Lenvatinib In Patients Research Articles

Overall Survival in Real-World Patients with Unresectable Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab Versus Sorafenib or Lenvatinib as First-Line Therapy: Findings from the National Veterans Health Administration Database.

Background/Objectives: This study evaluated comparative overall survival (OS) of United States veterans with unresectable hepatocellular carcinoma (uHCC) receiving first-line (1L) atezolizumab plus bevacizumab vs. sorafenib or lenvatinib, overall and across racial and ethnic groups. Methods: In this retrospective study, patients with uHCC who initiated atezolizumab plus bevacizumab (post-2020) or sorafenib or lenvatinib (post-2018) were identified from the Veterans Health Administration National Corporate Data Warehouse (1 January 2017-31 December 2022). Patient characteristics were evaluated in the year prior to 1L treatment initiation. Kaplan-Meier and multivariable Cox regression methods were used to compare OS starting from treatment between cohorts, both overall and by race and ethnicity. Results: Among the 1874 patients included, 405 (21.6%) received 1L atezolizumab plus bevacizumab, 1016 (54.2%) received sorafenib, and 453 (24.2%) received lenvatinib, with a median follow-up time of 8.5, 7.6, and 8.2 months, respectively. Overall, patients receiving atezolizumab plus bevacizumab had longer unadjusted median OS (12.8 [95% CI: 10.6, 17.1] months) than patients receiving sorafenib (8.0 [7.1, 8.6] months) or lenvatinib (9.5 [7.8, 11.4] months; both log-rank p < 0.001). After adjustment, atezolizumab plus bevacizumab was associated with a reduced risk of death by 30% vs. sorafenib (adjusted HR: 0.70 [95% CI: 0.60, 0.82]) and by 26% vs. lenvatinib (0.74 [0.62, 0.88]; both p < 0.001). OS trends in the White, Black, and Hispanic patient cohorts were consistent with that of the overall population. Conclusions: Atezolizumab plus bevacizumab was associated with improved survival outcomes compared with sorafenib and lenvatinib in patients with uHCC, both overall and across racial and ethnic subgroups.

OA18.03 Real-World Data on the Efficacy and Safety of Lenvatinib in Patients with Previously Treated Thymic Carcinoma

OA18.03 Real-World Data on the Efficacy and Safety of Lenvatinib in Patients with Previously Treated Thymic Carcinoma

Lenvatinib for the Treatment of Hepatocellular Carcinoma After Liver Transplant

What Is the Issue? Liver transplant is 1 of the main curative therapies for liver cancer; however, hepatocellular carcinoma (HCC) recurrence presents in 10% to 20% of patients after liver transplant. Lenvatinib, an oral multikinase inhibitor drug, was approved for use in Canada as a first-line standard therapy for unresectable HCC, based on a pivotal trial that excluded patients who underwent a prior liver transplant. Data were scarce on the efficacy and safety of lenvatinib for treatment of HCC recurrence in patients who received a liver transplant, and were limited to a few case series and case reports. What Did We Do? We identified and summarized the literature on the evidence of the clinical effectiveness and safety of lenvatinib for the first-line treatment of patients with unresectable HCC recurrence after liver transplant. We searched key resources, including journal citation databases and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We identified a multinational, multicentre, retrospective, single-arm chart review study evaluating the efficacy and safety of lenvatinib in patients with HCC recurrence after liver transplant. Lenvatinib was primarily used as a first-line treatment for most patients (n = 42; 93.3%) and as a second-line treatment for 3 patients (6.7%). The single-arm chart review study showed lenvatinib treatment had an overall response rate (ORR) of 20.0%, a median overall survival of 14.5 months, and a median progression-free survival (PFS) of 7.6 months. These findings were similar to those randomized to lenvatinib in the pivotal phase III REFLECT trial, which excluded patients who had a prior liver transplant. What Does This Mean? The findings of this report suggest that lenvatinib has a potential role as a first-line treatment of patients with HCC recurrence after liver transplant. As the current evidence is limited to a retrospective single-arm chart review study, which had several limitations (e.g., lack of sample size calculation, noncomparative, and retrospective design), further investigations are needed to establish the clinical efficacy and safety of lenvatinib as a first-line treatment for unresectable HCC recurrence after liver transplant.

