Combination Of Lenvatinib Research Articles

945P Adjuvant lenvatinib in combination with TACE for hepatocellular carcinoma patients with high risk of postoperative relapse (LANCE): Updated results from a multi-center prospective cohort study

Multiple studies had demonstrated that surgical resection provided better overall survival (OS) than other treatments even for BCLC stage B or C hepatocellular carcinoma (HCC) patients in China. However, there was no standard adjuvant therapy to decrease the risk of post-operative tumor relapse. Several studies showed transcatheter arterial chemoembolization (TACE) as adjuvant therapy could reduce tumor recurrence and prolong the disease-free survival (DFS) and OS. However, its effect is not satisfactory.

A multicenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer

<h3>Objectives:</h3> Results from a phase 1b/2 study showed lenvatinib (LEN) + pembrolizumab (pembro) has efficacy in patients (pts) with advanced endometrial carcinoma following prior treatment. Here, we describe the phase III study results of LEN + pembro vs treatment of physician's choice (TPC) following platinum-based therapy in pts with advanced endometrial cancer (aEC). <h3>Methods:</h3> Pts were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m² IV Q3W or paclitaxel at 80 mg/m² IV QW [3 weeks on; 1 week off]). Eligible pts had aEC with 1 prior platinum-based chemotherapy regimen or up to 2 prior platinum-based chemotherapy regimens, if 1 was given in the neoadjuvant/adjuvant setting. Randomization was stratified by DNA mismatch repair (MMR) status (centrally determined); pts with proficient (p)MMR tumors were further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. Primary endpoints were PFS by blinded independent central review per RECIST v1.1 and OS. Key secondary endpoints included objective response rate (ORR) and safety. A graphical approach for multiplicity to control for type 1 error was used to test PFS for pts with pMMR aEC, then pts irrespective of MMR tumor status (ie, all comers), followed by OS (pMMR aEC, then all comers) and ORR (pMMR aEC, then all comers). Efficacy analyses were conducted in randomized pts; safety analyses were conducted in pts who received treatment. <h3>Results:</h3> A total of 827 Pts (pMMR, n=697; dMMR, n=130) received LEN + pembro (n=411) or TPC (n=416). Median follow-up was 12.2 mo for pts randomized to LEN + pembro and 10.7 mo for pts randomized to TPC (data cutoff October 26, 2020). PFS was significantly improved with LEN + pembro vs TPC in pMMR aEC (median 6.6 vs 3.8 mo; HR 0.60) and in all-comers (median 7.2 vs 3.8 mo; HR 0.56). OS was significantly longer with LEN + pembro vs TPC in pMMR aEC (median 17.4 vs 12.0 mo; HR 0.68) and in all-comers (median 18.3 vs 11.4 mo; HR 0.62). ORR was significantly greater with LEN + pembro vs TPC in pMMR aEC (30.3% vs 15.1%) and in all-comers (31.9% vs 14.7%). Additional results are in the table. Median treatment duration was 231 days with LEN + pembro and 104.5 days with TPC. Overall, any-grade treatment-emergent adverse events (TEAEs) occurred at similar rates across treatment arms. Grade ≥3 TEAEs occurred in 89% of pts with LEN + pembro and 73% of pts with TPC. In the LEN + pembro arm, 30.8% pts discontinued LEN, 18.7% discontinued pembro, and 14.0% discontinued both study treatments due to a TEAE; the most common TEAEs were hypertension (64%), hypothyroidism (57%), diarrhea (54%) and nausea (50%). <h3>Conclusions:</h3> LEN + pembro demonstrated statistically significant and clinically meaningful improvements in PFS, OS, and ORR vs TPC both in pts with aEC that was pMMR and in pts with aEC irrespective of MMR status. The safety profile of LEN + pembro was manageable and consistent with previously reported studies.

