Outcomes of tyrosine kinase inhibitors after immunotherapy in advanced hepatocellular carcinoma: A multi-center study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16181-e16181
Author(s):  
Thomas Yau ◽  
Joycelyn Jie Xin Lee ◽  
Jeffrey Sum Lung Wong ◽  
Vikki Tang ◽  
Jess Chan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Tumour Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Multi Centre Study

e16181 Background: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are widely adopted in contemporary advanced HCC (aHCC) treatment algorithms. Nevertheless, the optimal strategy for treatment after ICI exposure is unknown. We evaluated the pattern of use, response, survival and safety of TKIs in aHCC patients who previously received ICIs. Methods: We performed an international, multi-centre study of aHCC patients who received TKIs after prior treatment with ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and adverse events (AE) were assessed. Results: Between January 2015 and December 2020, one-hundred and forty-eight patients were included. The median age was 63 (range 29-84) and 78.4% were of Child-Pugh Grade A. 75.7% had hepatitis-B related HCC. 64.9% received TKI as single agent and 35.1% received TKI in combination with other agents. 75% who received TKI combinations had concomitant ICIs. 48.6% had prior TKIs. The median follow-up was 23.3 months. For single agent TKI patients, the ORR was 14.6%, DCR was 38.5%, median TTP was 3.9 months (95% C.I. 3.3-4.5) and median OS was 8.6 months (95% C.I. 5.8-11.4). For patients receiving TKI combinations, the ORR was 25%, DCR was 38.5%, median TTP was 3.5 months (95% C.I. 1.7-5.2) and median OS was 15.1 months (95% C.I. 5.7-24.5). There were no significant differences in ORR, DCR and median OS between patients who had primary resistance to prior ICI compared to those with acquired ICI resistance and between those who were TKI-naive compared to those who were TKI-exposed. Notably, patients who received TKI-ICI combinations had significantly superior survival compared to single agent TKI patients (median OS 15.1 months (95% C.I. 6.7-23.5) vs. 8.6 months (95% C.I. 5.6-11.7), p = 0.011) but not significantly superior ORR, DCR or TTP. Amongst patients who received single agent TKI and were naive to both sorafenib and lenvatinib, those who received lenvatinib had significantly superior DCR, TTP and OS compared to those who received sorafenib (DCR 51.5% vs 25.8%, p = 0.035; median TTP 6.3 months (95% C.I. 3.0-9.7) vs. 1.8 months (95% C.I. 0-3.6), p = 0.003; median OS 12.0 months (95% C.I. 7.0-17.0) vs. 5.9 months (95% C.I. 1.9-10.0), p = 0.008). 70.3% and 15.5% of all patients, and 77.1% and 15.6% of patients who received single agent TKI experienced all grade and grade ≥3 AEs respectively. The most common AEs were hand foot syndrome, skin rash and diarrhea. Conclusions: TKIs can achieve encouraging anti-tumour response and survival outcomes with acceptable safety in prior ICI-treated aHCC patients. Moreover, TKI-ICI combinations were associated with better survival than single agent TKIs. Notably, among patients who received single agent TKIs, lenvatinib had significantly better responses and survival results than sorafenib.

scholarly journals Safety and Efficacy of Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Fei Yang ◽  
Jun Yang ◽  
Wei Xiang ◽  
Bin-Yan Zhong ◽  
Wan-Ci Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Immune Checkpoint ◽  
Transarterial Chemoembolization ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Safety And Efficacy

