Tyrosine Kinase Inhibitors Lenvatinib Research Articles

Significance of Continuous Low-Dose Lenvatinib for the Treating of the Patients with Unresectable Thyroid Carcinoma.

The tyrosine kinase inhibitor lenvatinib has been confirmed as an effective treatment option for patients with unresectable thyroid carcinoma. We conducted a retrospective analysis of the significance of the effect of continued lenvatinib treatment for the longest duration possible at a reasonable daily dose and with a minimum discontinuation period in 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020. A Cox proportional hazard model-based analysis revealed that the overall survival of the patients treated with a <8 mg/day mean dose of lenvatinib was significantly better than that of the patients treated with 8-24 mg/day (hazard ratio [HR] 0.38 for 1.14-4.54 mg/day, and HR 0.01 for 4.56-7.97 mg/day) adjusted for various factors (e.g., sex, age, drug interruption period). The cumulative dose of lenvatinib administered tended to be higher in the patients treated with low doses (< 8 mg/day) than in the patients treated with relatively high doses (8-24 mg/day). Considering its adverse events, the continuation of lenvatinib treatment with an adequate daily dose and drug interruption may help prolong the survival of patients with unresectable thyroid carcinoma.

Combination of pembrolizumab and lenvatinib in second-line therapy for MSS/pMMR advanced endometrial cancer: literature review and a case report

Despite the existing standard treatments for endometrial cancer, the prognosis for these patients remained poor until recently. None of currently available cytostatics ensured long-term disease control and long-term survival of patients receiving standard platinum-based therapy. Poor treatment outcomes in patients with advanced endometrial cancer necessitated changes in therapeutic approaches and development of more effective treatment regimens. Better understanding of carcinogenesis mechanisms, emergence of a new molecular classification of endometrial cancer, and implementation of tailored treatment approaches based on tumor types led to a significant breakthrough in the treatment of advanced endometrial cancer. Currently, the most effective second-line therapy for endometrial cancer with high level microsatellite instability (MSI-h) or deficient mismatch repair system (dMMR) (25 % of cases), and no indications for surgery is pembrolizumab monotherapy. Most of cancers (about 75 %) are represented by microsatellite-stable and mismatch repair proficient tumors (MSS/рMMR). Patients with such tumors demonstrating disease progression after systemic therapy should receive a combinations of the immune checkpoint inhibitor pembrolizumab and the multi-targeted tyrosine kinase inhibitor lenvatinib. In this article, we review relevant literature and report a case of successful treatment of MSS/pMMR advanced endometrial cancer with a combination of pembrolizumab and lenvatinib as a second-line therapy (after disease progression in response to platinum-containing first-line chemotherapy), which ensured long-term disease control.

Coronary Artery and Peripheral Vascular Disease in a Patient with Poorly Differentiated Thyroid Cancer Treated with the Tyrosine Kinase Inhibitor Lenvatinib

A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.

Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology.

Organoid models have the potential to recapitulate the biological and pharmacotypic features of parental tumors. Nevertheless, integrative pharmaco-proteogenomics analysis for drug response features and biomarker investigation for precision therapy of patients with liver cancer are still lacking. We established a patient-derived liver cancer organoid biobank (LICOB) that comprehensively represents the histological and molecular characteristics of various liver cancer types as determined by multiomics profiling, including genomic, epigenomic, transcriptomic, and proteomic analysis. Proteogenomic profiling of LICOB identified proliferative and metabolic organoid subtypes linked to patient prognosis. High-throughput drug screening revealed distinct response patterns of each subtype that were associated with specific multiomics signatures. Through integrative analyses of LICOB pharmaco-proteogenomics data, we identified the molecular features associated with drug responses and predicted potential drug combinations for personalized patient treatment. The synergistic inhibition effect of mTOR inhibitor temsirolimus and the multitargeted tyrosine kinase inhibitor lenvatinib was validated in organoids and patient-derived xenografts models. We also provide a user-friendly web portal to help serve the biomedical research community. Our study is a rich resource for investigation of liver cancer biology and pharmacological dependencies and may help enable functional precision medicine.

The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the Tumor Microenvironment.

Background: Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. Design: We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAFWT/V600E-ATC-derived cells coimplanted with pericytes. Results: ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAFWT/V600E-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Conclusions and Implications: Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAFWT/V600E-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.

Abstract 5489: Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC)

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tyrosine kinase inhibitors (TKIs) are approved as a first-line treatment for unresectable HCC. Lenvatinib and cabozantinib are two of the most used TKIs, but the therapeutic duration is limited due to the development of drug resistance. Therefore, understanding the mechanisms of resistance and combining TKIs with other drugs antagonizing resistance should lead to antitumor synergy, eliminating drug resistance. It turns out that the simultaneous use of TKIs together with an inhibitor of stearoyl-CoA desaturase 1 (SCD1) prevents the development of drug resistance, leading to a durable response. SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis, converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). MUFAs are an alternative energy source to glucose, integral to cellular membranes, and prevent endoplasmic reticulum (ER) stress and other signaling pathways. In our laboratory, we developed a novel, highly specific SCD1 inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We tested the concomitant use of SSI-4 with lenvatinib and cabozantinib, tyrosine kinase inhibitors (TKIs) FDA-approved for HCC, in HCC cell lines in vitro and using HCC PDX in vivo mouse models. Our studies showed that the combination of the SCD1 inhibitor with both lenvatinib and cabozantinib showed a highly synergistic effect and no development of drug resistance i.e. durable response versus single TKI therapy. Ongoing mechanistic studies are examining whether known molecular targets of tested TKI’s such as VEGFR1, 2, and 3, PDGFRα, FGFR, KIT, and RET dominate in HCC drug resistance to lenvatinib and cabozantinib, and how the use of SSI-4 overcomes the phenomenon of resistance. Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland. Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5489.

Lenvatinib Administration for Anaplastic Thyroid Carcinoma with Brain Metastasis.

We describe the use of the tyrosine kinase inhibitor lenvatinib in a patient with brain tumor metastases from anaplastic thyroid carcinoma (ATC). A 52-year-old Japanese male presented with consciousness loss. Imaging revealed a thyroid tumor and multiple brain lesions. After the brain tumor's resection, pathology results provided the diagnosis of ATC. Total thyroidectomy was performed, followed by whole-brain irradiation. Additional brain lesions later developed, and lenvatinib therapy was initiated with no remarkable complications. However, the treatment effects were limited, and the patient died 2 months after starting lenvatinib, 202 days after the initial brain surgery. Relevant literature is discussed.

The multitargeted tyrosine kinase inhibitor lenvatinib shows promising efficiency and overcomes resistance in FGFR2-driven cholangiocarcinoma

The multitargeted tyrosine kinase inhibitor lenvatinib shows promising efficiency and overcomes resistance in FGFR2-driven cholangiocarcinoma

A theranostic metallodrug modulates immunovascular crosstalk to combat immunosuppressive liver cancer

Hepatocellular carcinoma (HCC) is a highly malignant, fatal disease with a complex tumor microenvironment (TME) characterized by severe immunosuppression and malformed vascular structures, thus most advanced HCC patients do not respond well to current mainstream pharmacotherapy and T-cell-related immunotherapy. Therefore, an efficient immunovascular crosstalk modulation strategy may help combat HCC by reversing immunosuppression and vessel normalization, especially by reprogramming tumor associated macrophages (TAMs). In this study, tyrosine kinase inhibitor lenvatinib (Len) was loaded into mesoporous Fe3O4 (mFe) nanoparticles (NPs), and bovine serum albumin (BSA) was attached to the NP surface to produce a metallodrug (BSA-mFe@Len NPs). In acidic TME, BSA allowed pH-responsive Len release and mFe exposure. Len directly triggered HCC apoptosis and changed the abnormal TME via vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination at tailored dosages. After TAM phagocytosis, mFe NPs reprogrammed TAMs into M1 phenotypes to synergistically amplify antitumor immunity. The metallodrug achieved significant tumor growth inhibition, induced tumor vessel normalization effects, and acquired instant antitumor immunity as well as long-term immune memory in vivo. Furthermore, it displayed good T2 weighted magnetic resonance imaging performance, indicating potential theranostic applications. Collectively, this research provides new insights for unleashing the multifaceted potential of current pharmaceuticals in synergy with metallic nanomedicine for treating intractable liver cancer. Statement of significanceCurrent pharmacotherapy and immunotherapy have limited success in treating advanced hepatocellular carcinoma (HCC) due to its complex tumor microenvironment (TME). Hence, this work first put forward a theranostic metallodrug by loading lenvatinib (Len) into mesoporous Fe3O4 (mFe) nanoparticles (NPs) and coating a pH-degradable bovine serum albumin corona onto the surface. The metallodrug was able to modulate immunovascular TME for combating HCC via metalloimmunotherapy induced by the mFe NPs and Len's multiple functions (direct triggering of tumor apoptosis, vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination). In vivo experiments showed that the metallodrug could significantly inhibit HCC growth and evoke long-term antitumor immune memory, paving a new avenue for treating advanced HCC patients.

METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma.

Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.

Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor-4 inhibition in hepatocellular carcinoma.

The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron‐dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid‐derived 2‐like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib‐induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib‐induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor‐4 (FGFR4) or Nrf2 and overexpressing‐Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system Xc − (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing‐FGFR4 suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2‐silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2‐overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low‐FGFR4 expression than in those with high‐FGFR4 expression. Patients with FGFR4‐positive HCC displayed significantly longer progression‐free survival than those with FGFR4‐negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.

Вторая линия терапии распространенного рака эндометрия. Обзор литературы и клинический случай

Currently, endometrial cancer (EC) remains a socially significant and urgent problem in oncology. In the structure of malignant neoplasms of the uterus, endometrial carcinoma remains the most common type of cancer. According to GLOBOCAN, in 2018, there were 382 069 new cases of uterine cancer worldwide and 89 929 deaths associated with this pathology. Unlike the first line of chemotherapy for advanced EC, the second shows worse results. The overall response rate to second-line chemotherapy is much lower than first-line chemotherapy. Drugs such as oxaliplatin, topotecan, liposomal doxorubicin, etoposide, cyclophosphamide, pemetrexed, gemcitabine, and ifosfamide have shown worse results in studies compared to paclitaxel alone as second-line therapy for advanced endometrial cancer. The clinical efficacy of pembrolizumab monotherapy was a breakthrough in the treatment of EC, as evidenced by a Phase II study published in 2017. The results of molecular genetic studies allow the development and personalization of anticancer drug therapy. The FDA recently approved the use of the tyrosine kinase inhibitor lenvatinib (VEGFR1-3, FGFR 1-4, KIT, RET, PDGFRa) and pembrolizumab as a second-line EC without MSI-H or dMMR. The above clinical observation demonstrates the experience of treating a patient with advanced endometrial cancer in the second line. The combination of lenvatinib with pembrolizumab resulted in a partial response from the first months of therapy. Combination therapy showed a satisfactory tolerability profile in a patient with comorbid pathology; adverse events did not require discontinuation or dose reduction of pembrolizumab and lenvatinib.

Advances in targeted therapy for anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a highly malignant and aggressive thyroid malignancy with rapid onset and poor prognosis. There is no effective treatment for ATC yet. Molecular targeted therapy provides a new idea for ATC treatment. Tyrosine kinase inhibitor lenvatinib has potential in treating ATC patients with favorable efficacy in clinical trials. The effectiveness of the v-raf murine sarcoma viral oncogene homologue B1 () gene inhibitor dabrafenib in combination with trametinib for the treatment of positive ATC patients has been demonstrated in clinical trials. The has proposed dabrafenib in combination with trametinib as the preferred modality for the treatment of patients with positive ATC. The immune checkpoint inhibitor pembrolizumab can be applied to treat thyroid cancer with high tumor mutational load and may be considered as the preferred modality for the treatment of ATC patients with high programmed death ligand-1 expression. The mammalian target of rapamycin pathway inhibitors, peroxisome proliferators-activated receptor γ agonists, endothelial growth factor receptors-targeting monoclonal antibody cetuximab and novel vascular blocker fosbretabulin are still in the clinical research stage, which are expected to provide new directions for the development of novel targeted drugs. This article reviews the current research progress on targeted drugs for the treatment of ATC.

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Changes in blood pressure during treatment with the tyrosine kinase inhibitor lenvatinib.

BackgroundWithin the class of tyrosine kinase inhibitors (TKIs), which are used for the treatment of numerous advanced cancers, lenvatinib is associated with a higher prevalence of hypertension (HT) compared with other TKIs. In this study, we investigated the effect of lenvatinib on blood pressure (BP) and associated factors.MethodsThis single-centre, retrospective observational study included 25 consecutive patients treated with lenvatinib for unresectable hepatocellular carcinoma from April 2018 to December 2018 at the study institution. We assessed changes in BP using ambulatory BP monitoring, urinary sodium excretion, kidney function, use of antihypertensive agents and diuretics, and fluid retention following treatment initiation with lenvatinib.ResultsAt 1 week after treatment initiation, the mean BP and the percentage of patients with riser pattern significantly increased compared with those at the baseline. Although there were no significant changes at 1 week, urinary sodium excretion (153.4 ± 51.7 and 112.5 ± 65.0 mEq/day at 1 and 3 weeks, respectively, P < 0.05) and estimated glomerular filtration rate significantly decreased and the number of patients with fluid retention increased at 3 weeks. Furthermore, patients with fluid retention had significantly higher BP or required more intensive BP treatment compared with those without fluid retention.ConclusionsLenvatinib might lead to HT without fluid retention soon after the initiation of treatment, subsequently leading to a reduction in urinary sodium excretion, thereby contributing to a rise in BP by fluid retention.

