Safety Of Tyrosine Kinase Inhibitors Research Articles

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study [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 PO4-04-06.

Efficacy and safety of tyrosine kinase inhibitors for advanced metastatic thyroid cancer: A systematic review and network meta-analysis of randomized controlled trials.

Tyrosine kinase inhibitors (TKIs) have been approved for treating patients with clinically advanced metastatic thyroid cancer. However among the many TKIs, it remains unknown which regimen is the best choice for these patients. We conducted a systematic review and network meta-analysis to compare the survival benefits and efficacy of the available first-line regimens. We conducted an active search for phase II, III, or IV randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to compare the effects of at least 2 drugs in the systemic treatment of advanced or metastatic thyroid cancer up to May 2023. The network meta-analysis model was adjusted using Bayesian Network model. Twelve trials with 2535 patients were included in our meta-analysis. The overall survival (OS), progression-free survival (PFS), and serious adverse events (SAEs) were taken as reference indicators. We also performed subgroup analyses of OS and PFS in medullary thyroid cancer (MTC) and radioiodine-refractory differentiated thyroid cancer (RR-DTC) to explore the variations of TKIs in different groups. As a result, apatinib had the best effect on overall survival (OS) (hazards ratio [HR] = 0.42, 95% confidence interval [CI] = 0.18-0.98), lenvatinib 18 mg/d has the best effect on progression-free survival (PFS) (HR = 0.13, 95% CI = 0.064-0.27), and cabozantinib 60 mg/d has the best safety profile. Our network meta-analysis showed that we believe that cabozantinib has the potential to become a widely used drug in clinical practice.

The Applicability of Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia

INTRODUCTION The advent of tyrosine kinase inhibitors (TKIs) has shifted the treatment paradigm of adult CML, limiting SCT to a last-resort option for TKI-ineligible or resistant cases. However, determination of the optimal dosing and duration, potential long-term side effects, and the viability of therapy discontinuation remain under-explored aspects of TKIs in pediatric CML. Emerging data supports administering novel TKIs as initial or second-line treatments in pediatric CML amid variable results. This review discusses the RCTs conducted on pediatric patients with CML who received TKIs, aiding in better understanding of the effectiveness and safety of TKIs in the pediatric CML population. METHODS We searched Medline, OVID, and Web of Science for all RCTs reporting the efficacy and safety of TKI in pediatric CML (< 18 years). We compiled the individual efficacy and safety data into distinct tables, emphasizing demographics, treatment modalities, and outcomes pertaining to both the safety and efficacy of TKI. RESULTS This review analyzed 17 Randomized Controlled Trials (RCTs) with 887 pediatric CML patients. Median age was 11.3 years (range 6.5-14 years). Efficacy studies had 718 patients, safety studies had 851.. The median white blood cell count was 234 x10 9/uL [range 19 to 378; reported in 9 RCTs], median hemoglobin level was 9 g/dL [range 5.6 to 10.8; from 7 RCTs], and the median platelet count was 431.5 x10 9/µL, [range 31 to 594; from 6 RCTs]. TKIs were first-line treatment in 65% of the studies, Imatinib being the commonest (61% of studies). Dasatinib and Nilotinib were used in 17% and 11% of studies, respectively, while 6% received a combination of imatinib and chemotherapy. Efficacy reporting in the RCTs was a major concern that challenged the accumulation of results (Table 1). BCR-ABL response of <10% ranged from 60 % to 78%, and the complete cytogenetic response (CCYR) at 24 months ranged from 62% to 94%. Progression free survival (PFS) ranged from 56.8% to 100%; however, the timepoint for PFS analysis was not standardized among studies (36 to 48 months). Safety data from 16 studies (851 patients) included anemia (n=228), thrombocytopenia (n=161), neutropenia (n=257), hepatotoxicity (n=98), and cutaneous side-effects (n=156). Cardiovascular complications with second generation TKIs included QTc prolongation with Nilotinib (n= 11) and heart failure with Dasatinib (n=4). Nausea/vomiting were reported in 119 patients on imatinib, vs. 64 and 37 patients on Dasatinib and Nilotinib, respectively. Diarrhea occurred in 40 patients on Imatinib ,and 20 and 2 patients in Dasatinib and Nilotinib cohorts, respectively. Other AEs included impaired bone growth (70 on Imatinib and 10 on Dasatinib), headache (44 on Imatinib, 38 on Nilotinib and 13 in Dasatinib), musculoskeletal pain (161 on Imatinib, 31 on Dasatinib and 8 on Nilotinib). Treatment AEs leading to drug discontinuation were reported in 22 patients (6 studies), however the exact AE leading to drug discontinuation were not reported. CONCLUSION There remains a limited experience in treating pediatric CML with TKIs. Hence, evidence from prospective clinical trials and real-life clinical practice are required to establish appropriate guidelines for the standard therapeutic management in this population. Imatinib has the most extensice efficacy and toxicity data in pediatric patients. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children should be considered in long term follow-up clinical trials.