The use of pembrolizumab and lenvatinib combination therapy in endometrial cancer: an examination of toxicity and treatment efficacy in clinical practice

<h3>Objectives:</h3> Pembrolizumab/lenvatinib demonstrated impressive response rates in advanced/recurrent endometrial cancer (EC) in a recent phase II clinical trial, leading to its accelerated FDA approval. However, tolerability of the recommended 20 mg starting dose of lenvatinib may pose clinical challenges. To comprehend how this regimen translates into daily clinical practice, we evaluated our preliminary data regarding toxicity and efficacy of pembrolizumab/lenvatinib in the treatment of advanced/recurrent EC at the University of Texas MD Anderson Cancer Center. <h3>Methods:</h3> In this single-institution, retrospective cohort study, we evaluated recurrent/advanced EC patients who received ≥1 cycle of pembrolizumab/lenvatinib treatment. Toxicity was evaluated through rates of hospitalization and treatment interruptions or discontinuations, as well as number of dose reductions. Clinical efficacy was evaluated by best radiologic response to treatment. Clinical benefit was defined as having stable disease or partial/complete response. <h3>Results:</h3> From October 2019 to July 2020, 83 EC patients were identified but 16 were excluded for unconfirmed administration of pembrolizumab/lenvatinib or lack of toxicity or response data. Thus, 67 EC patients were included in the analysis with a median follow-up of 5 months (range 1 - 11). The median age and number of prior lines of therapy were 67 (range 31–77) and 2 (range 1–9), respectively. The majority had an ECOG performance status of 0 to 1 (91%). The predominant histologic subtype was endometrioid and serous (n=19 each) followed by carcinosarcoma (n=13), mixed (n=8), clear cell (n=4), and other (n=4). The most common starting dose of lenvatinib was 14 mg (n=43; 64.2%), followed by 20 mg (n=15; 22.4%). Treatment-related hospitalizations occurred in 26.9% of patients but did not differ between lenvatinib dosage groups (p=0.37). Compared to those with a lower starting dosage level, patients started on 20 mg doses had significantly higher treatment discontinuations (100% vs 69.2%, p=0.01) and numbers of lenvatinib dose reductions (1.0 vs 0.38, p=0.004), with a trend of higher treatment interruptions (93.3% vs 73.1%, p=0.09). Among the 56 patients with evaluable radiologic response, there were 21 (37.5%) patients with either a partial (n=18) or complete response (n=3), while 18 patients (32.1%) had stable disease. Of the patients with complete response, all patients had a starting lenvatinib dose of 14 mg. Based on a starting lenvatinib dose of 20 mg vs < 20 mg, there were no differences in response to therapy (23.1% vs 41.9%; p=0.56; respectively) or clinical benefit rates (53.8% vs 74.4%, p=0.18; respectively). There were no differences in response rates among histologic subtypes (p=0.76). Patients with carcinosarcoma histology had a response and clinical benefit rate of 25% (3 of 12) and 58.3% (7 of 12), respectively. <h3>Conclusions:</h3> In treatment of recurrent/advanced EC, lower starting dosage of lenvatinib was associated with fewer treatment interruptions/discontinuations and dose de-escalations compared to the FDA recommended 20 mg dosage level while maintaining equivalent response and clinical benefit rates. Furthermore, patients with carcinosarcoma histology also appeared to benefit from pembrolizumab/lenvatinib. While larger studies are needed to validate these safety and efficacy findings, our preliminary data supports starting a lower dosage of lenvatinib in clinical practice.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancercell lines that express EGFR and in vivo in xenografted liver cancercell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibitionof fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinibtreatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.

PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients

Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival.

Rapid Response to the Combination of Lenvatinib and Pembrolizumab in Patients with Advanced Carcinomas (Lung Adenocarcinoma and Malignant Pleural Mesothelioma).

