{"id":28252,"date":"2022-08-02T07:00:00","date_gmt":"2022-08-02T07:00:00","guid":{"rendered":"http:\/\/5f9d145142910727344ca9aa287af9ad"},"modified":"2024-11-03T15:13:18","modified_gmt":"2024-11-03T15:13:18","slug":"antitumour-activity-of-combination-of-lenvatinib-and-pembrolizumab-in-patients-with-advanced-melanoma-with-confirmed-progression-on-previous-anti-pd-l1-based-treatment","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/antitumour-activity-of-combination-of-lenvatinib-and-pembrolizumab-in-patients-with-advanced-melanoma-with-confirmed-progression-on-previous-anti-pd-l1-based-treatment\/","title":{"rendered":"Antitumour Activity of Combination of Lenvatinib and Pembrolizumab in Patients with Advanced Melanoma with Confirmed Progression on Previous Anti-PD-(L)1-Based Treatment"},"content":{"rendered":"

A combination of lenvatinib plus pembrolizumab demonstrated antitumour activity and tolerability in patients with melanoma resistant to prior anti-PD-(L)1-based treatment, irrespective of baseline clinical characteristics, intercurrent systemic treatment, or the number of previous therapies. Findings from a phase II LEAP-004 study that evaluated the combination of a multikinase inhibitor lenvatinib and PD-1 inhibitor pembrolizumab in patients with unresectable stage III-IV melanoma who had progressive disease  confirmed per RECIST v1.1 for immune-based treatments (iRECIST) within 12 weeks of a PD-1 or PD-L1 inhibitor given alone or in combination are published by Dr. Ana Arance of the Hospital Clinic Barcelona and IDIBAPS in Barcelona, Spain and colleagues on 22 July 2022 in the Journal of Clinical Oncology<\/em>.<\/p>\n

The authors wrote in the background that resistance to immune checkpoint inhibitors is multifaceted and can occur in the absence of benefit (primary resistance) or after a period of response or disease stability (secondary resistance). Treatment options for patients with melanoma that recurred after or progressed on anti-PD-1-based treatment, particularly anti-PD-1 plus anti-CTLA-4 combinations, are needed.<\/p>\n

Evidence suggests the lenvatinib helps shift the tumour microenvironment to an immune-stimulatory state by inhibiting VEGFR and FGFR. In mouse models, lenvatinib plus PD-1 inhibition had significantly greater antitumour activity than either agent alone. Clinically, the combination of lenvatinib and pembrolizumab has shown efficacy and a consistent safety profile in several tumour types, including patients with advanced melanoma in a phase Ib\/II study cohort.<\/p>\n

The phase II LEAP-004 study was conducted to evaluate the combination of lenvatinib and pembrolizumab in the population of patients with advanced melanoma who progressed on PD-1 or PD-L1 inhibitors. Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease within 12 weeks of the last dose of a PD-(L)1 inhibitor given alone or with other therapies, including CTLA-4 inhibitors, received lenvatinib 20 mg orally once daily plus \u2264 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review.<\/p>\n

In total 103 patients were enroled and treated. The median study follow-up was 15.3 months. In the total population, ORR was 21.4% (95% confidence interval [CI] 13.9 to 30.5), with 3 (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). In the 30 patients with progressive disease on prior anti-PD-1 plus anti-CTLA-4 treatment, ORR was 33.3%. The median progression-free survival in the total population was 4.2 months (95% CI 3.8 to 7.1) and overall survival (OS) was 14.0 months (95% CI 10.8 to not reached).<\/p>\n

Grade 3-5 treatment-related adverse events occurred in 47 patients (45.6%), most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).<\/p>\n

The authors commented that a limitation of this study is the single-arm design. The ongoing phase III LEAP-003 study is comparing lenvatinib plus pembrolizumab with placebo plus pembrolizumab as first-line treatment for advanced melanoma. Because of limitations of the data collected in LEAP-004, the study team was unable to apply the definitions of primary and secondary resistance outlined by the Society of the Immunotherapy of Cancer.<\/p>\n

To exclude the possibility of continued benefit of anti-PD-(L)1 treatment and account for possible pseudoprogression in this single-arm study, the study team used a stringent definition of progressive disease on previous anti-PD-(L)1 treatment in line with recommendations from the Friends of Cancer Research that required progressive disease to be confirmed by iRECIST on a second scan performed at least 4 weeks after initial documentation of progressive disease and to occur on or within 12 weeks of the last dose of anti-PD-(L)1 treatment, which must have been given for at least 2 doses. The 21.4% ORR and 54.5% 12-month OS rate observed are promising given strict definition of progressive disease, the high unmet need for effective treatments for anti-PD-(L)1 resistance, and the substantial proportion of patients with poor prognostic factors, as for example 55.3% had elevated LDH or heavily pretreated disease as 58.3% patients had at lease 2 prior lines of treatment.<\/p>\n

Responses were observed in almost all subgroups examined, including patients with progressive disease on previous anti-CTLA-4 plus anti-PD-(L)1 combination therapy where ORR was 33.3%. The one subgroup in which no responses were observed was 16 patients who received prior anti-CTLA-4 monotherapy. The study team also observed generally similar ORRs regardless of whether patients experienced primary resistance in the adjuvant setting (18.2%) or primary (22.6%) or secondary resistance (22.7%) in the metastatic setting, suggesting that lenvatinib plus pembrolizumab provides a similar likelihood of response across clinical resistance phenotypes.<\/p>\n

The study team has not performed analyses of possible molecular biomarkers of response, although such analyses are planned. A deeper understanding of the biology underlying resistance phenotypes will enable future treatment development.<\/p>\n

The authors commented that the LEAP-004 findings are encouraging because this is an expanding population with limited treatment options.<\/p>\n

The study was funded by Eisai Inc, Nutley, NJ, US and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, US.<\/p>\n

Reference<\/h4>\n

Arance A, de la Cruz-Merino L, Petrella TM, et al.<\/em> 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<\/a>. JCO<\/em>; Published online 22 July 2022. DOI: 10.1200\/JCO.22.00221<\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

A combination of lenvatinib plus pembrolizumab demonstrated antitumour activity and tolerability in patients with melanoma resistant to prior anti-PD-(L)1-based treatment, irrespective of baseline clinical characteristics, intercurrent systemic treatment, or the number of previous therapies. Findings from a phase II LEAP-004 study that evaluated the combination of a multikinase inhibitor lenvatinib and PD-1 inhibitor pembrolizumab in […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-28252","post","type-post","status-publish","format-standard","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28252","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=28252"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28252\/revisions"}],"predecessor-version":[{"id":44875,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28252\/revisions\/44875"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=28252"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=28252"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=28252"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}