986P Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations: Results from a multi-center phase Ib/IIa study

986P Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations: Results from a multi-center phase Ib/IIa study

Efficacy and Safety of Sorafenib or Lenvatinib for Advanced Hepatocellular Carcinoma after Failure of First-Line Atezolizumab Plus Bevacizumab: A Systematic Review and Meta-Analysis.

Although atezolizumab plus bevacizumab (hereinafter, atezolizumab-bevacizumab) is the standard first-line treatment for patients with advanced HCC, the optimal second-line regimen remains unknown. This study evaluated the efficacy and safety of sorafenib and lenvatinib in patients with advanced HCC that progressed under atezolizumab-bevacizumab treatment. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase, and the Cochrane Library for articles published before November 2023. Random-effects meta-analysis was performed to determine the pooled objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), comparing patients who received sorafenib versus lenvatinib. Seven studies involving 387 patients were included. The pooled ORR, DCR, OS, and PFS for sorafenib and lenvatinib together were 26% (95% CI: 14-43%), 63% (95% CI: 47-77%), 11.45 months (95% CI: 7.12-15.77, I2 = 92%, p < 0.01), and 3.78 months (95% CI: 2.34-5.23, I2 = 67%, p = 0.02), respectively. Although lenvatinib users had a longer median OS (12.42 vs. 10.75 months) and PFS (5.15 vs. 2.58 months) than sorafenib users, the pooled ORR, DCR, median OS, and PFS for these medications were comparable. Additionally, the distributions of all-grade and grade ≥ 3 adverse events for sorafenib and lenvatinib were comparable to those for these two medications when used as first-line therapies. Sorafenib or lenvatinib can provide effective treatment with manageable toxicity in patients with advanced HCC after disease progression under atezolizumab-bevacizumab.

Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).

Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

Impact of baseline hepatitis B virus viral load on the long-term prognosis of advanced hepatocellular carcinoma treated with immunotherapy.

Although the combination of lenvatinib and PD-1 inhibitors has become the standard regimen for the treatment of advanced hepatocellular carcinoma (HCC), real data on the impact of baseline hepatitis B virus (HBV)-DNA levels on the clinical efficacy of this regimen is still limited. To evaluate the effectiveness of camrelizumab combined with lenvatinib in patients with HCC at varying levels of HBV-DNA. One hundred and twenty patients with HCC who received camrelizumab and lenvatinib treatment were categorized into two cohorts: HBV-DNA ≤ 2000 (n = 66) and HBV-DNA > 2000 (n = 54). The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while additional outcomes included the rate of objective response rate (ORR), disease control rate (DCR), and any negative events. Cox proportional hazards regression analysis revealed independent predictors of OS, leading to the creation of a nomogram incorporating these variables. The median PFS was 8.32 months for the HBV-DNA ≤ 2000 group, which was similar to the 7.80 months observed for the HBV DNA > 2000 group (P = 0.88). Likewise, there was no notable variation in the median OS between the two groups, with durations of 13.30 and 14.20 months respectively (P = 0.14). The ORR and DCR were compared between the two groups, showing ORR of 19.70% vs 33.33% (P = 0.09) and DCR of 72.73% vs 74.07% (P = 0.87). The nomogram emphasized the importance of antiviral treatment as the main predictor of patient results, with portal vein tumor thrombus and Barcelona Clinic Liver Cancer staging following closely behind. The clinical outcomes of patients with HBV-associated HCC treated with camrelizumab in combination with lenvatinib are not significantly affected by HBV viral load.

Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]

Efficacy and safety of combination therapy with envafolimab and lenvatinib in patients with endometrial cancer after failure of first-line platinum-based therapy.

Efficacy and safety of combination therapy with envafolimab and lenvatinib in patients with endometrial cancer after failure of first-line platinum-based therapy.

Neoadjuvant pembrolizumab plus lenvatinib in patients with resectable stage III melanoma (NeoPele): Analysis of tumor microenvironment (TME) correlated to pathological response.