Simple SummaryOver the past decades, the multi-drug approach for treating various types of cancers was highly recommended. The aim of this study was to demonstrate the advantage of treating different carcinoma types with several combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). We showed that patients treated with the combination of lenvatinib and pembrolizumab showed an enhanced response to therapy compared to other treatments. Our ex-vivo studies exhibited reduced proliferation and PD-L1 levels for PDX explants treated with this combination compared to untreated explants or those treated with a single treatment. Based on the results of this study, we propose that the combination of levatinib and pembrolizumab shows great potential as a treatment option for patients with non-small cell lung carcinoma and malignant pleural mesothelioma, as previously suggested by recent clinical trials.The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. We present, to our knowledge, the first reported series of cases consisting of patients with metastatic non–small cell lung cancer and malignant pleural mesothelioma who were treated with several types of chemotherapy combinations and ICIs followed by disease progression. They were subsequently treated with combined immunotherapy and TKI treatment, resulting in a near complete response within a very short time. Clinical responses were supported by in vitro testing of each patient’s lymphocytic response to pembrolizumab after pre-exposure of target cancer cells to lenvatinib.

Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab.Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14–24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1–90%).Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%.Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma?

ABSTRACT Introduction While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results. Areas covered This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed. Expert opinion The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.

Abstract 486: A phase Ib/II, open-label study evaluating the efficacy and safety of Toripalimab injection (JS001) or combination with Lenvatinib as a neoadjuvant therapy for patients with resectable hepatocellular carcinoma (HCC)

Abstract Background: There is no standard of care for neoadjuvant or adjuvant therapy for resectable hepatocellular carcinoma (HCC) yet. This trial is designed to explore the safety and efficacy of toripalimab or toripalimab in combination of lenvatinib as peri-operative treatment in HCC. (NCT03867370) Methods: In this ongoing phase Ib/II trial, patients (pts) with HCC who are eligible for surgical resection are enrolled. In neoadjuvant part of study, pts in Arm A are given toripalimab 480 mg iv single dose and pts in Arm B are treated with toripalimab 480mg iv plus concurrent lenvatinib 12 or 8 mg daily orally (based on body weight). All pts receive scheduled surgery on day 21-28. Lenvatinib is given until at least 7 days before surgery. Pts with R0 section confirmed by pathological analysis and MRI 4 weeks after surgery can take part in the adjuvant part of study. Toripalimab at 240 mg iv is given every 3 weeks for 48 weeks in Arm A. Pts in Arm B 1:1 randomized to receive toripalimab per same schedule as Arm A or toripalimab plus concurrent lenvatinib for 48 weeks. The primary objective is the pathological response. Secondary objectives include safety/tolerability, ORR, DCR, time to operation and PFS. Results: From 1 June 2019 to 7 Sep 2020, 18 pts were enrolled (10 in Arm A and 8 in Arm B) and 16 pts were evaluable. Two pts withdrew consent, one was due to the Covid-19 pandemic, and another received liver transplantation subsequently. The HCC in 11 pts were BCLC A stage, 4 pts were BCLC 0 and 1 pt BCLC B. 14 patients were in Chinese HCC staging CNLC Ia, 2 pts were in CNLC Ib. 81.3% patients were recurrent HCC. 16.7% (3/18) of patients experienced Grade 3+ AEs, 1 patient in Arm B experienced treatment-related SAE (hyperglycemia, well controlled). 16 pts (8 in Arm A and 8 in Arm B) proceeded with resection as planned. There were no delays or cancellations in surgery related to immunotherapy or target treatment. No visible tumor was observed in resected specimen in one patient. No pathological complete response (pCR) was observed in other 15 pts. 3 pts (20%) achieved major pathologic response (MPR, residual tumor in &amp;lt;50% tumor bed) and 2 in Arm A and 1 in Arm B. Multiple immunohistochemistry analysis of the immune infiltrates in the tumor microenvironment showed an increase in T-cell infiltration in MPR tumor tissue compared with non-response tumor tissue. Conclusion: PD-1 inhibition with toripalimab or toripalimab plus multikinase inhibition with lenvatinib result in promising antitumor activity as preoperative therapy in resectable HCC. There were no new or unexpected toxicities resulting from combination. Citation Format: Ying-Hong Shi, Yuan Ji, Wei-Ren Liu, Yan-Rui Pang, Zhen-Bin Ding, Xiu-Tao Fu, Xin Zhang, Cheng Huang, Yun-Fan Sun, Xiao-Dong Zhu, Hui-Chuan Sun, Jian Zhou, Jia Fan. A phase Ib/II, open-label study evaluating the efficacy and safety of Toripalimab injection (JS001) or combination with Lenvatinib as a neoadjuvant therapy for patients with resectable hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 486.

