• LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors-Results from the gastric cancer cohort

      Chung, H. C.; Lwin, Z.; Gomez-Roca, C.; Longo, F.; Yanez, E.; Alvarez, E. C.; Graham, Donna; Doherty, M.; Cassier, P.; Lopez, J. S.; et al. (2021)
      Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients
    • LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours

      Lwin, Z.; Gomez-Roca, C.; Saada-Bouzid, E.; Yanez, E.; Munoz, F. L.; Im, S. A.; Castanon, E.; Senellart, H.; Graham, Donna; Voss, M.; et al. (2020)
      Background: Len (antiangiogenic multiple receptor tyrosine kinase inhibitor) + pembro (anti‒PD-1 agent) showed promising clinical outcomes across several cancers in early-phase trials and is FDA-approved for pts with previously treated advanced endometrial cancer that is not MSI-H or mismatch repair-deficient who are ineligible for curative surgery/radiation. We report the first results from the phase 2 LEAP-005 study (NCT03797326), which evaluates the efficacy and safety of len + pembro in pts with select previously treated advanced solid tumors. Methods: This open-label, multicohort study enrolled pts aged 18 y with one of the following previously treated, histologically/cytologically confirmed advanced tumors: triple negative breast (TNBC), ovarian, gastric, colorectal (non-MSI-H/mismatch repair proficient), glioblastoma multiforme (GBM), or biliary tract (BTC; ampulla of Vater excluded). Pts received len 20 mg/d + pembro 200 mg Q3W for 35 cycles or until confirmed PD or unacceptable toxicity. Primary endpoints are ORR by blinded independent central review per RECIST v1.1 or RANO (GBM only), and safety. Results: 187 pts have been enrolled in LEAP-005. Median study follow-up at Apr 10, 2020 data cutoff was 8.6 (range, 1.9‒13.1) mo. Encouraging efficacy was observed across cohorts, and toxicity was manageable (Table). Conclusions: Len + pembro showed promising antitumor activity and manageable toxicity across the previously treated tumor cohorts evaluated in LEAP-005. The study is ongoing; all cohorts will expand to enroll 100 pts/cohort.
    • Lenvatinib plus pembrolizumab for previously treated, advanced triple-negative breast cancer: Early results from the multicohort phase 2 LEAP-005 study

      Chung, H. C.; Saada-Bouzid, E.; Munoz, F. L.; Yanez, E.; Im, S. A.; Castanon, E.; Graham, Donna; Garcia-Corbacho, J.; Lopez, J.; Ghori, R.; et al. (2021)
      Background: Triple-negative breast cancer (TNBC) is associated with poor survival outcomes and treatment options are limited. These tumors lack therapeutic targets and become rapidly resistant to chemotherapy. The anti–PD-1 antibody pembrolizumab showed durable antitumor activity and manageable safety in patients with TNBC in the KEYNOTE-012, KEYNOTE-086, and KEYNOTE-119 studies. The combination of lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, with pembrolizumab has shown promising clinical outcomes in early-phase clinical trials across several cancer types. LEAP-005 (ClinicalTrials.gov, NCT03797326) is an ongoing study evaluating the efficacy and safety of lenvatinib combined with pembrolizumab in patients with previously treated advanced solid tumors. Here, we report the first results from the TNBC cohort of LEAP-005. Methods: This ongoing, multicohort, open-label, phase 2 study enrolled patients aged ≥18 y with previously treated, histologically or cytologically confirmed advanced TNBC. PD-L1 expression was assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100). Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg every 3 weeks intravenously for a maximum of 35 pembrolizumab doses, then lenvatinib alone until progressive disease or unacceptable toxicity. Primary endpoints were objective response rate (ORR) by blinded independent central review per RECIST version 1.1 and safety. Key secondary endpoints were disease control rate (DCR; defined as best overall response of complete response [CR], partial response [PR], or stable disease [SD] per RECIST v1.1), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety was monitored through 30 days after the last dose of study drug (90 days for serious AEs), with AEs graded using NCI CTCAE v4.0. Results: 31 patients have been enrolled in the TNBC cohort of LEAP-005. Median age was 56 y (range, 37 to 85), 58% had received ≥2 prior lines of therapy, and 26% had CPS ≥10 tumors. As of the April 10, 2020 data cutoff, median follow-up was 7 mo (range, 4 to 13). ORR was 29% (95% CI: 14–48), with 1 CR and 8 PRs. 9 pts had SD, and the DCR (CR + PR + SD) was 58% (95% CI: 39–76). 4 responses (1 CR and 3 PRs) were in patients with CPS ≥10 tumors (n=8) for an ORR of 50% (95% CI: 16–84), and 5 responses (all PRs) were in patients with CPS <10 tumors (n=22) for an ORR of 23% (95% CI: 8–45). Median DOR was not reached (range, 0+ to 8+ mo); 7 (78%) responses were ongoing at data cutoff. Median PFS was 4 mo (95% CI: 2–NR), with a 6-mo rate of 49%. Treatment-related AEs (TRAEs) occurred in 97% of pts; 10% discontinued due to TRAEs. 55% of pts had grade 3-5 TRAEs (1 death due to subarachnoid hemorrhage). Conclusions: Lenvatinib in combination with pembrolizumab showed promising antitumor activity with manageable toxicity in patients with previously treated advanced TNBC. Based on these early data, the cohort will be expanded to include 100 patients.
    • A phase 2 multicohort study (LEAP-005) of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors: Pancreatic cancer cohort