9566 Background: The phase II SWOG S1801 study showed an improved event-free survival with anti-PD-1 (PD1) neoadjuvant immunotherapy (neoIT) vs adjuvant PD1. One hypothesis explaining this benefit is the presence of tumor-draining lymph nodes (tdLN; defined as the nearest node to the tumor without direct involvement) as a potential reserve of stem-like (TCF7+) T cells, crucial to a good response to IT. We sought to analyze the immune infiltrate of the tumor-involved LN (ie TME) and tdLN from patients (pts) achieving major pathological response (MPR: complete [pCR] or near-complete [near-pCR] pathological response) vs non-MPR (partial [pPR] or no [pNR] pathological response). Methods: Pts with stage III melanoma treated with 6 weeks of PD1-based neoIT (PD1 + Lenvatinib) were included (NeoPele clinical trial; NCT04207086). Multiplex fluorescent immunohistochemistry of the TME before and after neoIT, and of the tdLN after neoIT was analyzed (T cell panel: CD3, TCF7, CD103, FoxP3, CD39 and Sox10; and B cell panel: CD20, CD21, CXCR5, TCF7, CD3 and SOX10). Lymphoid aggregates, characterized by clusters of CD21+ and CXCR5+ immune cells, were quantified. Results: Of the 20 pts, 11 (55%) had MPR (8 [40%] with pCR and 3 [15%] with near-pCR) and 9 (45%) had a non-MPR (4 [20%] with pPR and 5 [25%] with pNR). At baseline, MPR pts had a higher % of T cells (11% vs 3%, p = 0.0127) and follicular B helper T cells (CXCR5+; 29% vs 9%, p = 0.0293) than non-MPR pts in the TME. NeoIT led to an increase in the % of T cells, mainly in pts with MPR (median +30%; p = 0.0156) vs non-MPR (median +7%; p = 0.0312) pts, including an increase in the % of tumor-reactive (CD39+) T cells (p = 0.0195), but a decrease in % of tissue-resident stem-like (CD103+ TCF7+) T cells (p = 0.0195). Within the B cell compartment, there was an increase in the % of CD21+ B cells and mature (CD21+ CXCR5+) B cells in MPR vs non-MPR pts. At week 6, MPR pts maintained a higher % of T cells (36% vs 11%, p = 0.0172), follicular B helper T cells (20% vs 9%, p = 0.0133), and mature B cells (10% vs 2%, p = 0.0021) in the TME compared with non-MPR. NeoIT led to a significant increase in the number of lymphoid aggregates in the TME from MPR pts (median +42; p = 0,0156), but no difference in non-MPR pts. No differences were observed in the tdLN based on pathological response. Conclusions: MPR pts had a higher density of T cells in the TME at baseline, and a more differentiated and activated immune profile after neoIT compared with non-MPR pts. MPR pts had a significant increase in the number of lymphoid aggregates at week 6 compared to non-MPR pts; however, the role of these lymphoid aggregates, including the follicular B helper T cell subset and mature B cells, promoting a good pathological response to neoIT is yet to be clarified. Clinical trial information: NCT04207086 .

Cobimetinib plus atezolizumab for RAS and NF1/2-mutated poorly differentiated thyroid carcinoma.

