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, Christian; Tarnawski, Rafał; Tyulyandina, Alexandra; Pignata, Sandro; Gilbert, Lucy; Kaen, Diego; Rubio, María Jesús; Frentzas, Sophia; Beiner, Mario; Magallanes-Maciel, Manuel; Farrelly, Laura; Choi, Chel Hun; Berger, Regina; Lee, Christine; Vulsteke, Christof; Braicu, Elena Ioana; Wu, Xiaohua; McKenzie, Jodi A.; Lee, John J.; Makker, Vicky

doi:10.1136/ijgc-2021-003017

Cited by 50 publications

(29 citation statements)

References 16 publications

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“…We were aware of the activity of immunotherapeutic agents (anti-programmed death-1 monoclonal antibody) either alone [ 62 ] or in combination with tyrosine kinase inhibitors in advanced EMC that had failed prior to systemic therapy [ 63 ]. The demonstrated efficacy of these agents in phase I/II studies led to phase III trials that had recently reported superior survival outcomes over standard chemotherapy with paclitaxel and carboplatin [ 64 ] or are still ongoing [ 65 ]. Whether these agents will be used in the future as neoadjuvant treatment in advanced and inoperable EMC is yet to be seen.…”

Section: Resultsmentioning

confidence: 99%

Management of inoperable endometrial cancer

2022

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Some endometrial cancer (EMC) patients are not good candidates for primary surgery. The three major types of treatment for inoperable EMC are radiation therapy, chemotherapy, or their combination as neoadjuvant treatment before surgery. Radiation therapy alone (of different modes) has been used as the sole definitive therapeutic modality, particularly for early-stage disease that is limited to the uterine body and cervix with or without parametrial invasion. The most common treatment modality is neoadjuvant treatment before surgery. Postoperative adjuvant treatment is also occasionally used, depending mainly on the sites of the disease and the results of surgery. Data on neoadjuvant hormonal or radiation therapy are limited, with studies focusing on laboratory outcomes or having only a small number of patients. Most neoadjuvant treatments before surgery involved chemotherapy and fewer combined chemoradiotherapy. Surgery was generally performed, particularly in patients who had shown responses or at least stable disease to neoadjuvant treatment. Perioperative outcomes after neoadjuvant treatment were superior to those after primary surgery, whereas survival data were still inconsistent. Features that had or tended to have a favorable prognosis were younger age, early-stage disease, response to neoadjuvant treatment, low preoperative cancer antigen-125 level, and optimal surgery. Among different modalities of neoadjuvant treatment, which has become a frequent mode of treatment, neoadjuvant chemotherapy was more common than radiation therapy alone or chemoradiation.

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Section: Resultsmentioning

confidence: 99%

Management of inoperable endometrial cancer

2022

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“…Lenvatinib combined anti-PD-1 has been approved in endometrial carcinoma and renal cell carcinoma. In KEYNOTE-775/Study 309, lenvatinib and pembrolizumab demonstrated an ORR of 30%, PFS 6.6 months (HR 0.60) and OS 17.4 months (HR 0.68), which was superior to doxorubicin or paclitaxel in platinum-experienced endometrial carcinoma [ 23 ]. In renal cell carcinoma, the combination of lenvatinib and pembrolizumab was highly effective with an ORR of 38% in the phase Ib/II trial KEYNOTE-146 [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience

Lin

Chen

et al. 2022

Invest New Drugs

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Lenvatinib, a multi-tyrosine kinase inhibitor that inhibits vascular endothelial growth factor and fibroblast growth factor receptors pathway, activated the immune response in tumor microenvironment. However, the combination of lenvatinib and anti-PD-1 has been reported in early phase studies. Hence, this study aims to explore the efficacy and toxicity of lenvatinib combined with nivolumab in the real-world setting. Advanced HCC patients who underwent lenvatinib combined with nivolumab (L + N group) treatment at Taipei Veterans General Hospital (Taipei, Taiwan) were reviewed between January 2016 and December 2020. Treatment response and outcomes were collected and analyzed. A control group with lenvatinib (L group) was also included for comparison. Forty patients were included in L + N group and 47 in L group. The L + N group demonstrated a higher objective response rate than L group (45.0% vs. 23.4%, p = 0.03). The L + N group also achieved longer PFS (7.5 vs. 4.8 months, p = 0.05) and OS (22.9 vs. 10.3 months, p = 0.01) than L group. Patients with HBV infection and REFLECT criteria fit demonstrated a trend of better prognosis. The PFS for those with PR, SD and PD groups were 11.2, 6.4, and 2.2 months and OS were non-reached, 14.6 and 4.7 months, respectively. Portal vein thrombosis (HR 4.3, 95% C.I. 1.5–12.8) and AFP > 400 ng/mL (HR 3.3, 95% C.I. 1.1–9.3) were poor prognostic factors and nivolumab used remained a protective factor (HR 0.2, 95% C.I. 0.1–0.7). Dermatitis (35.0%), pruritis (27.5%), and hypothyroidism (27.5%) were the common toxicities. Few patients developed grade 3/4 toxicities, including dermatitis (15%), gastrointestinal bleeding (7.5%), hypertension (5.0%), pneumonitis (2.5%) and stomatitis (2.5%). This is the first real-world data reporting the promising efficacy and tolerable toxicities of lenvatinib combined with nivolumab in advanced HCC. Further randomized trials are prompted.

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“…More information on IHC including MMR proteins ( MLH1, MSH2, MSH6 , and PMS2 ) and p53 were shown in Supplementary Table 1 . Currently, two phase III RCTs are ongoing for newly diagnosed advanced or recurrent EC: the ENGOT-en9/LEAP-001 trial, comparing the efficacy and safety of pembrolizumab plus lenvatinib combination therapy vs. paclitaxel-carboplatin [ 23 ], and the ENGOT-en6/NSGO-RUBY trial, comparing the efficacy and safety of dostarlimab plus paclitaxel-carboplatin vs. placebo plus paclitaxel-carboplatin [ 24 ]. If these two trials commonly result in positive results from the experimental arms, incorporation of immune checkpoint inhibitors might further expand the use of NAC in the management of unresectable metastatic EC.…”

Section: Discussionmentioning

confidence: 99%

Clinical implications of neoadjuvant chemotherapy in advanced endometrial cancer: a multi-center retrospective cohort study

et al. 2022

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Background The mainstay of endometrial cancer treatment is surgical resection of tumors and postoperative adjuvant treatment is recommended if necessary. However, there is no consensus on the management of unresectable metastatic endometrial cancer. This study aimed to assess the feasibility and effectiveness of neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) in unresectable, metastatic endometrial cancer. Methods From the endometrial cancer cohorts of four institutions in Korea, we identified patients with International Federation of Gynecology and Obstetrics stages IIIC–IVB endometrial cancer who received NAC-IDS between January 2008 and December 2020. Through a medical record review, we collected patients’ clinicopathological data. Progression-free survival (PFS), overall survival (OS), and the factors affecting survival outcomes were analyzed. Results Overall, 32 patients were included with endometrioid (n = 18), serous (n = 5), carcinosarcoma (n = 6), and other histological types (n = 3). Among them, 28 (87.5%) patients had stage IVB disease. The most common neoadjuvant chemotherapy (NAC) regimen was paclitaxel-carboplatin (n = 25, 78.1%), which was administered for a median of six cycles. While 26 (81.3%) patients showed an objective response, two (6.3%) progressed despite NAC. At the time of interval debulking surgery (IDS), 23 (71.9%) patients achieved complete cytoreduction. During 31.0 months of the median follow-up, there were 23 recurrences and 11 deaths, corresponding to a median PFS of 19.7 months and a 3-year OS rate of 69.7%. In multivariate analyses, non-endometrioid histology and residual tumor after IDS were identified as independent poor prognostic factors for PFS (adjusted hazard ratio [HR], 7.322; P < 0.001 and 5.934; P = 0.001, respectively). Multivariate analysis for OS could not be conducted because of the small number of events, although non-endometrioid histology was the only factor associated with worse OS in univariate analysis (adjusted HR, 4.523; P = 0.032). Conclusions NAC-IDS may be a treatment option for unresectable metastatic endometrial cancer. Tumor histology and the possibility of complete cytoreduction are the primary considerations for NAC-IDS.

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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

Cited by 50 publications

References 16 publications

Management of inoperable endometrial cancer

Management of inoperable endometrial cancer

Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience

Clinical implications of neoadjuvant chemotherapy in advanced endometrial cancer: a multi-center retrospective cohort study

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