Approved Tyrosine Kinase Inhibitors Research Articles

A new face in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia.

The prognosis for patients with relapsed/refractory or measurable (minimal) residual disease-positive Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia (ALL) is poor. Currently, ponatinib is the only approved tyrosine kinase inhibitor (TKI) that is effective for Ph-positive ALL with the T315I mutation. Although the report by Liu etal. is a retrospective observational study, it offers prospects for the efficacy of chemotherapy combined with the novel third-generation TKI, olverembatinib, in these conditions, which may be validated in future prospective clinical trials. Commentary on: Liu etal. Efficacy and safety of olverembatinib in adult BCR::ABL1-positive ALL with T315I mutation or relapsed/refractory disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19804.

Programming tumor evolution with selection gene drives to proactively combat drug resistance.

Most targeted anticancer therapies fail due to drug resistance evolution. Here we show that tumor evolution can be reproducibly redirected to engineer therapeutic opportunity, regardless of the exact ensemble of pre-existing genetic heterogeneity. We develop a selection gene drive system that is stably introduced into cancer cells and is composed of two genes, or switches, that couple an inducible fitness advantage with a shared fitness cost. Using stochastic models of evolutionary dynamics, we identify the design criteria for selection gene drives. We then build prototypes that harness the selective pressure of multiple approved tyrosine kinase inhibitors and employ therapeutic mechanisms as diverse as prodrug catalysis and immune activity induction. We show that selection gene drives can eradicate diverse forms of genetic resistance in vitro. Finally, we demonstrate that model-informed switch engagement effectively targets pre-existing resistance in mouse models of solid tumors. These results establish selection gene drives as a powerful framework for evolution-guided anticancer therapy.

Abstract 1979: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations

Abstract Background: Oncogenic mutations and gene amplifications in the HER2 receptor tyrosine kinase are detected in approximately 2 - 4% and 1 - 5%, respectively, of non-small cell lung cancers (NSCLC) in the US. Exon 20 insertion mutations (exon20ins) are the predominant HER2 mutations in NSCLC, and ~50% of HER2-mutant metastatic NSCLC patients develop brain metastases. The antibody drug conjugate trastuzumab deruxtecan (T-DXd) has received FDA accelerated approval for HER2-mutant NSCLC, but currently there are no approved tyrosine kinase inhibitors (TKIs) for this indication. NVL-330 is a novel, brain-penetrant, HER2-selective TKI, designed to address the combined medical need of treating HER2-mutant tumors, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases. Here we characterized the preclinical pharmacological profile of NVL-330 in comparison to other investigational HER2-targeting TKIs and T-DXd. Methods: TKIs were profiled in cellular phospho-HER2, phospho-EGFR, and viability assays. In vivo antitumor studies were performed in nude mice with HER2-altered subcutaneous or intracranial tumors. T-DXd concentration was measured in an ELISA assay. The unbound brain-to-plasma partitioning ratio (Κp,uu) was determined at one hour after oral 10 mg/kg dosing in Wistar Han rats. Results: NVL-330 broadly inhibited HER2 oncogenic alterations, including amplified wild-type HER2, HER2 exon20ins and non-exon20ins mutants, with potency and selectivity over wild-type EGFR comparable to investigational HER2-selective TKI zongertinib. By contrast, NVL-330 had a higher Kp,uu than zongertinib in rats. In a patient-derived xenograft model harboring HER2 exon20ins, treatment with NVL-330 suppressed phospho-HER2 and downstream signaling, increased total HER2 and caused dose-dependent tumor regression at well tolerated doses. In the HER2amp NCI-N87 subcutaneous xenograft model, oral administration of 30 mg/kg NVL-330 twice per day induced tumor regression, similar to that achieved by intravenous administration of 10 mg/kg T-DXd once every three weeks, a human-relevant dose in mice. By comparison, in the intracranial setting with the same tumor model and dosing regimens, NVL-330 induced tumor regression, whereas T-DXd provided tumor stasis. Pharmacokinetic analysis in these intracranial tumor bearing mice indicated that NVL-330 had significantly higher brain penetrance than T-DXd. Conclusions: NVL-330 was broadly and selectively active against HER2 oncogenic alterations in vitro and in vivo, and demonstrated brain penetrance in rodents exceeding that of HER2 investigational TKI zongertinib and T-DXd. This preclinical profile supports the potential for NVL-330 to address a medical need for patients with HER2-driven cancers, including those with brain metastases. Citation Format: Yuting Sun, Kristin L. Andrews, Anupong Tangpeerachaikul, Tuan M. Nguyen, Baudouin Gerard, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1979.

Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver.

Despite the development and approval of seven anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) spanning over three "generations" since the discovery of ALK fusion positive (ALK+) non-small cell lung cancer (NSCLC), there remains intrinsic and acquired resistances to these approved TKIs. Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis. However, EML4-ALK variant 3 and TP53 mutations are intrinsic genomic alterations that negatively modulate efficacy of ALK TKIs. Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non–Small Cell Lung Cancer

The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Mechanisms of Resistance in Non-Small Cell Lung Cancer

Objectives: Treatment of patients with non-small cell lung cancer continues to evolve and the discovery and approval of tyrosine kinase inhibitors in patients with NSCLC and targetable alterations brought an important contribution in treating these patients. Material and Methods: This review aims to describe the main alterations that can affect the signaling pathways involved in NSCLC, present the therapy that can target these alterations and describe the mechanisms that can determine resistance to targeted therapy. Literature research was performed on PubMed and Google Scholar and 60 relevant articles were selected for the purpose of our review. Discussion: The data of the present research were structured in nine paragraphs, each one presenting the main alterations that can affect the signaling pathways in patients diagnosed with NSCLC, targeted therapy used in managing these cases and mechanisms of resistance to targeted therapy. Conclusions: Testing for molecular biomarkers should be mandatory for every newly diagnosed NSCLC patient in order to offer the most appropriate treatment.

Incidence-Based Mortality Rates for Chronic Myeloid Leukemia (CML) in Adult US Populations By Gender and Race: The Aftermath of Tyrosine Kinase Inhibitors (TKIs)

Incidence-Based Mortality Rates For Chronic Myeloid Leukemia (CML) In Adult US Populations by Gender and Race: The Aftermath of Tyrosine Kinase Inhibitors (TKIs) Background: Chronic Myeloid Leukemia (CML) is one of the leading causes of Leukemia in North America and world wide. According to the American Cancer Society, 1 in 526 Americans will develop CML during their lifetime. CML accounts for about 15% of all new cases of leukemia. Estimates for new cases diagnosed in the United States in 2023 is about 8,930, with roughly 42% of these new cases in females and 58% in males. We looked at the incidence based mortality rates (probability of dying from) of CML by gender and race in adult populations in the United States from 2000-2019 via SEER.gov database. Methods: We used Incidence -Based Mortality SEER Research Data, 17 Registries, Nov 2021 Sub (2000-2019), which provides the broadest geographic coverage for incidence-based mortality rates and is roughly 26.5% of the US population (based on the 2020 Census) for the calculation of incidence rates of CML. SEER*Stat 8.4.1 was used to obtain age-adjusted rates for different age-groups, races and genders. We used Join-point software, version 5.0.2. by the National Cancer Institute, annually to create log-linear time trends. There are no P-values noted for the CI as Joinpoint does not currently produce a test statistic or p-value for Empirical Quantile confidence intervals. Results: Fig 1: CML Incidence Based Mortality Rate per 100,000 and age-adjusted to the 2000 US standard population for males and females 2000-2019 We identified a total of 1,183,747,806 diagnosed cases of CML between 2000-2019 among males and females in the United States. A dainty rise in the number of diagnosed cases was appreciated over the years, with 52,890,308 cases diagnosed in the year 2000 and 64,920,828 in the year 2019. The trend for CML among males show an increasing Incidence Based Mortality between 2000-2019 with an Average Annual Percent Change(AAPC) of 4.69%*CI 3.40 to 5.95), and 5.85%*(CI 4.54 to 8.35) in females. The AAPC for Whites, Black, American Indian/Alaska native and Asian or Pacific Islander were 5.51%* (95% CI 4.72 to 6.59), 2.03%*(95% CI 0.64 to 3.79), 3.12% (-2.15 to 10.78), and 2.42%*(95% CI 0.22 to 6.05) respectively. Conclusion: The denouement of our study shows a significant high rate of change in increasing incidence based mortality rate of CML in the US adult population from ages 20 years and older prior to 2002.The rate of change significantly drops after 2002, as noted in males, females and whites. Incidence based mortality was also noted to be significantly higher among males compared to females. Regarding race, the trend shows higher rates among whites and blacks compared to Asians or American Indians. The evidence points to some changes or events in or around the year 2002 that have significantly impacted the probability of dying from CML in the adult populations in the United States. This significant change coincides with the approval of Tyrosine Kinase inhibitors, with Imatinib (Gleevec) being the first one approved in 2001.

