Type Of Tyrosine Kinase Inhibitors Research Articles

The efficacy and safety of antiangiogenesis tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: A meta-analysis of prospective studies.

The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events. Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events. Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies.

Impact of the Type of Tyrosine Kinase Inhibitor (imatinib or dasatinib) Used Before allo-HCT on Outcome of Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia. A Study on Behalf of the Acute Leukemia Working Party of the EBMT

The use of tyrosine kinase inhibitors (TKIs) during induction and consolidation, followed by allogeneic hematopoietic cell transplantation (allo-HCT), is a standard of care for patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL). The goal of this study was to compare results of allo-HCT according to the type of TKI used pre-transplant, either imatinib, dasatinib or both. This was a retrospective, registry-based analysis including adult patients with Ph-positive ALL treated with allo-HCT between years 2010-2022. The analysis included 606 patients pre-treated with imatinib, 163 with dasatinib and 94 with both imatinib and dasatinib. Allo-HCTs were performed in first complete remission from either unrelated (56%), matched sibling (36%) or haploidentical donors (8%). Relapse incidence at 2 years was 26% in the imatinib group and 21% in the dasatinib group and 19% in the imatinib + dasatinib group (P = .06) while non-relapse mortality was 19%, 15%, and 23%, respectively (P = .37). No significant differences were found for leukemia-free survival (55% vs. 63% vs. 58%, P = .11) and overall survival (72% vs. 76% vs. 65%, P = .32). The incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was comparable across study groups, while the incidence of grade 3-4 acute GVHD was significantly increased for patients pre-treated with dasatinib alone (20%) than in the imatinib group (10%) or imatinib + dasatinib group (13%) (P = .002). On multivariate analysis a chance of GVHD and relapse-free survival (GRFS) was significantly decreased while the risk of grade 3-4 acute GVHD was increased for the dasatinib compared to imatinib group (hazard ratio, HR = 1.27, P = .048 and HR = 2.26, P = .0009, respectively). This study provides no evidence for the advantage of one TKI over another in terms of LFS and OS. However, the use of dasatinib is associated with increased risk of severe acute GVHD and decreased GRFS.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

Survival outcomes and prognostic factors of advanced gastrointestinal stromal tumors: in the era of multiple tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have shown great efficacy in the treatment of advanced gastrointestinal stromal tumors (GISTs), significantly prolonging the survival of patients. In the era of imatinib, a few studies reported some prognostic factors for patients with advanced GISTs, such as age, sex, performance status, diameter of the largest lesions, KIT exon mutations, and some hematological examination results. However, with the advent of more TKIs, the prognostic factors for patients with advanced GISTs have not been fully understood in the era of multiple TKIs. In this study, we aimed to identify independent prognostic factors associated with the survival of patients diagnosed with advanced GISTs. Data on clinicopathologic characteristics, treatment approaches, and survival were retrospectively collected for patients with primary unresectable or recurrent GISTs treated from January 2010 to July 2023 at the First Affiliated Hospital of Chongqing Medical University, China. Univariable and multivariable Cox proportional hazards regression models were used to identify independent prognostic factors of survival. A total of 194 patients were included in the analysis. The median follow-up duration was 59.9 months (range, 2.7-141.7 months). The median overall survival (mOS) in this cohort was 76.5 months (95% confidence interval, 63.4 to 89.6 months). All patients received TKI therapy during the follow-up period, and 56.2% received two or more types of TKIs. In multivariable Cox analysis, younger age, a single lesion at enrollment, no previous use of TKIs, smaller tumor burden, good Eastern Cooperative Oncology Group performance status (ECOG PS ≤1), and lesions limited to the liver were independent prognostic factors for better survival. We found that a single lesion at enrollment, no previous use of TKIs, a smaller tumor burden, and lesions limited to the liver were associated with better survival. Drug resistance is a severe challenge for advanced GISTs, and several factors mentioned above may be correlated with the development of drug resistance, leading to the poor survival of patients.

