657
Views
0
CrossRef citations to date
0
Altmetric
Clinical Trial Protocol

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma

, , , ORCID Icon, ORCID Icon, , , , , , & show all
Received 16 Nov 2022, Accepted 26 Mar 2024, Published online: 02 May 2024

References

  • Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
  • Huang J, Koulaouzidis A, Marlicz W et al. Global burden, risk factors, and trends of esophageal cancer: an analysis of cancer registries from 48 countries. Cancers (Basel) 13(1), 141 (2021).
  • Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J. Clin. 71(1), 7–33 (2021).
  • Then EO, Lopez M, Saleem S et al. Esophageal cancer: an updated surveillance epidemiology and end results database analysis. World J. Oncol. 11(2), 55–64 (2020).
  • Lordick F, Carneiro F, Cascinu S et al. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33(10), 1005–1020 (2022).
  • NCCN clinical practice guidelines in oncology. Esophageal and esophagogastric junction cancers version 2.2022. www.nccn.org/guidelines/guidelines-detail?category=1&id=1433 (04/21/2022).
  • Sun JM, Shen L, Shah MA et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, Phase III study. Lancet 398(10302), 759–771 (2021).
  • Luo H, Lu J, Bai Y et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized clinical trial. JAMA 326(10), 916–925 (2021).
  • Doki Y, Ajani JA, Kato K et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N. Engl. J. Med. 386(5), 449–462 (2022).
  • Wang ZX, Cui C, Yao J et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): a multi-center Phase III trial. Cancer Cell 40(3), 277–288 (2022).
  • Shen L, Lu ZH, Wang JY et al. LBA52 Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: first results of the Phase III ORIENT-15 study. Ann. Oncol. 32, S1330 (2021).
  • Yoon H, Kato K, Raymond E et al. LBA-1 RATIONALE-306: randomized, global, placebo-controlled, double-blind Phase III study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC). Ann. Oncol. 33, S375 (2022).
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252–264 (2012).
  • Vrána D, Matzenauer M, Neoral Č et al. From tumor immunology to immunotherapy in gastric and esophageal cancer. Int. J. Mol. Sci. 20(1), 13 (2018).
  • Raufi AG, Klempner SJ. Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J. Gastrointest Oncol. 6(5), 561–569 (2015).
  • Cui C, Yu B, Jiang Q, Li X, Shi K, Yang Z. The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers. Clin. Exp. Pharmacol. Physiol. 46(1), 3–10 (2019).
  • Ohigashi Y, Sho M, Yamada Y et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11(8), 2947–2953 (2005).
  • Svensson MC, Borg D, Zhang C et al. Expression of PD-L1 and PD-1 in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma: relationship with mismatch repair status and survival. Front. Oncol. 9, 136 (2019).
  • Wakita A, Motoyama S, Nanjo H et al. PD-L1 expression is a prognostic factor in patients with thoracic esophageal cancer treated without adjuvant chemotherapy. Anticancer Res. 37(3), 1433–1441 (2017).
  • Jiang Y, Lo AWI, Wong A et al. Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma. Oncotarget 8(18), 30175–30189 (2017).
  • Yagi T, Baba Y, Ishimoto T et al. PD-L1 expression, tumor-infiltrating lymphocytes, and clinical outcome in patients with surgically resected esophageal cancer. Ann. Surg. 269(3), 471–478 (2019).
  • Kojima T, Shah MA, Muro K et al. Randomized Phase III keynote-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J. Clin. Oncol. 38, 4138–4148 (2020).
  • KEYTRUDA® (pembrolizumab) injection, for intravenous use. Merck & Co., Inc., Rahway, NJ, USA (2023).
  • Doi T, Piha-Paul SA, Jalal SI et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J. Clin. Oncol. 36(1), 61–67 (2018).
  • Shah MA, Kojima T, Hochhauser D et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the Phase II KEYNOTE-180 Study. JAMA Oncol. 5(4), 546–550 (2019).
  • Zhu C, Ma X, Hu Y et al. Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis. Oncotarget 7(28), 44545–44557 (2016).
  • Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15(5), 325–340 (2018).
  • Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell 176(6), 1248–1264 (2019).
  • Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat. Rev. Cancer 13(12), 871–882 (2013).
  • Gockel I, Moehler M, Frerichs K et al. Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. Oncol. Rep. 20(4), 845–850 (2008).
  • Touat M, Ileana E, Postel-Vinay S, André F, Soria JC. Targeting FGFR signaling in cancer. Clin. Cancer Res. 21(12), 2684–2694 (2015).
  • Wada J, Suzuki H, Fuchino R et al. The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res. 29(3), 881–888 (2009).
  • Suzuki H, Onishi H, Wada J et al. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur. J. Immunol. 40(1), 197–203 (2010).
  • Terme M, Pernot S, Marcheteau E et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73(2), 539–549 (2013).
  • Schmittnaegel M, Rigamonti N, Kadioglu E et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9(385), eaak9670 (2017).
  • Voron T, Colussi O, Marcheteau E et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T-cells in tumors. J. Exp. Med. 212(2), 139–148 (2015).
  • Capozzi M, De Divitiis C, Ottaiano A et al. Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment. Cancer Manag. Res11. 3847–3860 (2019).
  • Nair A, Lemery SJ, Yang J et al. FDA approval summary: lenvatinib for progressive, radio-iodine-refractory differentiated thyroid cancer. Clin. Cancer Res. 21(23), 5205–5208 (2015).
  • Nair A, Reece K, Donoghue MB et al. FDA supplemental approval summary: lenvatinib for the treatment of unresectable hepatocellular carcinoma. Oncologist 26(3), e484–e491 (2021).
  • Kato Y, Tabata K, Kimura T et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T-cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLOS ONE 14(2), e0212513 (2019).
  • Kimura T, Kato Y, Ozawa Y et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 109(12), 3993–4002 (2018).
  • Yamamoto Y, Matsui J, Matsushima T et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc. Cell 6, 18 (2014).
  • Taylor MH, Lee CH, Makker V et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J. Clin. Oncol. 38(11), 1154–1163 (2020).
  • Lee CH, Shah AY, Rasco D et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a Phase Ib/2 study. Lancet Oncol. 22(7), 946–958 (2021).
  • Makker V, Taylor MH, Aghajanian C et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J. Clin. Oncol. 38(26), 2981–2992 (2020).
  • Finn RS, Ikeda M, Zhu AX et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38(26), 2960–2970 (2020).
  • Kawazoe A, Fukuoka S, Nakamura Y et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, Phase II trial. Lancet Oncol. 21(8), 1057–1065 (2020).
  • FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma (01/12/2022).
  • Makker V, Colombo N, Casado Herráez A et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N. Engl. J. Med. 386(5), 437–448 (2022).
  • FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma (10/05/2022).
  • Taylor MH, Schmidt EV, Dutcus C et al. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol. 17(6), 637–648 (2021).
  • Cohen DJ, Tabernero J, Van Cutsem E et al. A randomized Phase III study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy versus chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015. J. Clin. Oncol. 40(Suppl. 4), TPS369 (2022).
  • Arance A, De La Cruz-Merino L, Petrella TM et al. Phase II LEAP-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination. J. Clin. Oncol. 41(1), 75–85 (2022).
  • Shitara K, Van Cutsem E, Bang YJ et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 Phase III Randomized Clinical Trial. JAMA Oncol. 6(10), 1571–1580 (2020).
  • Nishio M, Horai T, Horiike A et al. Phase I study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. Br. J. Cancer 109(3), 538–544 (2013).
  • Nishio M, Peled N, Zer A et al. 1313P Phase III LEAP-006 safety run-in (part 1): 1L pembrolizumab (pembro) + chemotherapy (chemo) with lenvatinib (len) for metastatic NSCLC. Ann. Oncol. 31, S848–S849 (2020).
  • Gupta A, Koetz B, Hanekom W, O'brien JP, Wanders J, Jansen M. Population pharmacokinetics (PK) and exposure/response relationships of the receptor tyrosine kinase inhibitor E7080 in phase I studies. Eur. J. Can. Suppl. 8(7), 143 (2010).
  • Motzer R, Alekseev B, Rha SY et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384(14), 1289–1300 (2021).