Phase II study of lenvatinib in combination with GEMOX chemotherapy for advanced intrahepatic cholangiocarcinoma.

e16163 Background: The prognosis of advanced intrahepatic cholangiocarcinoma (ICC) remains dismal with gemcitabine-based first-line chemotherapy. This study is to evaluate the safety and efficacy of lenvatinib in combination with gemcitabine and oxaliplatin (Gemox) chemotherapy in the advanced ICC. Methods: Locally advanced or metastatic ICC patients (pts) were given lenvatinib 12 mg/day (body weight ≥60 kg) or 8 mg/day (body weight &lt;60 kg) oral administration, once daily. They also received 1g/m² gemcitabine on Day 1 and Day 8, and 85 mg/m² oxaliplatin Q3W by IV for 6-8 cycles. The primary outcome was objective response rate (ORR) and secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). ORR, DCR and PFS were measured according to RECIST 1.1. Treatment would be terminated by confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. Results: From March 2020 to Sep. 2020, 30 pathologically-confirmed advanced ICC pts with a mean age of 59.2 (range, 33-74) years, including 14 women (46.7%), were enrolled at Zhongshan Hospital, Fudan University. At the end of last follow-up (February 10, 2021), the ORR was 30.0% (9/30; 95% CI: 14.7%-49.4%). The disease control rate (DCR) was 86.7% (26/30; 95% CI: 69.3%-96.2%). Median follow-up was 6.8 months. One pt with locally advanced disease was down-staged and then underwent resection. This patient remained disease-free survival at the end of last follow-up. 11 pts experienced disease progression and 8 pts have died. The median PFS and OS have not been reached. Median duration of response (DOR) has not been reached and responses were ongoing in 6/9 (66.7%) pts. 6-months OS rate was 92.6%. No grade 5 adverse event (AE) was observed in present study. 40.0% (12/30) of pts experienced grade 3 or higher AEs and 5 pts discontinued the treatment owing to fatigue (3 pts), jaundice (1 pt) and vomiting (1 pt). Conclusions: Addition of lenvatinib to Gemox chemotherapy provided modest efficacy with reasonable tolerability in advanced ICC patients. Clinical trial information: (NCT04361331). Clinical trial information: NCT04361331.

Gemox chemotherapy in combination with anti-PD1 antibody toripalimab and lenvatinib as first-line treatment for advanced intrahepatic cholangiocarcinoma: A phase 2 clinical trial.

4094 Background: The outcome of advanced intrahepatic cholangiocarcinoma (ICC) remains poor with current gemcitabine-based chemotherapy. This study is to evaluate the safety and efficacy of anti-PD1 agent toripalimab, lenvatinib in combination with oxaliplatin and gemcitabine (Gemox) chemotherapy. Methods: Locally advanced or metastatic ICC patients (pts) were given 240 mg toripalimab Q3W via intravenous (IV) infusion, 8 mg lenvatinib QD orally, and 1g/m² gemcitabine on Day 1 and Day 8, and 85 mg/m² oxaliplatin Q3W by IV for 6 cycles. The primary outcome was objective response rate (ORR), which was evaluated according to RECIST v1.1. Secondary outcomes included safety, progression-free survival (PFS) and overall survival (OS). Treatment would be terminated by confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. Whole exome sequencing was performed on available tumor tissues and PD-L1 expression was determined by immunohistochemistry staining. Results: From May 2019 to Oct 2019, 30 pathologically-confirmed advanced ICC pts with a mean age of 56.5 (range, 25-73) years, including 11 women (37%), were enrolled at Zhongshan Hospital, Fudan University (one pt withdrawn). At the end of last follow-up (February 1, 2021), the ORR was 80% (24/30; 95% CI: 61.4%-92.3%), and disease control rate (DCR) was 93.3% (28/30; 95% CI:77.9%-99.2%). Median follow-up was 16.6 months. One pt achieved complete response (CR). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. 23 pts experienced disease progression and 12 pts (including one pt withdrawn) have died. The median PFS was 10.0 months and median duration of response (DOR) was 9.8 months. The median OS have not been reached. 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%). No grade 5 adverse event (AE) was observed in present study. Grade 3 or 4 neutropenia and thrombocytopenia observed in 3 (10%) and 1 (3.3%) patient, respectively. Non-hematological toxic effects were jaundice (10 %), rash (6.7 %), proteinuria (6.7 %), increased AST level (3.3%), vomiting (3.3%), upper gastrointestinal hemorrhage (3.3%), sepsis (3.3%), gastrointestinal fistula (3.3%), adrenocortical insufficiency (3.3%), interstitial pneumonia (3.3%), and hyponatremia (3.3%). High ORR was significantly associated with positive PD-L1 expression ( p= 0.048) and DNA damage repair (DDR)-related mutations ( p= 0.022) in tumor samples. Conclusions: Gemox chemotherapy in combination with Anti-PD1 antibody Toripalimab and Lenvatinib provided remarkable efficacy with reasonable tolerability in advanced ICC patients. These findings warrant further validation in a large randomized clinical trial. Clinical trial information: NCT03951597.

PD-1 inhibitor combined with lenvatinib for unresectable liver cancer as the conversion therapy: An open-label, non-randomized, phase IV study.

e16173 Background: The combination of lenvatinib and PD-1 inhibitor has shown to be a promising regimen for advanced hepatocellular carcinoma (HCC). We aimed to assess the feasibility of conversion therapy by lenvatinib combined with PD-1 inhibitor in unresectable HCC in a non-randomized phase IV study (ChiCTR1900023914). Methods: Eligible patients had histologically or cytologically confirmed unresectable HCC (AASLD); BCLC B or C; an ECOG status of 0 or 1 and Child-Pugh A-B. Patients received lenvatinib (8-12mg, oral QD) and PD-1 inhibitor (IV Q3W) until disease progression, unacceptable toxicity or satisfied for curative surgery. Surgical patients received maintenance therapy based on the pathological evaluation (pCR: PD-1 inhibitor 6-12m, pPR: combination therapy 6-12m, pPD: personalized). The primary endpoint was conversion rate for surgery based on radiological assessment. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), relapse-free survival (RFS) and overall survival (OS) by modified RECIST. Tumor tissue samples were collected at diagnosis and surgery. Immune cell subsets (CD8+ T cell, macrophage, NK cell) in tumor and stromal were measured by multiplex fluorescent immunohistochemistry. Whole exosome sequencing was performed with tumor samples and matched white blood cells. Results: and received the combination therapy. 49 patients were evaluated for the efficacy, 51.0% patients (5 CR, 17 PR and 3 SD) were conversed successfully based on their radiological evaluation after 3-7 cycles of combination therapy, among whom 15 patients (30.6%) actually received curative surgery upon comprehensive evaluation and patient preference. The median duration of follow-up was 271 days. The ORR was 53.1% (26/49, 5 CR and 21 PR) and the DCR was 69.4% (34/49). The median RFS and median OS of the 15 surgical patients were unreached. The 12-month OS was 74.1% and the 12-month RFS was 61.1%. Treatment-related adverse events occurred in 46.9% (23/49) of patients (grade ≥ 3, 6.1%). In both pre- and post-therapy tumor tissues, more CD8+ T cells (pre: p = 0.083, post: p = 0.007) and M1 macrophages (pre: p = 0.127, post: p = 0.120) were present in responders compared with non-responders. The conversion therapy could promote macrophage differentiating into M1 type in treatment-sensitive patients, as post-therapy tumoral M1/M2 ratio were higher in responders than non-responders (p = 0.073). Higher frequency of KMT2C mutation (missense and splicing, p = 0.040) were observed in response group. Conclusions: Combination of PD-1 inhibitor with lenvatinib as conversion therapy could benefit unresectable advanced HCC patients to achieve curative surgery. Tumor microenvironment and genomic characteristics may explain the potential mechanism of the clinical response. Clinical trial information: ChiCTR1900023914.