CML in the very elderly: the impact of comorbidities and TKI selection in a real-life multicenter study

Tyrosine kinase inhibitors (TKIs) have greatly improved chronic myeloid leukemia (CML) treatments, with survival rates close to the general population. Yet, for the very elderly, robust data remains limited. This study focused on assessing comorbidities, treatment approaches, responses, and survival for elderly CML patients. Our study was conducted on 123 elderly (≥ 75 years) CML patients across four centers in Israel and Moffitt Cancer Center, USA. The median age at diagnosis was 79.1 years, with 44.7% being octogenarians. Comorbidities were very common; cardiovascular risk factors (60%), cardiovascular diseases (42%), with a median age-adjusted Charlson Comorbidity Index (aaCCI) of 5. Imatinib was the leading first-line therapy (69%), while the use of second-generation TKIs increased post-2010. Most patients achieved a major molecular response (MMR, 66.7%), and half achieved a deep molecular response (DMR, 50.4%). Over half (52.8%) of patients moved to second-line, and nearly a quarter (23.5%) to third-line treatments, primarily due to intolerance. Overall survival (OS) was notably longer in patients with an aaCCI score below 5, and in patients who attained DMR. Contrary to expectations, the Israeli cohort showed a shorter actual life expectancy than projected, suggesting a larger impact of CML on elderly survival. In summary, imatinib remains the main initial treatment, but second-generation TKIs are on the rise among elderly CML patients. Outcomes in elderly CML patients depend on comorbidities, TKI type, response, and age, underscoring the need for personalized therapy and additional research on TKI effectiveness and safety.

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial

Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). From Jan 2021 to Aug 2022, 48patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N=45), Grade 3 or 4 treatment emergent adverse events occurred in 29patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Imatinib@glycymicelles entrapped in hydrogel: preparation, characterization, and therapeutic effect on corneal alkali burn in mice.

Imatinib (IMB) is a type of tyrosine kinase inhibitor with great application potential for inhibiting corneal neovascularization (CNV), but its poor water solubility limits its application in eye disease treatment. In this study, novel IMB@glycymicelles entrapped in hydrogel (called IMB@glycymicelle-hydrogel) were prepared, characterized, and evaluated for their therapeutic effects on corneal alkali burn in mice. Imatinib could be successfully loaded in glycymicelles using glycyrrhizin as a nanocarrier with an optimized weight ratio of IMB:nanocarrier. The apparent solubility of IMB was significantly improved from 61.69 ± 5.55μg/mL to bare IMB to 359,967.62 ± 20,059.42μg/mL to IMB@glycymicelles. Then, the IMB@glycymicelles were entrapped in hydrogel fabricated with hydroxypropyl methylcellulose and sodium hyaluronate (HA) to prolong retention time on the ocular surface. Rabbit eye tolerance tests showed that IMB@glycymicelle-hydrogel possessed good ocular safety profiles. In a mouse model of corneal alkali burns, the topical administration of IMB@glycymicelle-hydrogel showed strong efficacy by prompting corneal wound healing, recovering corneal sensitivity, relieving corneal opacities, and inhibiting CNV, and these efficacy evaluation parameters were better than those of the positive drug HA. Overall, these results demonstrated that IMB@glycymicelle-hydrogel may be a promising candidate for the effective treatment of alkali ocular damage.

Development and validation of a tumor tissue based multivariate biomarker for predicting angiogenesis inhibitor clinical benefit in renal cell carcinoma (RCC).