PurposeTo explore the safety and efficacy of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of unresectable hepatocellular carcinoma (uHCC).Materials and MethodsFrom August 2019 to July 2020, patients who received TACE combined with ICIs and TKIs were retrospectively analyzed. Treatment-related adverse events (AEs) were recorded. The Kaplan–Meier method was used to estimate time to progression (TTP) and progression-free survival (PFS).ResultsIn total, 31 patients with uHCC were included. Eleven patients were classified as BCLC-C. Nineteen patients had multiple lesions, and the cumulative targeted lesions were 69 mm (range, 21-170 mm) according to mRECIST. Twenty-nine (93%) patients experienced at least one AE during the treatment. Four (12.9%) patients developed AEs of higher grade (grade≥3). The objective response rate (ORR) and disease control rate (DCR) were 64.5% and 77.4%, respectively. The median time to response was 7 weeks (range, 4-30 w), and the duration of response was 17.5 weeks (range, 2-46 w). From the first ICIs, TTP and PFS were 6.5 months (95% CI, 3.5-11) and 8.5 months (95% CI, 3.5-NE), respectively.ConclusionsTACE combined with ICIs and TKIs shows an acceptable safety profile and considerable efficacy in patients with HCC.

scholarly journals Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592090750 ◽  
Author(s):  
Elie Rassy ◽  
Ronan Flippot ◽  
Laurence Albiges
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Improved Outcomes

The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR), and immune checkpoint inhibitors (ICIs). Both treatment options have improved outcomes of patients and modified the natural history of mRCC. Clinical investigations have focused on evaluating combination regimens containing ICIs and VEGFR-directed TKIs. Namely, the combinations of axitinib plus pembrolizumab (KEYNOTE-426) and axitinib plus avelumab (JAVELIN RENAL 101) have shown improved outcomes compared with sunitinib in treatment-naïve patients with mRCC. In this review, we discuss the clinical data of single-agent TKIs and ICIs in mRCC and the rationale for the combination ICIs and TKIs based on preclinical and clinical evidence. We also explore the current challenges for regimen selection and development of predictive biomarkers.

scholarly journals Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials

2021 ◽  
Vol 11 ◽  
Author(s):  
Lisha Mou ◽  
Xiaohe Tian ◽  
Bo Zhou ◽  
Yongqiang Zhan ◽  
Jiao Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Normal Tissues ◽  
Targeting Delivery ◽  
Recent Developments ◽  
Delivery Techniques

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

scholarly journals Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

Antioxidants ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 74 ◽  
Author(s):  
Marta Romo-González ◽  
Sara Moreno-Paz ◽  
Violeta García-Hernández ◽  
Fermín Sánchez-Guijo ◽  
Ángel Hernández-Hernández
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Single Agent ◽  
Signaling Cascade ◽  
Xanthine Oxidoreductase

Chronic myeloid leukemia (CML) is characterized by the expression of the oncogenic kinase BCR-ABL. Although tyrosine kinase inhibitors (TKIs) against BCR-ABL represent the standard therapeutic option for CML, resistances to TKIs can be a serious problem. Thus, the search for novel therapeutic approaches is still needed. CML cells show an increased ROS production, which is required for maintaining the BCR-ABL signaling cascade active. In line with that, reducing ROS levels could be an interesting therapeutic strategy for the clinical management of resistant CML. To analyze the therapeutic potential of xanthine oxidoreductase (XOR) in CML, we tested the effect of XOR inhibitor allopurinol. Here, we show for the first time the therapeutic potential of allopurinol against BCR-ABL-positive CML cells. Allopurinol reduces the proliferation and clonogenic ability of the CML model cell lines K562 and KCL22. More importantly, the combination of allopurinol with imatinib or nilotinib reduced cell proliferation in a synergistic manner. Moreover, the co-treatment arms hampered cell clonogenic capacity and induced cell death more strongly than each single-agent arm. The reduction of intracellular ROS levels and the attenuation of the BCR-ABL signaling cascade may explain these effects. Finally, the self-renewal potential of primary bone marrow cells from CML patients was also severely reduced especially by the combination of allopurinol with TKIs. In summary, here we show that XOR inhibition is an interesting therapeutic option for CML, which can enhance the effectiveness of the TKIs currently used in clinics.

scholarly journals Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
B. Melosky ◽  
P. Cheema ◽  
J. Agulnik ◽  
R. Albadine ◽  
D. G. Bebb ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive

BackgroundInhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.MethodsClinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc.ResultsRandomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALKrearrangement.Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.Other systemic therapies should be exhausted before immunotherapy is considered.SummaryMultiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALKrearrangement.

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