      Chung, H.; Villanueva, L.; Graham, Donna; Saada-Bouzid, E.; Ghori, R.; Kubiak, P.; Gumuscu, B.; Lerman, N; Gomez-Roca, C.; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center,Yonsei University College of Medicine, Seoul, South Korea (2021)
      Background:Over the past few decades, the global incidence and mortality ratesassociated with pancreatic cancer have continued to increase. Pancreatic cancer has aparticularly poor prognosis, with a 5-year survival rate of only approximately 5%. Patientswith pancreatic cancer generally respond poorly to chemotherapy, and their treatmentoptions in the second-line or later setting are limited. In two multicohort, open-labeltrials, including the phase 1b/2 KEYNOTE-146 (NCT02501096) and phase 2 LEAP-005(NCT03797326) studies, the combination of theantiangiogenic multikinase inhibitorlenvatinib and the anti‒PD-1 monoclonal antibody pembrolizumab demonstratedpromising antitumor activity with a manageable safety profile in patients with previouslytreated (both studies) and untreated (KEYNOTE-146) histologically or cytologicallyconfirmed metastatic (both studies) and/or unresectable (LEAP-005) solid tumors. In theLEAP-005 trial, benefit was seen in cohorts with glioblastoma multiforme and biliary tractcancer (second-line treatment), triple-negative breast cancer (second- and third-linetreatment), gastric and colorectal cancer (third-line treatment), and ovarian cancer(fourth-line treatment). Based on these encouraging results and the unmet need forpatients with pancreatic cancer, the LEAP-005 protocol was amended to include apancreatic cancer cohort. Here we describe the LEAP-005 trial design for this cohort.Trial design:Eligible patients are aged 18 years with histologically or cytologicallyconfirmed metastatic pancreatic ductal adenocarcinoma and have received 1 or 2prior lines of therapy (including 1 platinum- or gemcitabine-containing regimen),have measurable disease per RECIST version 1.1, have ECOG performance status of0 or 1, and provide a tissue sample for evaluation of PD-L1 expression. Patientsreceive lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35cycles of pembrolizumab (approximately 2 years) or until confirmed disease pro-gression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinibcan continue beyond 2 years in patients experiencing clinical benefit. The primaryendpoints are ORR (per RECIST version 1.1 by blinded independent central review)and safety. The primary safety endpoints are treatment-emergent AEs, serious AEs,and discontinuations due to AEs, with AEs graded using National Cancer InstituteCommon Terminology Criteria for Adverse Events version 4.0. Secondary endpointsinclude disease control rate (comprising CR, PR, and SD), duration of response, PFS,and OS. Health-related quality of life is assessed using validated patient-reportedoutcome instruments including the European Organisation for the Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Tumorimaging is performed Q9W from treatment initiation for 54 weeks, then Q12W toweek 102, and Q24W thereafter. PD-L1 expression is assessed by a central laboratoryusing PD-L1 IHC 22C3 (Agilent Technologies, Carpinteria, CA). The pancreatic cancercohort began enrollment in March 2021. An interim analysis is planned when thefirst30 patients enrolled have been followed up for approximately 6 months.