6106 Background: Poorly differentiated thyroid carcinomas (PDTC) are a subset of thyroid cancers characterized by high-grade pathologic features. They hold an intermediate position on the spectrum of follicular-derived thyroid cancers. Due to their more aggressive clinical behavior, PDTCs typically exhibit shorter responses to the usual kinase inhibitors (KIs) used in advanced differentiated thyroid cancers and develop resistance earlier on. In fact, median progression free survival (PFS) with single-agent lenvatinib in patients with PDTC in the SELECT trial (n=28) was 14.8 months. Although there are increasing data to support the use of immunotherapy plus KI combinations in anaplastic thyroid cancer, evidence demonstrating the efficacy of this strategy in PDTC is sparse. We aimed to study the safety and efficacy of atezolizumab combined with KIs in PDTC. Methods: We enrolledpatientswith PDTC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients with RAS or NF- mutated tumors were treated with atezolizumab plus the MEK inhibitor (MEKi) cobimetinib. Primary outcome was median overall survival (mOS). Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Eight patients with RAS/NF-mutated PDTC were enrolled. Median age at treatment start was 68.5 years. All patients had distant metastatic disease at time of enrollment. Prior to study entrance, 7/8 patients (88%) had surgical resection of the primary tumor, 6/8 (75%) radioactive iodine, 2/8 (25%) external beam radiation to the neck, and 3/8 (38%) bridging cytotoxic chemotherapy. All patients were naïve to KIs. Six (75%) patients had RAS mutations (1 HRAS, 3 KRAS, 2 NRAS) and 3 (38%) had NF mutations (2 NF1, 1 NF2). One patient’s tumor harbored both KRAS and NF2 mutations at baseline. PD-L1 score was positive in 3/4 evaluable specimens. Median duration of follow-up was 65 months. Best response to therapy was stable disease in 6/8 (75%), partial response in 1/8 (12.5%) and progressive disease in 1/8 (12.5%). mOS was 23 months (95% CI, 12.8 – 33.2) and median PFS was 7 months (95% CI, 2.4 – 11.6). 4/8 patients received radioactive iodine (RAI) while on systemic therapy. Median dose of RAI was 149 millicuries (range, 108 – 153). mOS was significantly longer in patients who received RAI (32 vs 16 months; p= 0.034). The combination of cobimetinib + atezolizumab was overall well tolerated, with an expected adverse event profile. Conclusions: In patients with metastatic PDTC driven by RAS or NFmutations, combination of the anti-PD-L1 atezolizumab with MEKi cobimetinib showed some clinical efficacy, although PFS was shorter than with single-agent lenvatinib. However, SELECT trial did not delineate responses by driver mutations. This combination could thus be considered in selected patients at high risk of complications with antiangiogenic KIs. Clinical trial information: NCT03181100 .

BGB-A317-212: A multicenter, open-label, phase II study to evaluate the efficacy and safety of tislelizumab in combination with lenvatinib in patients with selected solid tumors.

2610 Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has demonstrated promising efficacy in several advanced solid tumors. However, some patients (pts) do not respond or develop resistance to tislelizumab monotherapy. Lenvatinib, a receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-4, PDGFR alpha, KIT, and RET, has shown a potential synergistic effect with anti-PD-1 therapy. Here, we report the primary results of a phase II study evaluating the combination of tislelizumab plus lenvatinib in pts with solid tumors (NCT05014828). Methods: Pts with histologically/cytologically confirmed selected solid tumors, naïve to lenvatinib and anti-programmed death-ligand 1 (PD-L1)/PD-1 therapies were enrolled. Part 1 (safety run-in) determined the recommended phase II dose (RP2D) of lenvatinib in combination with tislelizumab 400 mg IV every 6 weeks. In Part 2 (expansion), pts received lenvatinib at the RP2D from Part 1 (20 mg orally/day) plus tislelizumab per the Part 1 regimen until disease progression, withdrawal, or death. The primary endpoints were safety and RP2D determination (Part 1) and overall response rate (ORR; Part 2). Results: At data cutoff (Oct 20, 2023; median follow-up 12.1 months [mo; renal cell carcinoma, RCC]; 10.8 mo [head and neck squamous cell carcinoma, HNSCC]; 14.8 mo [gastric cancer, GC], and 22.0 mo [non-small cell lung cancer, NSCLC]), 58 pts were treated in Part 2 (RCC, n=23; HNSCC, n=27; GC, n=3; NSCLC, n=5), 6 of whom were also included in Part 1. The ORR was 66.7% in pts with RCC, 33.3% (HNSCC), 33.3% (GC), and 20.0% (NSCLC). Median duration of response (mDoR) was 18.5 mo and 9.6 mo in pts with NSCLC and HNSCC, respectively; not estimable (NE) for RCC and GC (Table). No new safety signals were identified; grade ≥3 treatment-related adverse events were reported in 78.3%, 59.3%, 33.3% and 60.0%, of pts with RCC, HNSCC, GC, and NSCLC, respectively (Table). Conclusions: Tislelizumab plus lenvatinib had a manageable safety profile and showed preliminary antitumor activity in pts with selected tumor types. Longer follow-up is needed to further investigate the potential of this combination to benefit pts with advanced solid tumors. Clinical trial information: NCT05014828 .[Table: see text]

Patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) with BRAF V600E and/or K601E mutation status: A real-world view of effectiveness of lenvatinib monotherapy.