Efficacy and safety of tyrosine kinase inhibitors plus PD-1 inhibitor in patients with transarterial chemoembolization- refractory hepatocellular carcinoma: a two-center retrospective study

Efficacy and safety of tyrosine kinase inhibitors plus PD-1 inhibitor in patients with transarterial chemoembolization- refractory hepatocellular carcinoma: a two-center retrospective study

Association of hepatitis B virus DNA levels with efficacy and safety outcomes in patients with hepatitis B virus-associated advanced hepatocellular carcinoma receiving tyrosine kinase inhibitor plus anti-PD-1 antibody: a multicenter propensity-matched study

BackgroundThe efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with anti-PD-1 antibodies (α-PD-1) in advanced hepatocellular carcinoma (HCC) with high hepatitis B virus (HBV) DNA levels (>500 IU/mL) remain unclear. MethodsWe retrospectively assessed patients from seven medical institutions diagnosed with HBV-related HCC, undergoing treatment with TKIs and α-PD-1 in conjunction with antiviral therapies. Based on HBV-DNA levels, patients were categorized into either high (HHBV-DNA, >500 IU/mL) or low HBV-DNA (LHBV-DNA, ≤500 IU/mL) cohorts Propensity score matching (PSM) was used to minimize baseline imbalance between groups. Results149 patients were included, with 66 patients exhibiting HBV-DNA > 500 IU/mL and 83 patients presenting HBV-DNA ≤ 500 IU/mL. Compared with the LHBV-DNA cohort, the HHBV-DNA cohort had a greater incidence of serum HBeAg positivity, tumor diameter ≥ 10 cm, and vascular invasion. Following PSM, 57 individuals were enrolled in each group. Oncological outcomes were comparable between HHBV-DNA and LHBV-DNA cohorts before and after PSM. Before PSM, the median PFS and OS were 6.1 months and 17.5 months in the HHBV-DNA cohort and 6.7 months and 19.3 months in the LHBV-DNA cohort (all P > 0.05). After PSM, the median PFS and OS were 6.0 months and 19.5 months in the HHBV-DNA cohort and 6.0 months and 17.1 months in the LHBV-DNA cohort, respectively (all P > 0.05). Safety profiles were equivalent across cohorts with no fatal incidents reported. Seven patients (4.7 %) had HBV reactivation.1 (0.7 %) from HHBV-DNA and 6 (4.0 %) from LHBV-DNA (P = 0.134). Only one patient developed HBV-related hepatitis. ConclusionsThe effectiveness and safety of TKIs plus α-PD-1 in advanced HCC with HBV-DNA > 500 IU/mL were not compromised in the context of concomitant antiviral therapy.

Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibodies with Hepatic Arterial Infusion Chemotherapy or Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma.

The combination of tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC) or transarterial chemoembolization (TACE) has shown encouraging anti-tumor effects in the treatment of hepatocellular carcinoma (HCC). We explored the efficacy and safety of TKIs and anti-PD-1 antibodies combined with HAIC or TACE in HCC. Data from 302 HCC patients receiving HAIC combined with TKIs and anti-PD-1 antibodies (HAIC-TP group) and 446 HCC patients receiving TACE combined with TKIs and anti-PD-1 antibodies (TACE-TP group) were retrospectively collected. Clinicopathological characteristics, tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were compared between two groups. Propensity score matching (PSM) analysis was performed to minimize bias. The HAIC-TP group exhibited better objective response rate (RECIST: 33.1% versus 7.8%, P < 0.001; mRECIST: 51.4% versus 17.5%, P < 0.001), longer PFS (12.4 months versus 8.2 months, P < 0.001), and longer OS (not reached versus 13.8 months, P < 0.001) than TACE-TP group. Surgery was performed after combination therapy in 34 patients of the HAIC-TP group and in 7 patients of the TACE-TP group (P < 0.001). Similar results were also observed in the PSM analysis. Multivariate analysis indicated type of treatment, alpha-fetoprotein, ALBI grade, portal vein tumor thrombus, and extrahepatic status were risk factors for poor prognosis. Nausea, vomiting, diarrhea, and abdominal pain occurred more frequently in the HAIC-TP group, whereas liver dysfunction occurred more frequently in the TACE-TP group. All AEs were acceptable and manageable as a result of treatment interruption or dose modification. The combination of HAIC with TKIs and anti-PD-1 antibodies is an effective and safe therapeutic regimen over TACE-based combination therapy for patients with HCC. A prospective study with a large sample size is required to validate the efficacy and safety of the combination therapy.

Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

Objective: This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. Results: A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. Conclusion: The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.

Efficacy and safety of pembrolizumab in advanced neuroendocrine tumors (NETs): A meta-analysis of clinical trials.

165 Background: Patients with recurrent or metastatic neuroendocrine tumors (NETs) have limited treatment options and a poor prognoses. Programmed death–ligand 1 (PD-L1) has been associated with the pathogenesis, progression, and prognosis of NETs. This article analyzes the efficacy and safety profile of PDL1 inhibitor Pembrolizumab in advanced NETs. Our objective is to identify all the clinical trials in which Pembrolizumab has been assessed in treating NETs and to evaluate the efficacy and safety profile in this patient population with high power. Methods: Systemic searches of PubMed, the Cochrane Library, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and serious adverse events (AEs). We calculated the pooled ORR for these studies using weighted pooled ORR = Σ (ORR_i * weight_i). We calculated the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). This statistical method was also used to calculate our study's pooled DCR, PFS, OS, and serious AEs. However, it is essential to note that the pooled data is only as reliable as the individual data estimates from each study and may be subject to bias or confounding factors. Results: Five clinical trials met the inclusion criteria, including patients with gastrointestinal, pancreatic, lung, and lower genital tract NETs. Outcome data were available for all five studies, comprising 177 patients with NETs who received Pembrolizumab as part of the treatment regimen (Table). The pooled ORR and DCR were 5.27% (95% CI 2.23-8.31) and 5.4% (95% CI 3-7.8), respectively. The pooled weighted PFS was 4.4 months, and pooled weighted OS was 23.3 months. These findings suggest that Pembrolizumab has a promising ORR, DCR, PFS, and OS. Safety was a secondary endpoint, and the pooled serious AEs were noted in 20.9% of patients. Conclusions: Pembrolizumab demonstrated statistically significant efficacy and safety profile in a subset of patients with NETs and was overall well-tolerated. In recent years, the combination strategy of tyrosine kinase inhibitors (TKI) with PDL-1 checkpoint inhibitors has shown promising clinical benefits in patients with various solid tumors. Further studies are needed to analyze the efficacy and safety of TKI with PD-L1 inhibitors in NETs. [Table: see text]

Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis.

Small tyrosine kinase inhibitors (TKIs) show activity against breast cancer brain metastases (BCBM) of the human epidermal growth factor receptor 2 (HER2)-positive subtype. This meta-analysis aimed to objectively explore the efficacy and safety of TKIs. Electronic databases were searched for relevant clinical trials. We conducted a pairwise meta-analysis, pooled analysis, and estimated summary survival curves to compare survival outcomes following TKIs therapy for BCBM patients using Stata version 16.0 or R x64 4.0.5. Thirteen clinical trials involving 987 HER2-positive BCBM patients were analyzed. A trend of longer progression-free survival (PFS) was observed in the TKI-containing arm compared to the non-TKI-containing arm (hazard ratio = 0.64, 95% confidence interval [CI]: 0.35-1.15, p = 0.132), although the difference is not statistically significant. Summary survival curves reported the summary median PFS and overall survival were 7.9 months and 12.3 months. Subgroup analysis revealed that TKIs combined with capecitabine (TKI + Cap) regimens resulted in improved survival outcomes. Tucatinib may be more effective in BCBM patients. The main grade 3-5 adverse events (AEs) were diarrhea (22%, 95% CI: 14%-32%), neutropenia (11%, 95% CI: 5%-18%), hepatic toxicity (7%, 95% CI: 1%-16%), and sensory neuropathy (6%, 95% CI: 2%-12%). TKIs therapy improved the survival outcomes of HER2-positive BCBM patients, especially when combined with capecitabine and tolerable AEs. We also identified the clinical value of tucatinib, which appears to be the most favorable TKI drug for BCBM patients.

Abstract P1-11-16: Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study

Abstract Background Trastuzumab emtansine (T-DM1) has shown great effectiveness in treating HER2-positive metastatic breast cancer, but therapies subsequent to T-DM1 failure remain controversial. Here, we investigated efficacy and safety of tyrosine kinase inhibitors (TKIs) based therapy in T-DM1 resistant HER2-positive metastatic breast cancer. Methods From August 2019 to April 2022, 53 HER2-positive metastatic breast cancer patients received TKIs-based therapy after T-DM1 failure in Jiangsu Province Hospital. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles were reported. Results 53 patients received TKIs-based therapies as a second or later line therapy. 51 (96.2%) patients received a combined therapy, including TKIs plus capecitabine, vinorelbine or trastuzumab. 2 (3.7%) patients received TKIs alone. The median follow-up time was 19.7 months (95%CI 15.4-24.0). The median PFS was 11.9 months (95%CI 7.9-15.9). OS has not reached. ORR was 19.6% and CBR was 72.5%. For patients who had brain metastasis (n=12), the median PFS was 10.5 months (95%CI 7.5-13.5) and intracranial ORR was 33.3%. Compared with lapatinib (n=30), pyrotinib (n=21) provided a better PFS after T-DM1 progression (8.0 months vs. 19.0 months, P=0.033). The most common adverse events were thrombocytopenia (12, 23.6%), diarrhea (8, 15.7%), leucopenia (8, 15.7%) and hand-foot syndrome (8, 15.7%). Conclusion TKIs-based therapy could prolong the survival of HER2-positive metastatic breast cancer patients after T-DM1 failure, including those with brain metastases. Compared with lapatinib, pyrotinib might provide better outcomes for overcoming T-DM1 resistance. Citation Format: Yongmei Yin, Wei Li, Xiang huang, Chunxiao Sun, Yijia Hua, Nan Jin, Xinyu Wu. Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-16.

Efficacy and Safety of Tyrosine Kinase Inhibitors Alone or Combination with Programmed Death-1 Inhibitors in Treating of Hepatitis C-Related Hepatocellular Carcinoma.

Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC). The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated. Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3-4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238). The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.

Beyond atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: overall efficacy and safety of tyrosine kinase inhibitors in a real-world setting.

In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy. The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population. All patients with advanced HCC, treated in first-line setting by atezolizumab-bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study. Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61-1.86), p = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20-0.79), p = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22-0.84), p = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively. Efficacy of any TKI in the second-line setting was not affected by atezolizumab-bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies.

Treatment options for unresectable hepatocellular carcinoma with hepatitis virus infection following sorafenib failure

BackgroundCurrently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment.MethodsFrom May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n = 37) and TKI-ICI group (n = 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors.ResultsWith a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50–64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months, P < 0.001) and median PFS (2.97 months vs 8.63 months, P < 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%, P = 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%, P = 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child–Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed.ConclusionThis real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.

Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients with Metastatic Pheochromocytomas/Paragangliomas.

Tyrosine kinase inhibitors (TKIs) can be used to treat locally unresectable or distantly metastatic pheochromocytomas/paragangliomas (PPGLs), such as sunitinib, according to the National Comprehensive Cancer Network guidelines in 2022. However, the precise effect of different TKIs in metastatic PPGLs is still unclear. The aim of this meta-analysis is to assess the efficacy and safety of TKIs in metastatic PPGLs. The PubMed, Cochrane Library, Scopus, Clinical Trial, and Embase databases were searched by synonyms of 48 TKIs and metastatic PPGLs from inception up to August 2022. Outcomes were tumor response or survival data and the incidence of adverse events (AEs) after treatment. The MIONRS scale and the JBI's tools for case series were used for interventional and observational studies to assess risk of bias, respectively. The combined effects with fixed- or random-effect models, the combined median with the weighted median of medians method and their 95% CIs were reported. A total of 7 studies with 160 patients were included. Tumor responses in metastatic PPGLs in 5 studies with available data showed the pooled proportion of partial response (PR), stable disease, and disease control rate (DCR) of, respectively, 0.320 (95% CI 0.155-0.486), 0.520 (95% CI 0.409-0.630), and 0.856 (95% CI 0.734-0.979). The combined median progressive-free survival in 6 studies was 8.9 months (95% CI 4.1-13.5) and the proportion of those who discontinued due to AEs in 5 studies was 0.143 (95% CI 0.077-0.209). This meta-analysis suggests that patients with metastatic PPGLs can benefit from TKI therapy with PR and DCR up to more than 30% and 80%. However, because of restricted studies, larger clinical trials should be performed in the future.

Efficacy and Safety of Tyrosine Kinase Inhibitors in the Treatment of Relapsed/Refractory Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is characterized by immune-mediated impairment of platelet production or platelet destruction leading platelet count of <100x103/mm3. First-line therapy of ITP includes IV immunoglobulin, steroids, and anti-D. However, long-term durable responses to these therapies are uncommon. Fc receptors on splenic phagocytes signal via spleen tyrosine kinases (Syk). Bruton tyrosine kinase (BTK) plays a crucial role in B-cell maturation and Fcy receptor-mediated phagocyte function. Therefore, inhibiting SyK or BTKIs can reduce macrophage activation leading to ITP. In this review, we assessed the efficacy and safety of BTKIs in the treatment of relapsed/refractory ITP. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Web of Science, Embase (Ovid), and clinicaltrials.gov. with mesh terms, "Immune thrombocytopenia” and "tyrosine kinase” from the inception of data till 07/01/2022. We screened 474 articles and included three randomized clinical trials (RCTs, N=195) and one non-RCT (N=60) in this review. In the included clinical studies, stable response (SR) was platelets ≥50000/ micro L on ≥4 of 6 biweekly visits, modified stable response (MSR) was ≥2 consecutive platelet counts, separated by at least 5 days of ≥50,000 per micro L and the overall response (OR) was ≥1 platelet count of ≥50 000/micro L within the first 12 weeks on treatment. Results: In 4 clinical trials (N=255), the range of age of relapsed/refractory TKI participants was 18 to 88. 135 patients were treated with Syk inhibitors, 60 with BTK inhibitors, and 60 with placebo. In two clinical trials (N=135), SR and OR were reported in 18/101 (17.8%) and 43/101 (42.5%) patients, respectively in patients treated with fostamatinib versus SR and OR in 1/49 (2%) and 7/49 (14%), respectively in patients treated with placebo. In a clinical trial by Yang et al. (N=45), SR and OR were reported in 5/16 (31%) and 11/16 (68.8%) patients, respectively treated with HMPL-523 (Syk inhibitor) versus SR and OR in 1/11 (9%) patients treated with placebo. In a clinical trial by Kuter et al. (N=60), SR and MSR were reported in 17/60 (28%) and 24/60 (40%) patients, respectively treated with rilzabrutinib. Table 1. Diarrhea, hypertension, dizziness, and neutropenia were serious side effects reported with fostamatinib leading to dose reduction in 9% of the patients. There were no dose-limiting adverse events reported with rilzabrutinib and HMPL-523. Table 1. Conclusion: Syk inhibitors (fostamatinib and HMPL-523) and oral BTK inhibitor (rilzabrutinib) were effective and well tolerated by most of the patients with relapsed/refractory ITP. Rilzabrutinib and HMPL-523 had no dose-limiting side effects. A randomized phase III clinical trial (NCT04562766) is in progress to assess the efficacy and safety of rilzabrutinib. More trials are in progress to assess the efficacy and safety of novel TKIs like baricitinib, orelabrutinib, and zanubrutinib. Table 2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical outcomes of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 immunotherapy for unresectable intrahepatic cholangiocarcinoma.

