inhibition blocks 3βHSD1, androgen biosynthesis and CRPC in xenograft models. These provide the rationale for use of the combination of abivertinib and abiraterone to block residual androgen synthesis that escapes abiraterone inhibition. Methods: The Maverick Trial is a multicenter, open-label phase 2 study within the US Dept of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC) of abivertinib with abiraterone in pts with mCRPC harboring the adrenal-permissive HSD3B1(1245C) allele (germline heterozygous or homozygous). HSD3B1 status will be confirmed centrally prior to enrollment via CLIA testing at the Cleveland Clinic. The study includes two cohorts: abiraterone-naïve and abiraterone-progressing. There will be cap of 50% of accrual in each cohort for pts heterozygous for the HSD3B1(1245C) allele. An interim futility analysis is embedded in each cohort, and toxicity rates will be continuously monitored for early stoppage according to predefined rules. Pts receive continuous treatment with abivertinib 200 mg BID with abiraterone 1000 mg QD + prednisone 5 mg BID until radiographic progression, unacceptable toxicity, intercurrent illness, or other reason, such as subject withdrawal. The primary endpoint is 6-month rPFS defined as percent of subjects alive and without progression by RECIST version 1.1 for measurable disease and PCWG3 criteria for bone metastases. Secondary and exploratory endpoints include objective response rate, duration of response, PSA progression, pharmacokinetics, pharmacodynamic tissue changes, and mechanisms of response and resistance to therapy via sequential tissue and blood sampling. The study is currently open at 1 site and will activate at 9 additional sites. It is sponsored by Sorrento Therapeutics, Inc, and managed by the Prostate Cancer Clinical Trials Consortium. Trial Registration: NCT05361915 Funding Source: Sorrento Therapeutics, Inc, the trial’s sponsor who is funding the trial. Clinical trial information: NCT05361915 .

Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.

9110 Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .

The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications.

Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody-drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies.

Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs' resistance.

Biological Electric Fields Guide Directional Migration and Promote Epithelial–Mesenchymal Transition in Lung Cancer

Background: Endogenous direct-current electric fields (dcEFs), as one of the essential biophysical signals that naturally occur in the tumor microenvironment, were previously demonstrated to suppress the cytotoxicity of the third-generation tyrosine kinase inhibitor osimertinib in epidermal growth factor receptor (EGFR)-mutant lung cancer. Materials and Methods: In the current study, we further investigated the electrotactic response of EGFR-mutant lung cancer with different osimertinib sensitivity, including osimertinib-sensitive PC-9GR cells and osimertinib-resistant PC-9GROR cells. Results: Firstly, in murine subcutaneous xenografts, robust endogenous electric currents were detected at the surface of tumors derived from osimertinib-resistant cells with a highly sensitive vibrating probe. Next, the electrotactic responses of two cell lines under EFs of different intensities were studied. Both PC-9GR and PC-9GROR cells exhibited directionally cathodal migration in a voltage-dependent manner, and osimertinib-resistant PC-9GROR cells displayed higher migration speeds. Epithelial-mesenchymal transition (EMT), which was previously reported to be closely related to tumor invasion and metastasis and could be suppressed by osimertinib, was enhanced under EF stimulation as reflected by increased vimentin and decreased E-cadherin in PC-9GR cells via western blotting and immunofluorescent staining regardless of osimertinib treatment. Additionally, pharmacological inhibition of phosphoinositide 3-kinase/protein kinase B (AKT) signals reduced electrotaxis and EMT. Conclusion: Taken together, these results suggested that activation of AKT pathway may play an important role in electrotaxis and EMT of EGFR-mutant lung cancer.

Sequential administration of PD‑1 inhibitor and cetuximab causes pneumonia.

Severe drug-induced lung injury (DLI) has been reported to be associated with sequential administration of osimertinib, a third-generation tyrosine kinase inhibitor, following a programmed cell death ligand 1 (PD-L1) inhibitor. However, the relationship of sequential treatment with an anti-epidermal growth factor receptor (EGFR) antibody and PD-1 inhibitor with the risk of DLI remains to be elucidated. The present study conducted a retrospective review of the medical records of a total of 179 patients with head and neck cancer who had received treatment with cetuximab and/or a PD-1 inhibitor (nivolumab or pembrolizumab) at Chiba University Hospital (Chiba, Japan) between September 2014 and December 2020. The incidence of pneumonia and the clinical background characteristics of the patients were analyzed. The patients were classified into subgroups for analysis of the outcomes in this study: Patients who had received sequential, but not concurrent, cetuximab and PD-1 inhibitor treatment (Group C+P; n=43); patients who had received cetuximab-containing chemotherapy, but not a PD-1 inhibitor (Group C; n=101); and patients who had received PD-1 inhibitor-containing chemotherapy, but not cetuximab (Group P; n=35). The rates of DLI in the three groups were: Group C+P, 18.6%; Group C, 7.9%; and Group P, 11.4%. Prior use of ICI was not associated with any increase in the risk of DLI. DLI is seen frequently in patients receiving sequential PD-1 inhibitor and anti-EGFR antibody therapy.

Regulation of dendritic cell maturation in osimertinib-treated lung adenocarcinoma patients

Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N=10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.

Abstract #1394296: The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient’s DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient’s oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.

