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. 2024 Dec 16;30(24):5612-5619.
doi: 10.1158/1078-0432.CCR-24-2519.

Histology-Specific Clinical Trial of Lenvatinib and Pembrolizumab in Patients with Sarcoma

Sujana Movva  1   2 , Kenneth Seier  3 , Viswatej Avutu  1 , Lauren B Banks  1   2 , Jason Chan  1   2 , Ping Chi  1   2   4 , Mark A Dickson  1   2 , Mrinal M Gounder  1   2 , Ciara M Kelly  1   2 , Mary L Keohan  1 , Robert Maki  1   2 , Evan Rosenbaum  1   2 , Tiffany Salcito  1 , Kaithleen Rodriguez  1 , Rebecca Dempsey  1 , Paul A Meyers  5 , Seth M Cohen  2   6 , Martee L Hensley  2   6 , Jason A Konner  2   6   7 , Alison M Schram  2   6   7 , Robert A Lefkowitz  8   9 , Joseph P Erinjeri  7   9   10 , Li-Xuan Qin  3 , William D Tap  1   2 , Sandra P D'Angelo  1   2
Affiliations

Histology-Specific Clinical Trial of Lenvatinib and Pembrolizumab in Patients with Sarcoma

Sujana Movva et al. Clin Cancer Res. .

Abstract

Purpose: Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma.

Patients and methods: This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety.

Results: Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively.

Conclusions: We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.

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Conflict of interest statement

Conflict of Interest Statement: S.M has received research funding from Ascentage Pharma Group; Hutchison MediPharma; Trillium Therapeutics, Pfizer and PTC Therapeutics. J.C. has received research funding from Cytek Biosciences; Ono Pharmaceutical and patent pending for methods to identify and treat high-plasticity cell state driving tumor progression in lung cancer. P.C. has received institutional funding from Deciphera; NewBay Pharma; Pfizer, consulting fees from Deciphera; NewBay Pharma; Zai Lab and stock/ownership interests and royalties from ORIC. M.A.D has received research funding from Aadi; Lilly; Sumitomo Dainippon Pharma Oncology. M.M.G has received consulting fees from Ayala Pharmaceuticals; Bayer; Boehringer Ingelheim; Daiichi Sankyo; Epizyme; Karyopharm Therapeutics; Rain Therapeutics; Regeneron; Springworks Therapeutics; TYME and honoraria/speaker’s bureau/travel expenses from Epizyme; Flatiron Health; Guidepoint Global; Med Learning Group; Medscape; More Health; PER touchIME, Amgen, Boehringer Ingelheim, Karyopharm Therapeutics. C.M.K has received research funding from Agios; Amgen; Curadev; Exicure; INCYTE; Kartos Therapeutics; Merck; Regeneron; Servier; Xencor and consulting fees from ChemoCentryx; Exicure; Immunicum; Kartos Therapeutics; Servier and has stock/ownership interests in Daichii Sankyo. R.G.M reports research funding from Amgen; Astex Pharmaceuticals; BioAtla; Boehringer Ingelheim; C4 Therapeutics; InhibRx; Regeneron; SARC: Sarcoma Alliance for Research though Collaboration; TRACON Pharma, consulting fees from Boehringer Ingelheim; Deciphera; Eisai; GlaxoSmithKline; Medtronic; PEEL Therapeutics and speakers’ bureau/royalties from MJH Life Sciences and UptoDate. E.R has received research funding from Arcus Biosciences; GlaxoSmithKline; Incyte and has stock/ownership interests in Iovance Biotherapteutics and PMV Pharma P.A.M has received research funding from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim; Salarius Pharmaceuticals and honoraria/speakers’ bureau/travel fees from Takeda; InterMune; France Foundation; Genentech/Roche; Eastern Pulmonary Conference. M.L.H has received consulting fees/royalties form Aadi; GlaxoSmithKline; Thrive; An Exact Sciences Company; Up to Date and has stock/ownership interests in Sanofi. A.M.S has received research funding from AstraZeneca; BeiGene; Black Diamond Therapeutics; Elevation Oncology; Kura Oncology; Lilly; Merus; Pfizer; PMV Pharma; Relay Therapeutics; Repare Therapeutics; Revolution Medicines; Surface Oncology and consulting fees from Mersana; Merus NV; Relay Therapeutics. J.P.E reports consulting fees from AstraZeneca. L.Q reports stock/ownership interests in Sironax. W.D.T reports research funding from AmMax Bio; Avacta Life Sciences; BioAtla; Blueprint Medicines; C4 Therapeutics; Cogent Biosciences; Daiichi Sankyo; Deciphera; Theseus Pharmaceuticals and consulting fees from Adcendo; Amgen; AmMax Bio; Ayala Pharmaceuticals; Bayer; BioAtla; Boehringer Ingelheim; Cogent Biosciences; Daiichi Sankyo; Deciphera; Epizyme; Foghorn Therapeutics; inhibrx; Kowa Pharmaceutical; Lilly; Medpacto; Servier and stock/ownership interests in Atropos; Certis Oncology Solutions and patents/IP for Companion Diagnostic for CDK4 inhibitors - 14/854,329; Enigma and CDH18 as companion Diagnostics for CDK4 inhibition – SKI2016-021-03. S.P.D reports consulting fees/honoraria from Adaptimmune; GlaxoSmithKline; Nektar; Pfizer; Rain Therapeutics; Servier. The remaining authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Treatment outcomes.
A, Best tumor response by RECIST. B, Percent change in tumor size over time. C, Duration of treatment. D, Progression-free survival by cohort.
See this image and copyright information in PMC

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