6098 Background: Lenvatinib was approved for the treatment of patients RAI-R DTC in the United States (US) in 2015, and the treatment landscape has evolved with agents targeting specific driver mutations. We assessed real-world clinical effectiveness of first line therapy with lenvatinib in patients with BRAF-mutated tumors, wild-type (WT) tumors, and patients who have not been tested for BRAF mutations (BRAF untested tumors). Methods: A retrospective chart review of RAI-R DTC patients in the US who initiated first-line lenvatinib monotherapy between February 13, 2015, and September 30, 2020. Data, including a boosted cohort of patients with BRAF-mutated tumors collected in late 2023, were abstracted from patients’ electronic health records and were de-identified. Descriptive analyses were conducted in patient cohorts with BRAF V600E and/or K601E mutated tumors, wild-type (WT) tumors, and BRAF untested tumors. Best response in first-line therapy was captured, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were assessed using Kaplan-Meier methods. Results: Of the 361 patients reviewed, 185 had records showing BRAF mutational status testing. 89 had BRAF V600E and/or K601E mutated tumors, 96 had WT tumors. 176 patients did not have BRAF mutational assessment. Of all subjects, 73.7% were White/Caucasian, 15.2% were African American, and 16.8% were Hispanic/Latino; 27.1% had ECOG performance status ≥2. The median follow-up times for each cohort were 30.0, 18.7 and 18.0 months, showing the longer follow up period for the BRAF-mutated cohort boost. Kaplan-Meier estimation for lenvatinib treatment discontinuation for the three cohorts at 24-months were as shown in the table below. Provider-reported overall response rate (complete or partial response) was 76.4%, 75.0% and 69.3% respectively. The estimated 24-month rwPFS rates (95% CI) were 74.1% (62.2%-82.8%), 61.7% (49.6%-71.8%), and 69.8% (60.9%-77.0%) respectively. Median rwOS was not reached for patients with BRAF-mutated and WT tumors, median OS was 54.2 months for BRAF untested tumors. Estimated rwOS rates at 12- and 48-months were 93.2% (85.4%-96.9%) and 83.9% (73.3%-90.3%) in BRAF-mutated patients, 90.6% (82.8%-95.0%) and 68.5% (53.4%-79.6%) in WT patients, and 90.2% (84.7%-93.8%) and 72.5% (61.6%-80.7%) in BRAF untested patients respectively. Conclusions: In this US real-world experience, the effectiveness of lenvatinib is consistent across a diverse cohort of RAI-R DTC patients with BRAF-mutated, WT, and BRAF untested tumors. This has implications for the first-line use of lenvatinib in BRAF mutated patients. [Table: see text]

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

Survival benefit from adjuvant TACE combined with Lenvatinib for patients with hepatocellular carcinoma and microvascular invasion after curative hepatectomy

Background and aimsThe prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. MethodsPatients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. Results346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099–0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129–0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. ConclusionThe combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.

Abstract CT292: Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases

Abstract Background: Many patients develop brain metastasis during the course of their disease and it represents the cause of death in more than half of them. The prognosis and survival of patients with brain metastases remains poor with limited palliative treatment options. Thus, there is a need to develop new strategies for the therapeutic management of patients with brain metastases. Inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activation and infiltration into tumors. Several studies have demonstrated now the efficacy of immune checkpoint inhibitors in patients with melanoma with active brain metastases. The modulation of VEGF-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. Lenvatinib is an oral, potent multiple receptor tyrosine kinase inhibitor that selectively inhibits VEGFRs, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases. The combination of lenvatinib and pembrolizumab is approved for patients with metastatic endometrial carcinoma and renal cancer, and it is investigated in other tumor types with promising preliminary results. We hypothesize that pembrolizumab and lenvatinib will be an effective treatment for TNBC, NSCLC, and other solid tumor types with brain metastases by decreasing angiogenic tumor activity and improving antitumor T-cell activity. Methods: This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases. The study has 3 cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other solid tumor types with established or preliminary clinical evidence of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. Eligible patients will have at least 1 unirraditated or progressing brain metastasis of 0.5-2 cm on brain MRI. The study is conducted using a Simon’s optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort). Pembrolizumab (200 mg intravenously on Day 1 of each cycle) and lenvatinib (20 mg orally once daily) are administered in 21-day cycles for a maximum of 24 months. The primary endpoint is intracranial objective response rate at 4 months as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exploratory analyses will include evaluation of tissue and blood-based immune-related correlates of response to the pembrolizumab and lenvatinib combination. The first patient was enrolled in January 2022 and accrual of patients is ongoing (NCT05064280). Citation Format: Ecaterina E. Dumbrava, Emma J. Montazari, Uyen M. Vu, Tiantian Cai, Mehmet Altan, Nuhad K. Ibrahim, Debra N. Yeboa, Jing Li, Frederick F. Lang, Gisela Sanchez, Isabella C. Glitza, Barbara J. O'Brien, Rashmi K. Murthy, Jianbo Wang, Tanisha T. Darko, Denisse Velazquez, Komal Shah, Funda Meric-Bernstam, Hussein Tawbi, Jordi Rodon. Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT292.