Disparities in dosing, drug reduction, and drug discontinuation among US FDA approved tyrosine kinase inhibitors

Background: Tyrosine kinase inhibitors (TKIs) have altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. However, patients are started on lower doses in practice. We assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs and observed the disparity among study populations to understand if there was adequate representation of diversity in race. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, race, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: Among all TKIs, median dose was 200 mg and average dose was 307.7 mg; 36 (24%) were approved bid vs 107 (72%) qd. Among approved indications, median rates of dose reduction rate (DRR), drug interruption rate (DIR), drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. Reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Black and Hispanic races are consistently underrepresented among the TKI studies. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate but these studies were done mostly in White individuals. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients while broadening the study population so that the studies will be generalizable to patients in clinical practice. Future studies are warranted to increase representation in the studies to address the disparities.

Evaluation of the effectiveness of a nationwide precision medicine program for patients with advanced non-small cell lung cancer in Germany: a historical cohort analysis

The national Network Genomic Medicine (nNGM) Lung Cancer provides comprehensive and high-quality multiplex molecular diagnostics and standardized personalized treatment recommendation for patients with advanced non-small cell lung cancer (aNSCLC) in Germany. The primary aim of this study was to investigate the effectiveness of the nNGM precision medicine program in terms of overall survival (OS) using real-world data (RWD). A historical nationwide cohort analysis of patients with aNSCLC and initial diagnosis between 04/2019 and 06/2020 was conducted to compare treatment and OS of patients with and without nNGM-participation. Patients participating within the nNGM (nNGM group) were selected based on a prospective nNGM database. The electronic health records (EHR) of the prospective nNGM database were case-specifically linked to claims data (AOK, German health insurance). The control group was selected from claims data of patients receiving usual care without nNGM-participation (non-nNGM group). The minimum follow-up period was six months. Overall, n=509 patients in the nNGM group and n=7213 patients in the non-nNGM group met the inclusion criteria. Patients participating in the nNGM had a significantly improved OS compared to the non-nNGM group (median OS: 10.5 months vs. 8.7 months, p=0.008, HR=0.84, 95% CI: 0.74-0.95). The 1-year survival rates were 46.8% (nNGM) and 41.3% (non-nNGM). The use of approved tyrosine kinase inhibitors (TKI) in the first-line setting was significantly higher in the nNGM group than in the non-nNGM group (nNGM: 8.4% (43/509) vs. non-nNGM: 5.1% (366/7213), p=0.001). Overall, patients receiving first-line TKI treatment had significantly higher 1-year OS rates than patients treated with PD-1/PD-L1 inhibitors and/or chemotherapy (67.2% vs. 40.2%, p<0.001). This is the first study to demonstrate a significant survival benefit and higher utilization of targeted therapies for aNSCLC patients participating within nNGM. Our data indicate that precision medicine programs can enhance collaborative personalized lung cancer care and promote the implementation of treatment innovations and the latest scientific knowledge into clinical routine care. The study was funded by the AOK Federal Association Germany.

