scholarly journals Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6310
Author(s):  
Marie Decraecker ◽  
Caroline Toulouse ◽  
Jean-Frédéric Blanc
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Standard Of Care ◽  
Special Focus ◽  
Second Line ◽  
First Line ◽  
First Line Therapy ◽  
Therapeutic Algorithms

The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.

Adherence and persistence to second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17009-e17009
Author(s):  
Digisha Trivedi ◽  
Shahla Amin ◽  
Ling Zhu ◽  
Sam Joo ◽  
Hugh Kawabata ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Medication Possession Ratio ◽  
Patient Characteristics ◽  
Treated Group ◽  
Second Line ◽  
First Line

e17009 Background: Some studies have demonstrated the correlation between adherence and persistence to therapy and the effectiveness of that therapy, thereby reinforcing the need to optimize both as a core treatment strategy. Because available data are limited, we examined real world adherence and persistence to the 2nd generation tyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukemia (CML). Methods: An observational retrospective study was conducted using pooled Invision Data Mart and Pharmetrics claims data. Adult CML patients with at least two prescriptions for a 2nd generation TKI between July 1, 2006 and December 31, 2010 were identified and followed for a maximum of 6 months from their index date (first observed prescription date). Dasatinib and nilotinib patients with prior imatinib use in 6 month pre-index period were classified as second-line and those with no prior use as first-line patients. Adherence to treatment was defined by the medication possession ratio (MPR) and persistence as the proportion of patients refilling prescriptions within 1.5 times the days supply during the follow-up period. Results: Of the 276 CML patients identified, 179 received dasatinib (n=50 first-line; n=129 second-line) and 97 received nilotinib (n=27 first-line; n=70 second-line). Patient characteristics were similar across treatment groups. Proportions with MPR ≥85% were 64% and 75% for first- and second-line dasatinib and 48% and 61% for first- and second-line nilotinib. Persistence rates were 36% and 47% for first- and second-line dasatinib and 26% and 39% for first- and second-line nilotinib. Conclusions: In both first- and second-line use, dasatinib was associated with higher adherence and persistence than the corresponding nilotinib-treated group. The reason for the difference between these TKIs is not known and will require further study.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 324-324
Author(s):  
Ciro Celsa ◽  
Giuseppe Cabibbo ◽  
Marco Enea ◽  
Salvatore Battaglia ◽  
Giacomo Emanuele Maria Rizzo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Data ◽  
Survival Curve ◽  
Second Line ◽  
First Line ◽  
Lifetime Horizon ◽  
First Line Therapy ◽  
Line Therapy ◽  
Unresectable Hepatocellular Carcinoma ◽  
Sequential Strategy

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.

Prognostic factors of chronic myeloid leukaemia

2020 ◽  
pp. 63-78
Author(s):  
Michele Baccarani ◽  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
First Line ◽  
Abl Tyrosine Kinase ◽  
Baseline Characteristics ◽  
Kinase Domain Mutations

Two decades following the successful introduction of the ABL tyrosine kinase inhibitors in clinics for the treatment of patients with chronic myeloid leukaemia (CML), the principal objective of treatment in chronic phase (CP) is survival, preferably without life-long therapy. In tandem, the methodology and tools for assessing the prognosis of the newly diagnosed patient with CML in CP has evolved substantially. Prior to the era of tyrosine kinase inhibitors (TKIs), risk assessment depended more on the response to treatment than on baseline characteristics. The Sokal score, introduced in 1984, was the first one dividing patients into three risk categories based on a mathematical formula taking into account the patient’s age, and baseline characteristics like blast cell count, spleen size, and platelet count. This, and the several other subsequent risk stratification methods developed during the chemotherapy and interferon-alpha era, have remained useful in the first-line TKI treatment, and identifies a variable proportion of high-risk patients with lower response rates and worse outcomes. In second line, the most important risk factors are the absence of haematologic or cytogenetic response on first line, the presence of hematologic toxicity the development of additional cytogenetic abnormities (ACA), and the development of BCR-ABL1 kinase domain mutations. In this chapter, we address the prognosis of CML and the various methods for risk stratification.

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