Stereotactic Body Radiotherapy Combined With Lenvatinib With or Without PD-1 Inhibitors as Initial Treatment for Unresectable Hepatocellular Carcinoma

PurposeThe aim of this study was to compare the clinical benefit and safety of the triple combination of stereotactic body radiotherapy (SBRT), lenvatinib and programmed death 1 (PD-1) inhibitors with the dual combination of SBRT and lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Methods and MaterialsPatients with uHCC who received SBRT in combination with lenvatinib and PD-1 inhibitors or SBRT in combination with lenvatinib alone as first-line treatment from October 2018 to July 2022 were reviewed in this study. The primary endpoints were overall survival (OS), and progression-free survival (PFS). The second endpoints were intra-hepatic PFS (IHPFS), extra-hepatic PFS (EHPFS) and objective remission rate (ORR). In addition, safety profiles were assessed by analyzing treatment-related adverse events (TRAEs) between the two groups to assess safety profiles. ResultsIn total, 214 patients with uHCC who received combination therapy were included in this retrospective study. Among them, 146 patients received triple combination therapy of SBRT, lenvatinib and PD-1 inhibitors (SBRT-L-P group), and 68 patients received dual therapy of SBRT and lenvatinib (SBRT-L group). The median OS times of the two groups were 31.2 months and 17.4 months, respectively (P<0.001). The median PFS time was significantly longer in the SBRT-L-P group than that in SBRT-L group (15.6 months vs. 8.8 months, p<0.001). Additionally, the median IHPFS (17.5 vs. 9.9 months, p<0.001) and EHPFS (20.9 vs. 11.6 months, p<0.001) were significantly longer in the SBRT-L-P group than that in SBRT-L group. The ORR in the SBRT-L-P group was higher than that in the SBRT-L group (63.0 vs. 39.7%, p=0.002). The incidence and severity of TRAEs in the SBRT-L-P group were comparable to those in the SBRT-L group. ConclusionThe use of both lenvatinib and PD-1 inhibitors with SBRT in patients with uHCC was associated with improved overall survival compared to lenvatinib and SBRT alone with a manageable safety profile.

Long-term follow-up and exploratory analysis of lenvatinib in patients with metastatic or recurrent thymic carcinoma: Results from the multicenter, phase 2 REMORA trial

ObjectivesThe main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented. Materials and MethodsThe single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777). ResultsThe updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1–34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %–49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2–not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4–26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22–0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile. ConclusionThis follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes.

Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity.

Lenvatinib is a multitargeted tyrosine kinase inhibitor capable of promoting apoptosis, suppressing angiogenesis, inhibiting tumor cell proliferation, and modulating the immune response. In multiple cancer types, lenvatinib has presented manageable safety and is currently approved as an effective first-line therapy. However, with the gradual increase in lenvatinib application, the inevitable progression of resistance to lenvatinib is becoming more prevalent. A series of recent researches have reported the mechanisms underlying the development of lenvatinib resistance in tumor therapy, which are related to the regulation of cell death or proliferation, histological transformation, metabolism, transport processes, and epigenetics. In this review, we aim to outline recent discoveries achieved in terms of the mechanisms and potential predictive biomarkers of lenvatinib resistance as well as to summarize untapped approaches available for improving the therapeutic efficacy of lenvatinib in patients with various types of cancers.

Lenvatinib in recurrent hepatocellular carcinoma after liver transplantation.

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients &lt;60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least &gt;28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H0: ORR = 5%; H1: ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .