Second-line lenvatinib in patients with recurrent endometrial cancer

Vergote, Ignace; Powell, Matthew A.; Teneriello, Michael; Miller, David S.; García, Agustin A.; Mikheeva, Olga N.; Bidziński, Mariusz; Cebotaru, C.; Dutcus, Corina E.; Ren, Min; Kadowaki, Tadashi; Funahashi, Yasuhiro; Penson, Richard T.

doi:10.1016/j.ygyno.2019.12.039

Cited by 60 publications

(36 citation statements)

References 30 publications

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“…8 12-16 Lenvatinib monotherapy was also evaluated in a phase 2 trial of 133 patients with recurrent endometrial cancer with an objective response rate of 14.3% with a manageable safety profile. 17 Clinical trials evaluating pembrolizumab plus lenvatinib in patients with endometrial cancer demonstrated objective response rates of 32-40%. 10 11 Results were similar among patients with mismatch repair-proficient tumors (30-36%).…”

Section: Discussionmentioning

confidence: 99%

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

Marth

Tarnawski

Tyulyandina

et al. 2021

Int J Gynecol Cancer

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BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.Primary ObjectiveTo compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.Study HypothesisPembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers).Trial DesignPhase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no).Major Inclusion/Exclusion CriteriaAdults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded.Primary EndpointsProgression-free and overall survival (dual primary endpoints).Sample SizeAbout 875 patients.Estimated Dates for Completing Accrual and Presenting ResultsEnrollment is expected to take approximately 24 months, with presentation of results in 2022.Trial RegistrationClinicalTrials.gov, NCT03884101.

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Section: Discussionmentioning

confidence: 99%

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

Marth

Tarnawski

Tyulyandina

et al. 2021

Int J Gynecol Cancer

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“…The treatment of EC patients with multitarget tyrosine kinase inhibitors sorafenib, sunitinib, nintedanib and lenvatinib achieved disappointing results [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ] ( Table 5 ).…”

Section: Antiangiogenic Agentsmentioning

confidence: 99%

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

Gadducci

Cosio

2021

Cancers

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Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

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“…Interestingly, lenvatinib has been previously reported to have a potential anti-tumor activity in recurrent or metastatic EC [ 39 , 40 ]. Growing evidence indicates that dysregulation of the FGFR signaling pathway is involved in human tumorigenesis [ 41 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches

Lin

Huang

et al. 2021

Cancers

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Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.

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Second-line lenvatinib in patients with recurrent endometrial cancer

Cited by 60 publications

References 30 publications

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches

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