Cabozantinib-induced edema in zebrafish represents an adverse effect characterized by defects in lymphatic vasculature and renal function.

Tyrosine kinase inhibitors (TKIs) are a major class of targeted cancer therapy drugs. Overcoming the limitations of approved TKIs and the development of new TKIs continues to be an important need. The adoption of higher throughput and accessible animal models to evaluate TKI adverse effects will help in this regard. We exposed zebrafish larvae to a set of 22 Food and Drug Administration-approved TKIs and assessed mortality, early developmental abnormalities, and gross morphological abnormalities posthatching. We found edema posthatching as a consistent and prominent consequence of VEGFR inhibitors, and of cabozantinib in particular. The edema occurred at concentrations that did not cause lethality or any other abnormality, and was independent of the developmental stage. Further experiments identified loss of blood and lymphatic vasculature, and suppression of renal function in larvae exposed to 10 µM cabozantinib. Molecular analysis showed downregulation of the vasculature marker genes vegfr, prox1a, sox18, and the renal function markers nephrin and podocin as the potential molecular basis for the above defects, implicating them in the mechanism of cabozantinib-induced edema. Our findings reveal edema as a previously unreported phenotypic effect of cabozantinib and identify the likely mechanistic basis. These findings also highlight the need for studies investigating edema due to vascular and renal dysfunction as a potential clinical adverse effect of cabozantinib, and possibly other VEGFR inhibitors.

Mortality rate and social disparity trends with tyrosine kinase inhibitory availability in chronic myelogenous leukemia: An analysis in the US from 1999 to 2020.

7055 Background: We analyzed CML mortality from 1999 to 2020 in the US in relation to FDA approval of tyrosine kinase inhibitors (TKIs). These agents were introduced in the 2000s, revolutionizing the treatment of CML and providing a paradigm for targeted therapy in oncology. Starting with imatinib in 2001, followed by dasatinib (2006), nilotinib (2007), and bosutinib (2012). TKIs have increased tolerability and efficacy for the treatment of CML as compared to previous treatment modalities. We investigated age-adjusted mortality rates (AAMR) and annual percent change (APC) in this population in relation to TKI approval. Methods: Using the CDC WONDER database, we examined mortality trends from 1999 to 2020 for CML in the US. AAMRs were calculated per 100,000 people and stratified by sex, race/ethnicity, and census region. AAMR groups were listed as pre-TKI era and 1 year post-FDA approval of different TKI agents. We computed the APC trends for the respective stratification with Joinpoint, a regression analysis program. Results: Between 1999 and 2020 there were 35,268 deaths from CML. In 1999, overall AAMR initially was 0.8, which improved to 0.5 by 2020 with a respective APC of -2.5%. In our subgroup analysis there was a consistent and significant decrease in AAMR since the introduction of Imatinib in 2001. With additional TKI releases, AAMR continued to decline in all subgroups. APC for mortality rates was similar between all subgroups [-2.0 to -2.8%] indicating a similar benefit regardless of subgroup. Male AAMR was consistently higher than female AAMR. Black and white patients (0.5, 2020) have a 2.5x higher AAMR (0.2, 2020) compared to Asian patients. Census region did not show a significant difference between each other. Conclusions: Since the FDA approval of imatinib in 2001 and the subsequent release of TKIs there has been a significant impact on reducing AAMR for patients with CML. The decline was seen in sex, race, and census region. The APCs were similar between all subgroups indicating a consistent improvement in survival. Possible etiologies of disparities in AARM for males in comparison to females and for black and white patients in comparison to Asian patients include gender and race-associated gene polymorphisms possibly inducing differences in drug metabolism. Further gender and race specific pharmacokinetic studies would be useful to further elucidate etiology of the disparity and may lead to changes in TKI dosing strategies. [Table: see text]

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Initial results from the phase (ph) 1 portion of a ph 1/2 study of THE-630 in patients (pts) with advanced gastrointestinal stromal tumor (GIST).

e23508 Background: Activating mutations in KIT are found in most pts with GIST. First-line imatinib provides initial clinical benefit in advanced disease, but prognosis is poor for pts whose tumors progress, despite 3 other approved tyrosine kinase inhibitors (TKIs). Resistance is typically driven by secondary KIT mutations in the ATP-binding pocket (exons 13/14) or activation loop (exons 17/18). No approved drug has potent activity against both classes of resistance mutations, and many pts have polyclonal resistance after multiple lines of therapy. THE-630 is an investigational pan-variant KIT inhibitor. Based on preclinical models, an average plasma concentration (Cav) of 100 nM is predicted to have potent activity against all major classes of KIT-activating and resistance mutations. Here, we report initial data from a first-in-human study in pts with advanced GIST (NCT05160168). Methods: This ph 1/2 study is assessing the safety (including dose-limiting toxicities [DLTs] and recommended ph 2 dose [RP2D]), pharmacokinetics (PK), and antitumor activity of THE-630. Pts enrolled in the ph 1 portion were ≥18 y, had unresectable or metastatic GIST previously treated with imatinib and ≥1 additional TKI, and had ECOG performance status ≤2. Pts received THE-630 (QD; 28-day cycles) in a 3+3 dose-escalation design. PK was assessed on days 1 and 15 in cycle 1, antitumor activity was assessed by modified RECIST 1.1, and circulating tumor DNA (ctDNA) was assessed using Guardant360. Results: As of 13 Jan 2023, 19 pts had been treated in the ph 1 portion at THE-630 daily doses of 3 mg (n = 3), 4 mg (n = 7), 6 mg (n = 3), 9 mg (n = 3), and 12 mg (n = 3). Median age was 57 y (range 39–72); 13 pts had ≥4 prior TKIs. Median treatment duration was 55 days (range 1–252). PK analysis shows approximately dose-proportional increase in systemic exposure across doses tested. Mean steady-state Cav at 12 mg was 47 nM. There was 1 DLT at 4 mg (grade 5 myocardial infarction in a pt with 8 prior TKIs and hyperlipidemia where relationship to THE-630 could not be incontrovertibly ruled out). No other DLTs or related serious adverse events have occurred; 13 pts had treatment-related AEs (TRAEs), 91% of which were grade 1–2. The most common TRAEs were fatigue (n = 4), dry mouth (n = 3), anemia, ALT increase, AST increase, diarrhea, dyspepsia, dyspnea, and hypertension (n = 2 each). Reductions in select KIT-mutant allele fractions in ctDNA were observed, consistent with THE-630 levels achieved thus far. Stable disease (SD) was the best response in 1/7 pts at 4 mg, 1/3 pts at 6 mg, and 3/3 pts at 9 mg. Post data cut, SD was seen in 3/3 pts at 12 mg. Dose escalation continues to determine the RP2D. Conclusions: THE-630 had an acceptable initial safety profile, and escalation continues, as target exposure for pan-variant KIT activity is not yet reached. Reduction in KIT-mutant allele fractions in ctDNA and initial evidence of disease control were observed. Clinical trial information: NCT05160168 .

Clinical uses and safety concerns of tyrosine kinase inhibitors with a focus on novel drugs: A narrative review.