ENGOT-en9/LEAP-001: A phase III, randomized, active-controlled, open-label study of pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin for newly diagnosed advanced or recurrent endometrial cancer

Objective: The prognosis for women diagnosed with advanced or recurrent endometrial cancer (EC) is poor, with an estimated 5-year overall survival (OS) of ~17%. The standard first-line treatment for these patients is paclitaxel-carboplatin chemotherapy (CT); however, there is an imperative need for more tolerable and effective therapies. Combination therapy with the PD-1 inhibitor pembrolizumab (pembro) and the tyrosine kinase inhibitor lenvatinib resulted in an objective response rate (ORR) of 39% in women with EC in the phase 1b–2 trial KEYNOTE-146.

Abstract CT289: Pembrolizumab plus lenvatinib vs docetaxel in patients with previously treated metastatic non-small-cell lung cancer (NSCLC) and PD after platinum-doublet chemotherapy and immunotherapy: Phase 3, randomized, open-label LEAP-008 trial

Abstract Background: Pembrolizumab is approved for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥1%. The multireceptor tyrosine kinase inhibitor lenvatinib enhances antitumor activity of PD-1 inhibitors in vitro and has shown clinical activity with pembrolizumab in patients with metastatic NSCLC (NCT02501096). LEAP-008 (NCT03976375) evaluates the efficacy and safety of second/subsequent-line pembrolizumab plus lenvatinib vs docetaxel in patients with previously treated metastatic NSCLC refractory to anti-PD-(L)1 therapy and platinum-doublet chemotherapy. Methods: In this randomized, global, open-label, active-controlled study, patients (n = 405) with metastatic NSCLC who progressed after platinum-doublet chemotherapy and anti-PD-(L)1 therapy are randomized 4:4:1 to pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily (Arm 1, n = 180), docetaxel 75 mg/m2 Q3W (Arm 2, n = 180), or lenvatinib 24 mg once daily (Arm 3, n = 45). Patients are stratified by anti-PD-(L)1 therapy sequencing (immediate prior therapy vs not immediate prior therapy), PD-L1 TPS (&amp;lt;50% vs ≥50%), and Eastern Cooperative Oncology Group performance status (0 vs 1). Treatment continues until PD, unacceptable AEs, concurrent illness preventing study drug administration, investigator decision, or patient withdrawal. Blood pressure is regularly assessed and, if elevated, anti-hypertensive medications are administered and lenvatinib may be withheld and resumed, with or without dose reduction, or discontinued per protocol. Imaging is assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Q6W from randomization until week 36, then Q9W until week 54, then Q12W until PD or start of new anti-cancer regimen. Dual primary outcomes are OS and PFS (RECIST version 1.1 by BICR). Secondary outcomes include ORR (RECIST version 1.1 by BICR), duration of response (RECIST version 1.1 by BICR), safety (AEs graded by National Cancer Institute Common Terminology for Adverse Events version 4.0), and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Lung Cancer Module 13). PFS and OS will be analyzed by the Kaplan-Meier method and stratified log-rank test; differences in ORR will be analyzed by the Miettinen and Nurminen method. Citation Format: Natasha B. Leighl, Rina Hui, Delvys Rodríguez-Abreu, Makoto Nishio, Matthew D. Hellmann, Chooi Lee, Xuan Deng, Debra Kush, Hossein Borghaei, Justin Gainor. Pembrolizumab plus lenvatinib vs docetaxel in patients with previously treated metastatic non-small-cell lung cancer (NSCLC) and PD after platinum-doublet chemotherapy and immunotherapy: Phase 3, randomized, open-label LEAP-008 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT289.