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

3564 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326. [Table: see text]

Lenvatinib plus pembrolizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma: A real world study.

e16138 Background: The combination of lenvatinib (LEN) and pembrolizumab (PEMBRO) showed promising response rates and survival in a phase 1b trial for patients with unresectable hepatocellular carcinoma (HCC). Whether LEN plus PEMBRO provides better outcomes than LEN monotherapy remains unclear. The aim of this study was to compare the outcomes of LEN plus PEMBRO versus lenvatinib monotherapy in patients with unresectable HCC in the real world setting. Methods: A total of 123 patients with unresectable HCC were retrospectively enrolled, including 61 patients with LEN monotherapy and 62 patients with LEN plus PEMBRO. We evaluated progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and modified RECIST (mRECIST) criteria. Results: One hundred and one (82.1%) patients were in BCLC stage C and 81 (65.9%) patients received LEN or LEN plus PEMBRO as first line setting. During a median follow-up period of 8.0 months, 71 (57.7%) and 31 (25.2%) of patients had disease progression and death, respectively. The median PFS was 8.4 and 4.9 months in the LEN plus PEMBRO and LEN monotherapy groups, respectively (p = 0.033). The median OS was not reached in the LEN-PEM group and was 17.2 months in the LEN monotherapy group (p = 0.064). Patients with LEN plus PEMBRO had higher objective response rate (ORR: 34.4% vs 23.7% by RECIST 1.1, p = 0.277; 57.4% vs 32.2% by mRECIST, p = 0.010) and higher disease control rate (83.6% vs 62.7% by RECIST 1.1, p = 0.017; 85.2% vs 62.7% by mRECIST, p = 0.009). In subgroup patients with BCLC stage C, LEN plus PEMBRO provided significantly longer PFS (9.1 vs 4.8 months, p = 0.008), higher ORR (60% vs 33.3%, p = 0.015) and higher DCR (88% vs 60.4%, p = 0.004) by mRECIST criteria. Conclusions: LEN plus PEMBRO provides significantly better ORR, DCR and PFS then LEN monotherapy for patients with unresectable HCC.

KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).

TPS4595 Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.

Immune checkpoint inhibitors in endometrial cancer.

The incidence of endometrial cancer (EC) is increasing worldwide. The prognosis for patients diagnosed with early-stage remains good, whereas for patients with recurrent or metastatic disease, the prognosis is poor and treatment options, until recently, were limited. In 2017, pembrolizumab was approved by the US Food and Drug Administration (FDA) for those patients with mistmach repair deficiency (MMRd) or high microsatellite instability (MSI-H) tumors. However, only 20-30 % of EC have MSI, and just over half of these patients benefit from treatment. In 2019, the FDA granted breakthrough therapy designation to lenvatinib in combination with pembrolizumab for the potential treatment of patients with advanced microsatellite stable EC that has progressed after treatment with at least one previous systemic therapy. It appears clear that immune check-point inhibitors will have a definite place in the management of EC, both as single agent or in combination with other targeted agents. In this review, we summarize the current evidence of immune check point blockade and the identification of potential biomarkers, beyond MSI-H or MMRd, that could help to predict response to this agents in correlation with the genomic EC subtypes.

Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study

PurposeTo compare the efficacy and safety of combined treatment with lenvatinib and transarterial chemoembolization (TACE) versus TACE only in patients with unresectable hepatocellular carcinoma (uHCC).MethodsOf the 120 patients enrolled in this study, 60 patients received treatment with TACE only, and 60 patients received TACE plus lenvatinib. We retrospectively compared the clinical outcomes including overall survival (OS), progression-free survival (PFS), and tumor response between the two groups. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Adverse events were analyzed to assess the safety profiles.ResultsThe 1-year and 2-year OS rates were significantly higher in the TACE + lenvatinib group (88.4% and 79.8%) than that in the TACE group (79.2% and 49.2%, p = 0.047). A similar PFS benefit was observed in the TACE + lenvatinib group (1-y PFS rate: 78.4% vs. 64.7%, 2-y PFS rate: 45.5% vs. 38.0%, p < 0.001). The best overall objective response rate (ORR) was also better with TACE + lenvatinib treatment (ORR: 68.3% vs. 31.7%, p < 0.001) and disease control rate (DCR) numerically increased in the TACE + lenvatinib treatment (93.3% vs. 86.7%, p = 0.224). Patients’ liver function remained comparable to baseline in the TACE + lenvatinib group. The most common adverse events were decreased albumin (55.0%), hypertension (48.3%) and decreased platelet count (46.7%) in the TACE + lenvatinib group.ConclusionsCombination treatment with TACE and lenvatinib may significantly improve clinical outcomes over TACE monotherapy with a manageable safety profile for unresectable HCC. The efficacy of the combination treatment should be validated in prospective studies with a large sample size.Graphical abstract

A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma

BackgroundNon-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. ObjectiveTo determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participantsThis open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. InterventionLenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysisThe primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitationsThe study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. ConclusionsLenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summaryWe examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registrationThis trial is registered at ClinicalTrials.Gov as NCT02915783.

The Angiotensin II Receptor Blocker Losartan Sensitizes Human Liver Cancer Cells to Lenvatinib-Mediated Cytostatic and Angiostatic Effects.

Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage.

Health-related quality-of-life outcomes from a phase II open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment.

314 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer, constituting 80% to 85% of primary renal neoplasms. Preserving health-related quality of life (HRQOL) is an important goal during RCC treatment, but HRQOL analyses in prospective clinical trials in RCC are limited. We report changes in HRQOL, a secondary endpoint of this phase II trial. Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of two different starting doses of lenvatinib (18 mg vs. 14 mg daily [QD]) in combination with everolimus (5 mg QD), following one prior vascular endothelial growth factor–targeted treatment (NCT03173560). HRQOL was measured using three different instruments, including the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L. Change from baseline HRQOL was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale (i.e., 10 points for EORTC, 3 points for FKSI-DRS, 0.08 points for EQ-5D index, and 10 points for EQ-VAS). The distribution of TTD and median TTD for each treatment arm were estimated using the Kaplan-Meier method. Results: Baseline characteristics, including baseline scores of the 343 participants randomly assigned to 14 mg QD lenvatinib (n = 172) and 18 mg QD lenvatinib (n = 171), were well balanced. The average scores for the 18 mg QD group were generally higher, with lower symptom severity than the 14 mg QD group. The least squares mean estimates for change from baseline were favorable for the 18 mg QD group over the 14 mg QD group for the FKSI-DRS and most EORTC QLQ-C30 scales; however, the differences between treatments did not exceed the minimally important difference for clinical significance. Both study arms showed an increase diarrhea severity. Median TTD was longer among participants in the 18 mg QD group than those in the 14 mg QD group for most scales. Conclusions: In most scales, participants who received an 18 mg QD lenvatinib starting dose had better HRQOL and longer time to deterioration than those who received a 14 mg QD starting dose. These findings suggest that the approved treatment regimen of an 18 mg starting dose of lenvatinib in combination with everolimus remains favorable for RCC treatment, following one prior vascular endothelial growth factor–targeted treatment. Clinical trial information: NCT03173560 .