Objective:To review the safety issues surrounding tyrosine kinase inhibitors (TKIs), specifically, hematological adverse effects, cardiovascular issues, renal adverse effects and nephrotoxicity, endocrine system adverse effects, concerns related to the reproductive system, dermatological and gastrointestinal adverse effects. Data Sources: A literature search was performed through Web of Science, PubMed, Google Scholar, Scopus, and the Food and Drug Administration. Data Summary: Several safety issues have been raised following the use of TKIs. Most TKIs show hematological side effects. Considering cardiovascular toxicities, as opposed to imatinib which is relatively safe, new-generation TKIs may be associated with severe cardiovascular side effects. Both acute and chronic renal failure were reported with TKIs such as gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. Many endocrine adverse effects have been reported including hypercholesterolemia and hypertriglyceridemia (with lorlatinib) and thyroid dysfunction (with dasatinib). TKIs may interfere with fetus implantation, growth, and gonadal development. Females receiving TKIs and encountering unwanted pregnancy may have a normal pregnancy, miscarriage, or an abnormality in the fetus. Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI. Gastrointestinal side effects are common with TKIs. Diarrhea was the most frequently reported adverse effect of many TKIs. Conclusions: TKIs are increasingly taking up a critical role in the treatment of cancers due to their specific action toward malignant cells compared to conventional cytotoxic chemotherapy. Despite a dramatic improvement in the survival of patients with cancer following approval of TKIs, various early and late adverse effects were reported.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

HPLC methods for studying pharmacokinetics of tivozanib and in vitro metabolic interaction with dexamethasone in rat

Tivozanib is a recently approved tyrosine kinase inhibitor for the treatment of renal cell carcinoma. In this work, two new HPLC methods coupled with fluorescence (FLD), or photodiode array detectors (PDA) were developed and used for the first time for tivozanib quantification in rat plasma and liver microsomes. The described methods were efficient with a 4-min runtime employing a Gemini-NX C18 column (50 × 2.1 mm, 3 µm) and a mobile phase of acetonitrile and ammonium acetate buffer (pH 4.7, 10 mM) (40:60, v/v) delivered at a flow rate of 0.4 mL/min. The use of HPLC-FLD allowed the quantification of 50 ng/ mL tivozanib using only 100 µL rat plasma. The HPLC-FLD method was validated according to the US food and drug administration (FDA) bioanalytical guidelines and was applied successfully in a rat pharmacokinetic study (n = 7) following oral administration of 1 mg/ kg tivozanib. Furthermore, HPLC-PDA was used for monitoring the depletion of 1 μM (454.9 ng/mL) tivozanib in rat liver microsomes and was applied to study the effect of dexamethasone induction on tivozanib metabolism in vitro. Results showed that dexamethasone enhanced the intrinsic clearance of tivozanib by 60 % suggesting a potential drug-drug interaction at the metabolism level. Dexamethasone is commonly used in the management of cancer disease and thus coadministration with tivozanib therapy may cause treatment failure in patients. The simplicity, speed and cost-effectiveness of the reported methods are ideal for supporting in vivo and in vitro tivozanib studies, including drug-drug interaction studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.

Quantitative Consideration of Clinical Increases in Serum Creatinine Caused by Renal Transporter Inhibition.