Body Composition and Leptin/Ghrelin Levels during Lenvatinib for Thyroid Cancer

Weight loss is one of the most frequent adverse events during treatment with multikinase inhibitors, but scanty data are available on its extent and characteristics. This is the first assessment of the body composition by bioelectrical impedance analysis and of circulating leptin and ghrelin levels, in patients with advanced thyroid cancer before and at regular intervals during treatment with the tyrosine kinase inhibitor lenvatinib. Body mass index (BMI) decreased in all patients, with an average ∆ reduction of –6.4, –9.8, and –15.3% at 3, 6, and 12 months of treatment, respectively. Interestingly, in most patients, after the first year of treatment, BMI remained stable. In all patients, fat mass (FM) reduced more than fat-free mass, the highest decrement being of –60 and –16%, respectively. A decrease in the body cell mass, a parameter mainly due to muscle tissue, was observed only in patients with a vast baseline muscular mass. Total body water decreased in parallel to BMI. During treatment, leptin tightly paralleled the decrease of BMI values, consistent with the decrease in FM, whereas ghrelin levels increased upon BMI decrease. The loss of the FM accounts for the largest portion of BMI reduction during lenvatinib treatment. The increase in ghrelin could account for the BMI stabilization observed after 1 year of treatment. Nevertheless, oral nutritional supplements should be given as early as possible and athletic patients should be encouraged to maintain physical activity. In some circumstances, parenteral nutrition is required for the rehabilitation of these patients.

Therapy With Tyrosine Kinase Inhibitor Lenvatinib in Radioactive Iodine-Naive Advanced Differentiated Thyroid Cancer

Therapy With Tyrosine Kinase Inhibitor Lenvatinib in Radioactive Iodine-Naive Advanced Differentiated Thyroid Cancer

1063TiP - ENGOT-EN9/LEAP-001: A phase III, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer

BackgroundWhile early stage endometrial cancer (EC) is associated with a favorable prognosis, prognosis for advanced or recurrent EC is poor. Paclitaxel and carboplatin chemotherapy (CT) is often used as first-line treatment for these patients; however, there exists an imperative need for more effective and tolerable therapies. In KEYNOTE-146, combination therapy with the PD-1 inhibitor pembrolizumab (pembro) and the tyrosine kinase inhibitor lenvatinib resulted in an ORR of 39% in patients with EC (Makker et al. ASCO 2018). Based on these promising data, the ENGOT-EN9/LEAP-001 study was initiated to assess this combination therapy in women with recurrent or advanced EC. Trial designThe ENGOT-EN9/LEAP-001 study (NCT03884101) is a phase 3, randomized, open-label, active-controlled trial comparing combination therapy with pembro and lenvatinib to paclitaxel and carboplatin CT in patients with newly diagnosed stage III-IV or recurrent EC (NCT03884101). Approximately 720 patients not previously treated with systemic chemotherapy (except as part of a chemoradiation regimen), antiangiogenic agents, PD-1 or PD-L1 inhibitors, or other T-cell receptor–targeted agents will be randomized 1:1 to pembro (200mg Q3W) plus lenvatinib (20mg daily) or paclitaxel and carboplatin CT (pac 175mg/m2 plus carb AUC 6 Q3W). Patients will first be stratified by proficient vs deficient mismatch repair status (pMMR vs dMMR), and pMMR patients will be further stratified by ECOG performance status (0 vs 1), measurable disease (yes vs no), and prior chemoradiation (yes vs no). Treatment will continue until disease progression, initiation of new anticancer treatment, unacceptable adverse events, or withdrawal of consent for up to 35 cycles for pembro or 7 cycles of paclitaxel and carboplatin CT. Primary endpoints are PFS per RECIST v1.1, assessed by blinded independent central review, and OS. Secondary endpoints are ORR, health-related quality of life, safety and tolerability, and pharmacokinetics of lenvatinib. Exploratory endpoints include duration of response, disease control rate, and clinical benefit rate. Enrollment is ongoing. Clinical trial identificationNCT03884101; 21, 2019. Editorial acknowledgementNathan Rodeberg, PhD, and Diane Neer, ELS, of MedThink SciCom, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA, are responsible for the governance, coordination and running of the study. FundingFunding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. DisclosureC. Vulsteke: Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self): Janssen; Honoraria (self): Novartis; Honoraria (self): Leo-Pharma; Honoraria (self): Merck MSD; Honoraria (self): AstraZeneca; Honoraria (self): Astellas. V. Makker: Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: ArQule; Research grant / Funding (self): Karyopharm; Research grant / Funding (self): AstraZeneca. I.A. McNeish: Honoraria (self): Clovis Oncology; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Takeda; Honoraria (self): Tesaro. L. Dutta: Full / Part-time employment: Eisai. C. Xu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. S.M. Keefe: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. S. Pignata: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Honoraria (self): Clovis Oncology; Honoraria (self): Tesaro; Honoraria (self): Inctre. All other authors have declared no conflicts of interest.