467 Background: Angiogenesis inhibitors, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), are standard of care therapy (alone and in combination) for several advanced cancers, including RCC. There is an unmet need for a biomarker to identify patients with RCC most likely to benefit from VEGFR TKIs to guide individualized treatment decision making. Hence, we sought to develop and validate a biomarker for predicting single-agent systemic VEGFR TKI benefit in patients with RCC. Methods: Candidate biomarkers were selected by co-expression patterns in VEGFR TKI sensitive/resistant tumor types from pan-solid tumor TCGA expression profiling data and the literature. The angiogenesis inhibitor treatment response score (Angio TRS) was developed as a multivariate expression-based algorithm from RNA-based quantitative transcriptional profiling (qTP) performed in parallel with clinical FFPE tumor based comprehensive genomic profiling, with the Angio TRS High/Low threshold set at the median of clear cell RCC samples. The locked Angio TRS (and High/Low status) was then validated in a cohort of adult RCC patients treated with a systemic line of single agent VEGFR TKI therapy within a prospective observational trial; group outcomes (by time to next therapy [TTNT]) were compared by univariate analysis, Cox proportional hazards modeling (adjusting for age, biologic sex, histology, nuclear grade [incorporating sarcomatoid features], therapy line, and TKI type), and unadjusted Kaplan Meier analysis. Laboratory information for IMDC risk group status was not available. Results: Across 3,721 solid tumor tissue samples, median Angio TRS was highest in known VEGFR TKI sensitive tumors (RCC, thyroid carcinoma, sarcoma). Angio TRS was then validated in a separate cohort of 86 patients with RCC treated with single agent systemic VEGFR TKI (median follow-up 29.2 months; 76% male, 77% clear cell, 14% with sarcomatoid features, 84% 1st line, and 71% treated with sunitinib, pazopanib or axitinib); 52% of patients were Angio TRS High. By univariate analysis, Angio TRS status (p=0.008) and nuclear grade 4 (with or without sarcomatoid features; p=0.06 & 0.07) were most significantly associated with VEGFR TKI TTNT; by multivariate analysis, only Angio TRS status was significantly associated with TTNT (High vs. Low median TTNT 15.8 vs. 5.6 months, adjusted hazard ratio 0.46, p=0.012). Conclusions: Angio TRS is a multivariate expression-based algorithm performed on FFPE tumor tissue, validated to be prognostic of clinical outcome for patients with RCC treated with single agent VEGFR TKI when controlling for clinical factors. Angio TRS may support individualized treatment decision making in patients with advanced RCC. Additional independent validation in a cohort of Kaiser Permanente patients will be presented. Clinical trial information: NCT03061305 .

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P<0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

Prevalence and Associated Factors for Thyroid Dysfunction Among Patients On Targeted Therapy for Cancers: A Single-Center Study from Thailand.

This study aimed to explore the prevalence and associated factors of thyroid dysfunction among cancer patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). A cross-sectional study was done in patients who received TKIs at Rajavithi Hospital in 2019. For patients treated with ICI, a retrospective chart review for patients seen in 2018 to 2019 was conducted. If there were abnormal thyroid function tests (TFT), thyroid autoantibodies were tested. There were 144 patients on TKIs with a mean age of 56.0 years. Thyroid dysfunction was found in 14.6% of patients and most had subclinical hypothyroidism (n = 16, 11.1%). Imatinib (n = 11, 10.8%) and sunitinib (n = 4, 100%) were the 2 most common TKIs given to patients with thyroid dysfunction. Thyroid dysfunction was associated with male sex, chronic kidney disease and hepatitis B virus infection but not with previous thyroid disease and presence of thyroid autoantibodies.There were 18 patients who received ICIs. The mean age was 63.3 years. Twelve patients (66.7%) used programmed cell death protein-1 antibody (anti-PD1), mainly nivolumab. Thyroid dysfunction was found in 50%, which occurred at a median duration of 46 days. Most patients had overt hypothyroidism and 55.6% needed levothyroxine replacement. Thyroid dysfunctions from TKIs were mostly asymptomatic and mild in severity. Some types of TKIs might be associated with thyroid dysfunction. On the other hand, thyroid dysfunction from ICIs usually occurs within 6 months and requires levothyroxine replacement.

Hematological Adverse Events with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Systematic Review with Meta-Analysis.

Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical meta-analysis was to assess the prevalence of other hematological adverse events (AEs) that occur during or after predominantly first-line treatment with TKIs. Data from seventy peer-reviewed, published studies were included in the analysis. Hematological AEs were assessed as a function of TKI drug type (dasatinib, imatinib, bosutinib, nilotinib) and CML phase (chronic, accelerated, blast). AE prevalence aggregated across all severities and phases was significantly different between each TKI (p < 0.05) for anemia-dasatinib (54.5%), bosutinib (44.0%), imatinib (32.8%), nilotinib (11.2%); neutropenia-dasatinib (51.2%), imatinib (29.8%), bosutinib (14.1%), nilotinib (14.1%); thrombocytopenia-dasatinib (62.2%), imatinib (30.4%), bosutinib (35.3%), nilotinib (22.3%). AE prevalence aggregated across all severities and TKIs was significantly (p < 0.05) different between CML phases for anemia-chronic (28.4%), accelerated (66.9%), blast (55.8%); neutropenia-chronic (26.7%), accelerated (63.8%), blast (36.4%); thrombocytopenia-chronic (33.3%), accelerated (65.6%), blast (37.9%). An odds ratio (OR) with 95% confidence interval was used to compare hematological AE prevalence of each TKI compared to the most common first-line TKI therapy, imatinib. For anemia, dasatinib OR = 1.65, [1.51, 1.83]; bosutinib OR = 1.34, [1.16, 1.54]; nilotinib OR = 0.34, [0.30, 0.39]. For neutropenia, dasatinib OR = 1.72, [1.53, 1.92]; bosutinib OR = 0.47, [0.38, 0.58]; nilotinib OR = 0.47, [0.42, 0.54]. For thrombocytopenia, dasatinib OR = 2.04, [1.82, 2.30]; bosutinib OR = 1.16, [0.97, 1.39]; nilotinib OR = 0.73, [0.65, 0.82]. Nilotinib had the greatest fraction of severe (grade 3/4) hematological AEs (30%). In conclusion, the overall prevalence of hematological AEs by TKI type was: dasatinib > bosutinib > imatinib > nilotinib. Study limitations include inability to normalize for dosage and treatment duration.

ALK Inhibitor Treatment Patterns and Outcomes in Real-World Patients with ALK-Positive Non-Small-Cell Lung Cancer: A Retrospective Cohort Study.

Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied. We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs. This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib. The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3months) and OS (54.1 versus 45.8months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures. We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.

Effect on outcomes of toxicity-related dose reduction in TKI monotherapy or TKI-IO combination therapy for advanced renal cell carcinoma.

4528 Background: Tyrosine kinase inhibitors (TKI) in monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). Dose reduction due to toxicity is extremely frequently and represents an important clinical management issue, with frequent dose reduction, treatment suspension and change of schedule. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO). Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Italian and Spanish institutions. A descriptive analysis was performed. Univariate logistic regression models were carried out to estimate the association between best response (CR or PR vs SD or PD) and type of TKI (monotherapy or combination therapy). Survival curves were estimated using the Kaplan-Meier method and were compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: A total of 401 patients were divided in cohort 1 (329 patients) and cohort 2 (72 patients). Median Follow-up was 81.22 months in cohort 1 and 19.02 months in cohort 2. Most frequent toxicities that lead to dose reduction were mucositis (20.13%), Asthenia (16.88%) and Hand-foot syndrome (15.58%). Overall Response Rate was higher in patients that reduced dose, both in cohort 1 (48% vs 29%, p&lt;0.01) and cohort 2 (81% vs 40%, p&lt;0.01). In cohort 1 Progression Free Survival (PFS) was longer in patients with dose reduction (27.14 months vs 16.59 months) (HR 0.77 [0.6; 0.98]; p=0.04). Overall Survival (OS) was also improved (55 months vs 34.17) (HR 0.71 [0.53; 0.93]; p=0.01). In cohort 2, both PFS (39.13 months vs 41.3 months) (HR 0.63 [0.27; 1.48]; p=0.29) and OS (39.13 months vs 55.85 months) (HR 0.65 [0.26; 1.63]; p=0.29) did not statistically differ between patients that reduced dose and patients that did not reduce dose. Conclusions: TKI dose reduction due to toxicity seems to be related to improved outcomes, both in ORR and PFS/OS. ORR was statistically improved in both cohort 1 and cohort 2. PFS and OS in cohort 1 favoured patients that experienced dose reduction. PFS and OS in cohort 2 did not show a statistically significant difference, probably due to the short follow-up and small number of patients. However, outcomes seem to show a trend toward favouring patients that reduce dose.

Retreatment with EGFR inhibitor in non-small cell lung cancer patients previously exposed to EGFR-TKI: A systematic review and meta-analysis.

e21159 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard therapy for EGFR-mutated non-small cell lung cancer (NSCLC) patients. Unfortunately, patients eventually develop resistance to EGFR-TKI and disease progression. Re-exposure after a drug-free interval may be an alternative to overcome tumor resistance. We performed a systematic review and meta-analysis to assess EGFR-TKI retreatment’s efficacy in advanced NSCLC. Methods: We systematically searched PubMed, Embase, and Cochrane databases for clinical trials and observational cohort studies evaluating EGFR-TKI retreatment in advanced NSCLC patients. We aimed to assess the objective response rate (ORR), disease control rate (DCR), and survival outcomes. Subgroup analyses were performed according to the type of EGFRmutation and the TKI drug used in retreatment. We further stratified studies to assess the efficacy of rechallenging with the same drug used initially or a different one. Heterogeneity was assessed using the Cochran Q test, and I2 statistics and random effects models were fitted. Results: We included 16 studies (7 prospective clinical trials, and 9 retrospective cohorts) with 806 patients. Most of them had adenocarcinoma (70.8%), were females (58.1%), and were non-smokers (74.5%). The most frequently TKI given as the initial treatment was gefitinib (58.1%), whereas in the rechallenge it was erlotinib (36.6%) followed by gefitinib (31.6%). In a pooled analysis of patients who were retreated with TKI, the median PFS was 4.1 months (95%CI 3.0 - 4.4), and OS was 12.6 months (95%CI 10.2 - 12.6). ORR was 16% (95%CI 10 - 22%) and DCR was documented in 63% (95%CI 0.54 - 0.72%). Patients harboring a sensitive EGFR mutation had a significantly higher DCR, compared to patients with EGFRT790M mutation, and those with unknown mutational status, (DCR: 70%, 62%, and 48%, respectively, p = 0.02). Patients rechallenged with gefitinib, erlotinib, or afatinib had a similar DCR of 60%, while patients re-exposed to osimertinib had a greater DCR of 70% (95%CI 59 - 80%), (p &lt; 0.01). Regarding ORR, no significant difference was observed amongst the groups defined by the type of EGFR mutation (p = 0.74) or type of TKI used (p = 0.05). Rechallenge using the same versus a different TKI resulted in similar ORR and DCR. In a subgroup analysis of 102 patients who had disease control with the first TKI, 62% (95%CI 45 – 79%) achieved disease control with TKI rechallenge. Conclusions: Our meta-analysis suggests that a subgroup of advanced EGFR-mutated NSCLC patients who failed TKI treatment benefit from rechallenge with an EGFR-TKI after a TKI-free interval. Re-exposure with either the same or a different TKI was shown to be equally effective. Patients treated with osimertinib and those with EGFR-sensitive mutations have better responses to the treatment.

Incidence of serious adverse events caused by tyrosine kinase inhibitor treatment following immune checkpoint inhibitor therapy in advanced NSCLC patients with oncogenic driver alterations.

Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown. We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0. Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3months after ICIs than in patients (n = 23) who initiated TKI treatment 3months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55). The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs.

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.

The Economic Burden of Chronic Myeloid Leukemia in Patients with Later Lines: Findings from a Real-World Analysis in Italy.

Chronic myeloid leukemia (CML) is a hematopoietic myeloproliferative disorder that accounts for 20% of all leukemias of adults. The introduction of tyrosine kinase inhibitors (TKIs) (imatinib, bosutinib, dasatinib, nilotinib, ponatinib) has yielded significant benefits for patients with CML in terms of survival and quality of life. This real-world analysis evaluated the economic burden for managing patients with CML in 2nd or ≥ 3rd TKI lines in Italian settings of clinical practice. A retrospective observational analysis was performed exploiting the administrative databases of a sample of entities covering around 15 million inhabitants. From 2015 to 2018, the study included adult patients with at least one prescription for TKIs, (and for some TKIwithat least one hospitalization discharge diagnosis for CML, or at least one prescription for BCR-ABL examination). The index date was the first TKI prescription. Healthcare resource consumption and costs for patients with CML in 2nd and ≥ 3rd line treatment with TKIs were analyzed for drug prescriptions, hospitalizations, specialist visits, and diagnostic services. In total 635 patients were included, 491 in 2nd line and 144 in 3rd line with TKIs. Dasatinib was the most frequently prescribed drug in 2nd line (28.9%) and imatinib in later lines (26.4%). With progressing lines of treatment, healthcare consumption showed a trend towards increased non-TKI prescriptions per patient (8 for 2nd line and 9.7 for ≥ 3rd line). The management of patients with CML in later lines resulted in increased overall healthcare burden, with hospitalizations accounting for about half of total expenditure, whatever the treatment line and type of TKI. This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or ≥ 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML.

Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer.

Breast cancer (BC) is caused by epigenetic modifications and genetic heterogeneity and exhibits various histological feature. HER2+ (Human epidermal growth factor receptor 2) is a more aggressive type of breast cancer, diagnosis and prognosis are difficult for HER2+ BC. Anti-HER2+ inhibitors have been effectively used for patient treatment. High mortality rate is reported in HER2+ BC, due to availability of limited therapeutic options. Despite advances in systemic medications to treat metastatic breast cancer (MBC), HER2-positive MBC is still challenging for patients and treating clinicians. The clinical characteristics of the disease have changed after treatment with HER2-targeted therapy. Various types of Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with HER2+ BC including afatinib, lapatinib, neratinib, tucatinib, and pyrotinib, have been developed as HER2-targeted therapies. The antibody-drug conjugates adotrastuzumab, emtansine, famtrastuzumab, and deruxtecan, as well as the anti-HER2 monoclonal antibody pertuzumab are used in both early-stage and metastatic situations, either alone or in conjunction with chemotherapy and other HER2-targeting therapies. The emergence of drug resistance in anti-HER2 therapies has been observed. To overcome drug resistance and limited efficacy in current treatment options, nano formulations can be used in patients with HER2+ BC treatment. Anti-HER2 ligands can be used in various nano formulations to target HER2 receptors. Here we will discuss, targeted TKIs in patients with HER2+ BC, clinical studies of HER2+ targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2+ MBC (metastatic breast cancer) and anti-HER2 ligand in various nano formulations to target HER2 receptors.

Clinical outcomes of second-generation tyrosine kinase inhibitors versus imatinib in older patients with CML.

Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first-line treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second-generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML-CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18-64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow-up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR-ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5-year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5-year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first-line treatment is an effective option for both younger and older CML-CP patients with or without comorbidities. This trial was registered at UMIN-CTR as 00003581.

Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment-Free Remission in Chronic-Phase Chronic Myeloid Leukemia: An Observational Retrospective Multi-Center Study

Introduction: Discontinuation of tyrosine kinase inhibitor (TKI) therapy and achievement of treatment-free remission (TFR) in chronic-phase chronic myeloid leukemia (CP-CML) patients is feasible and can be implemented in clinical practice. We conducted a retrospective study at 3 tertiary care centers in Riyadh, Saudi Arabia of all CP-CML patients who discontinued TKI therapy. Methods: All CP-CML patients being followed at participating centers who discontinued TKI, were eligible. TKI discontinuation was carried out as per clinical practice guidelines. Criterion to restart TKI therapy in relapsed patients was loss of major molecular response (MMR; BCR-ABL > 0.1). We collected data on gender, age, prognostic risk-score, type(s) of TKI therapy, type and duration of last TKI before discontinuation, total duration of TKI therapy and response, time to achieve MMR, relapse data including time to relapse and response to re-initiation of TKI therapy, and analyzed the risk factors for relapse. Study was approved by the institutional review boards of all participating centers. Results: Fifty-five patients (35 females) with a median age of 40 years (range 16-74) were included in the study. Median age at TKI stop was 48 years (range 21-80). Majority of the patients (48; 87.27%) received imatinib as first line therapy; 29 (53.74) patients were receiving imatinib at TKI-stop, and 26 (47.27) a second-generation TKI (dasatinib or nilotinib). Fifty-two (94.5%) patients discontinued TKI as per clinical practice (shared decision between treating physician and the patient), and 3 (5.5%) stopped because of pregnancy; 2 patients fulfilled the criteria to stop post-delivery as they remained in deep MR, they were offered to continue stopping. One patient refused to restart TKI (dasatinib) after delivery although she had only 24 months of deep response but continues to have deep remission after 91 months of follow up. Median time to achieve MMR after diagnosis was 12 (range 2-164) months. All the patients had achieved MR4.5 or better (complete molecular response) before stop. Median time from diagnosis to TKI stop was 86 months (IQR 60;132) and median time of last TKI before stop was 66 months (IQR 47;114). After a median follow up of 42 months (IQR 12.5;69) post TKI-discontinuation, 15 (28%) patients relapsed. Median time to relapse was 5 months (range 3-38). Most of the relapses occurred during the first 6 months, except 3 patients who relapsed after 10, 11, and 38 months. Most of the relapsed patients had intermediate or high risk Sokal score. All the relapsed patients achieved MMR after a median of 3 months (range 2-6) after restarting TKI. None of the patients progressed to advanced phase. Conclusion: In real-life practice, TKI discontinuation was possible without relapse for CP-CML patients in deep molecular response, with over two-third of patients continuing in TFR. Majority of the relapsed patients belonged to the intermediate/high-risk score Sokal category at diagnosis. Although this study has the limitation of a retrospective study, our experience in this population confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in clinical practice.