Creatinine is a common biomarker of renal function and is secreted in the renal tubular cells via drug transporters, such as organic cation transporter 2 and multidrug and toxin extrusion (MATE) 1/2-K. To differentiate between drug-induced acute kidney injury (AKI) and drug interactions through the renal transporter, it has been examined whether these transporter inhibitions quantitatively explained increases in serum creatinine (SCr) at their clinically relevant concentrations using drugs without any changes in renal function. For such renal transporter inhibitors and recently approved tyrosine kinase inhibitors (TKIs), this mini-review describes clinical increases in SCr and inhibitory potentials against the renal transporters. Most cases of SCr elevations can be explained by considering the renal transporter inhibitions based on unbound maximum plasma concentrations, except for drugs associated with obvious changes in renal function. SCr increases for cobicistat, dolutegravir, and dronedarone, and some TKIs were significantly underestimated, and these underestimations were suggested to be associated with low plasma unbound fractions. Sensitivity analysis of SCr elevations regarding inhibitory potentials of MATE1/2-K demonstrated that typical inhibitors such as cimetidine, DX-619, pyrimethamine, and trimethoprim could give false interpretations of AKI according to the criteria based on relative or absolute levels of SCr elevations. Recent progress and current challenges of physiologically-based pharmacokinetics modeling for creatinine disposition were also summarized. Although it should be noted for the potential impact of in vitro assay designs on clinical translatability of transporter inhibitions data, mechanistic approaches could support decision-making in clinical development to differentiate between AKI and creatinine-drug interactions. SIGNIFICANCE STATEMENT: Serum creatinine (SCr) is widely used as an indicator of kidney function, but it increases due to inhibitions of renal transporters, such as multidrug and toxin extrusion protein 1/2-K despite no functional changes in the kidney. Such SCr elevations were quantitatively explained by renal transporter inhibitions except for some drugs with high protein binding. The present analysis demonstrated that clinically relevant inhibitors of the renal transporters could cause SCr elevations above levels corresponding to acute kidney injury criteria.

Characterization and survival benefit of drugs approved for advanced renal cell carcinoma.

633 Background: The treatment landscape of advanced renal cell carcinoma (RCC) drastically changed with the approval of tyrosine kinase inhibitors (TKIs). Since then, immunotherapy (IO) and now TKI plus IO combination therapies is considered standard-of-care. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for RCC from 2005 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2005 and 2022, there were 16 drug (single or combination) approvals for advanced RCC. Most therapy approvals (93.75%) were granted through accelerated approval. Eight approvals were TKIs, 6 approvals were TKI plus IO combination therapies, and 1 approval each were for immunotherapy and a VEGF inhibitor. Average PFS benefit for 1st line approvals was 5.63 months (range 1.9-14.7) and average PFS benefit for 2nd or later line approvals was 2.95 months (range 0.2-9.1). Average OS benefit in the 1st line setting was 3.6 months and average OS benefit in the 2nd or later line setting was 5.4 months. Conclusions: Despite 16 drug (single or combination) approvals for advanced RCC since 2005, the improvements in average PFS and OS were modest. As OS data matures from recent TKI plus IO combination therapies, OS benefit may improve. Nonetheless, continued drug development is urgently warranted in advanced RCC. [Table: see text]

To Study Demographic Profile, Risk Stratification, and Response to Treatment in Chronic Myeloid Leukemia Patients

Abstract Background: Chronic myeloid leukemia (CML) is the most common leukemia in India. The annual incidence of CML in India was originally reported to be 0.82.2 per 100,000 population. CML is a clonal disorder that is usually easily diagnosed by the Philadelphia chromosome. The approval of tyrosine kinase inhibitors has significantly reduced the mortality rate associated with CML and revolutionized treatment. Materials and Methods: Eighty patients diagnosed with CML were studied. Investigations were done and with European Treatment and Outcome Study (EUTOS) patients were stratified into low- and high-risk group and then treatment with Imatinib was given to all patients and molecular response was evaluated. Results: In the study population, out of 80 patients, 40 were female and 40 were male with M: F is 1:1. Out of total 80 patients’, maximum patients (54) were in 31-60 years age group. Our study showed that the most common symptom of presentation is abdominal discomfort followed by fever. Out of total 80 patients, 25 (31.3%) patients had high EUTOS score and 55 (68.8%) patients had low EUTOS score. On 6 months’ follow-up, 36.3% patients had complete molecular response, 16.3% patients had major molecular response and 47.5% patients had no molecular response, but on 12 months’ follow-up, 71.3% patients had complete molecular response, 16.25% patients had major molecular response, and 12.5% patients had no molecular response. Conclusion: In this observational study, we found a significant correlation between EUTOS score and molecular response at 6 months and 12 months follow-up after Imatinib therapy. Chronic myeloid leukemia, European treatment and outcome study score, response, tyrosine kinase inhibitor