To compare the treatment efficacy and safety of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death 1 (PD-1) immunotherapy combined with transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). Patients with unresectable ICC received TKIs and anti-PD-1 immunotherapy combined with HAIC (HTP group) or TACE (TTP group)were included. The clinicopathological characteristics, treatment efficacy, and adverse events (AEs) were compared between the two groups. The factors associated with response rate to the treatments were evaluated. A total of 58 patients were enrolled, with 39 in the HTP group and 19 in the TTP group. Patients in the HTP group exhibited a better objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] 48.7% vs 15.8%, P=0.02; modified RECIST [mRECIST] 61.5% vs 21.1%, P=0.004) and disease control rate (DCR; 82.1% vs 36.8%, P=0.001) compared to the TTP group. The median progression-free survival (PFS) rate was not reached and the 1-year PFS rate was 61.9% in the HTP group, whereas the median PFS was 11.0months and the 1-year PFS rate was 31.6% in the TTP group. The type of treatment and tumor size were significant factors for the response rate. More patients in the HTP group presented rash, abdominal pain and hand-foot syndrome, but all AEs were relieved after symptomatic treatment, and no treatment-related death occurred. For unresectable ICC, treatment with a combination of HAIC with TKIs and anti-PD-1 immunotherapy was effective and safe. Tumor size might serve as a significant factor for the response rate following treatment for unresectable ICC.

Tyrosine kinase inhibitors (TKIs) in trastuzumab emtansine (T-DM1) resistant HER2-positive metastatic breast cancer: A real-world study.

e13029 Background: Trastuzumab emtansine (T-DM1) has shown great effectiveness in treating HER2-positive metastatic breast cancer, but therapies subsequent to T-DM1 progression are still controversial. Here, we investigated efficacy and safety of tyrosine kinase inhibitors (TKIs) based therapy in T-DM1 resistant HER2-positive metastatic breast cancer. Methods: From August 2019 to February 2022, 53 HER2-positive metastatic breast cancer patients received TKIs-based therapy after T-DM1 progression in Jiangsu Province Hospital. We reported progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles of TKIs in treating T-DM1 resistant HER2-positive metastatic breast cancer. Results: 53 patients received TKIs-based therapies as a second or later line therapy. 51 (96.2%) patients received a combined therapy, including TKIs plus capecitabine, vinorelbine or trastuzumab. 2 (3.7%) patients received TKIs alone. The median follow-up time was 19.7 months (95%CI 14.829-24.571). The median PFS was 10.6 months (95%CI 5.530-15.670). OS has not reached. ORR was 18.9% and CBR was 72.5%. For patients who had brain metastasis (n = 12), the median PFS was 10.5 months (95%CI 7.406-13.594) and intracranial ORR was 33.3%. Compared with lapatinib (n = 30), pyrotinib (n = 21) provided a better PFS, but no significant difference was observed (8.0 months vs. 19.0 months, P = 0.076). The most common adverse events were thrombocytopenia (12, 22.6%), hand-foot syndrome (11, 20.8%) and diarrhea (6, 11.3%). Conclusions: TKIs-based therapy could improve the survival of T-DM1 resistant HER2-positive metastatic breast cancer patients, including those with brain metastasis. This provides a novel therapeutic option for HER2-positive breast cancer treatments.

Evaluation of tyrosine kinase inhibitors combined with antiprogrammed cell death protein 1 antibody in tyrosine kinase inhibitor-responsive patients with microsatellite stable/proficient mismatch repair metastatic colorectal adenocarcinoma: protocol for open-label, single-arm trial

IntroductionThe prognosis of patients with advanced metastatic colorectal adenocarcinoma (mCRC) after multiple-line therapy remains poor due to the high tumour load, high level of malignancy and strong drug resistance. The...

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background.Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long.Study design and methods.With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic.A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics.Results.The study was launched in December 2019; however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS.Conclusions.Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Display omitted] DisclosuresŽácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 9/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 9/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents. DisclosuresNo relevant conflicts of interest to declare.