Synthesis and preclinical evaluation of two osimertinib isotopologues labeled with carbon-11 as PET tracers targeting the tyrosine kinase domain of the epidermal growth factor receptor

IntroductionOsimertinib is a third-generation tyrosine kinase inhibitor (TKI) that is able to inhibit the EGFR treatment resistance mutation T790M and primary EGFR mutations Del19 and L858R. The aim of the study was to evaluate the potential of carbon-11 labeled osimertinib to be used as a tracer for the PET imaging of tumors bearing the T790M mutation. MethodsOsimertinib was labeled with carbon-11 at two positions, and the effect of the labeling position on the metabolism and biodistribution was studied in female nu/nu mice. The mutation status specificity of osimertinib was confirmed in vitro in a cell growth inhibition experiment, and the tumor-targeting potential of the carbon-11 isotopologues was evaluated using female nu/nu mice xenografted with NSCLC cell lines; the wild-type EGFR expressing A549, the primary Del19 EGFR mutated HCC827 and the resistance T790M/L858R mutated H1975. One of the osimertinib tracers was selected based on the results acquired and evaluated for tracer specificity and selectivity by assessment of tumor uptake in a PET study where HCC827 tumor-bearing mice were pretreated with osimertinib or afatinib. Results[Methylindole-11C]- and [dimethylamine-11C]osimertinib were synthesized by 11C-methylation of precursors AZ5104 and AZ7550, respectively. Rapid metabolism of both analogs of [11C]osimertinib was observed. Although the tumor uptake and retention of [methylindole-11C]- and [dimethylamine-11C]osimertinib in tumors were similar, the tumor-to-muscle ratios appeared to be higher for [methylindole-11C]osimertinib. The highest uptake, tumor-to-blood, and tumor-to-muscle ratio were observed in the Del19 EGFR mutated HCC827 tumors. However, the specificity and selectivity of [methylindole-11C]osimertinib PET could not be demonstrated in HCC827 tumors. The uptake of [methylindole-11C]osimertinib was not significantly higher in T790M resistance mutated H1975 xenografts compared to the negative control cell line A549. ConclusionsOsimertinib was successfully labeled at two positions with carbon-11, yielding two EGFR PET tracers, [methylindole-11C]osimertinib and [dimethylamine-11C]osimertinib. The preclinical evaluation demonstrated uptake and retention in three NSCLC xenografts; A549, HCC827, and H1975. The highest uptake was observed in the primary Del19 EGFR mutated HCC827. The ability of [methylindole-11C]osimertinib to distinguish between the T790M resistance mutated H1975 xenografts and the wild-type EGFR expressing A549 could not be confirmed in the ex vivo study.

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management.

Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real-world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio-oncologists, one vascular surgeon, one haemato-oncology pharmacist and one specialist nurse practitioner. The panel recommended that patients commencing second-/third-generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision-making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.

Abstract 1631: Combination of olverembatinib (HQP1351) with BCL-2 inhibitor lisaftoclax (APG-2575) overcomes resistance in gastrointestinal stromal tumors (GISTs)

Abstract GISTs are common malignant mesenchymal tumors that occur in the GI tract, with an estimated incidence rate of 1% to 2%. About 75% to 80% of patients with GIST have mutations in the KIT gene, while 5% to 10% have mutations in the platelet-derived growth factor receptor α (PDGFRA) gene. Tyrosine kinase inhibitors (TKIs) offer patients an improved quality of life but increased pharmacological resistance to TKIs is often observed. BCL-2 is expressed in &amp;gt;80% of GISTs, and amplification of BCL-2 and BCL-xL are common features associated with disease progression. One approach to enhance GIST eradication is to concurrently inhibit oncogenic KIT signaling while actively engaging apoptotic pathways. Olverembatinib (HQP1351) is a new, third-generation TKI that targets BCR-ABL1, KIT and PDGFRA and is currently in development for relapsed or refractory chronic myeloid leukemia and GIST. Lisaftoclax (APG-2575) is a selective BCL-2 inhibitor under development for hematologic malignancies. The purpose of this study was to evaluate whether combining a BCL-2 inhibitor, lisaftoclax, with olverembatinib enhances treatment effect on imatinib-resistant GISTs. Compared to imatinib-sensitive GIST cell lines (GIST882 and GIST-T1), increased BCL-2 protein expression was observed in imatinib-resistant GIST cells, particularly in GIST430, GIST48, and GIST48B lines. Cell-based antiproliferation studies showed additive activity of olverembatinib and lisaftoclax in imatinib-resistant GIST cells. In vivo studies using imatinib-resistant GIST430 cell-derived xenograft models further revealed that coadministration of olverembatinib at 15 mg/kg (every other day for 3 weeks) with lisaftoclax at 50 mg/kg (daily for 3 weeks) resulted in enhanced antitumor effects compared to either agent alone. Tumor growth inhibition (TGI) rates for combined treatment with olverembatinib and lisaftoclax reached 76.8%, which was superior to the TGI rate of either agent alone: 57.6% and 31.2% for olverembatinib and lisaftoclax, respectively. Regarding putative mechanisms, olverembatinib treatment was shown to downregulate BCL-xL and MCL-1 protein expression, possibly via inhibition of KIT signal pathway and downstream signal transducer and activator of transcription 3 (STAT3). Lisaftoclax triggered apoptosis by disrupting the BCL-2:BIM complex. Therefore, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly augmented cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1), thus triggering apoptosis and subsequently enhancing antitumor effects. Our results demonstrate that olverembatinib and BCL-2 inhibitor lisaftoclax have additive antitumor effects in imatinib-resistant GIST. This novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with TKIs. Citation Format: Ping Min, Guangfeng Wang, Eric Liang, Bingxing Wu, Huidan Yu, Dajun Yang, Yifan Zhai. Combination of olverembatinib (HQP1351) with BCL-2 inhibitor lisaftoclax (APG-2575) overcomes resistance in gastrointestinal stromal tumors (GISTs) [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 1631.