Treatment of patients with advanced or metastatic cancers with the transforming growth factor-β receptor type 1 inhibitor LY3200882 demonstrated a tolerable safety profile and early signs of efficacy, according to the results from a first-in-human, dose-escalation phase I trial presented at the 33rd Annual Meeting of the Society for Immunotherapy of Cancer.
Timothy A. Yap, MD
Treatment of patients with advanced or metastatic cancers with the transforming growth factor-β receptor type 1 (TGF-βR1) inhibitor LY3200882 demonstrated a tolerable safety profile and early signs of efficacy, according to the results from a first-in-human, dose-escalation phase I trial presented at the 33rd Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2018).
“In this dose-escalation study of LY3200882 monotherapy, the recommended phase II dose has been established at 50 mg [twice daily] at 2 weeks on/2 weeks off, is safe and well tolerated, and [provides] appropriate plasma pharmacokinetic exposures,” said Timothy A. Yap, MD, medical director of the Institute for Applied Cancer Science, associate director for translational research of the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. “We have seen hints of pharmacodynamic target modulation, and also signals of preliminary antitumor activity.”
The TGFβ pathway is commonly deregulated in cancer and also plays a role in tumorigenesis. TGFβ is a pleiotropic cytokine, and tumorigenesis converts TGFβ from a tumor suppressor to a tumor promoter, Yap explained in a presentation during the meeting.
“It induces angiogenesis and epithelialmesenchymal transition, inhibits immune surveillance, and promotes tumor proliferation,” said Dr. Yap. “Therefore, the development of potent and selective inhibitors against TGFβ is a rationale and promising antitumor strategy.”
In the multicenter, nonrandomized, open-label study (NCT02937272), investigators worked to determine the recommended phase II dose of LY3200882 monotherapy in patients with refractory advanced or metastatic disease. LY3200882 is a next-generation small molecular TGF-βR1 inhibitor that has been shown to be highly potent as well as highly selective.
Five cohorts of patients (n = 30; 19 males and 11 females) with advanced or metastatic cancer following progression on standard therapy received LY3200882 twice daily at increasing doses of 5 mg (n = 4), 10 mg (n = 3), 20 mg (n = 3), 35 mg (n = 3), and 50 mg (n = 17) for 14 days in a 28-day cycle. The median age of patients was 47 years (range, 32-74). The tumor types included were glioma (n = 15), glioblastoma (n = 5), pancreatic cancer (n = 3), cervical cancer (n = 3), chondrosarcoma (n = 2), appendix carcinoma (n = 1), and colorectal adenocarcinoma (n = 1).
To be eligible for enrollment, patients must have had an ECOG performance status of 0 or 1, adequate organ function, discontinued prior therapy for 14 or 21 days before LY3200882 treatment for non-myelosuppressive and myelosuppressive agents, respectively, and an estimated life expectancy of at least 12 weeks.
The primary endpoint was to determine the recommended phase II dose; secondary endpoints were safety, antitumor activity, and pharmacokinetics. Additionally, exploratory endpoints were pharmacodynamics.
Findings showed that a twice-daily dose of 50 mg at a 2-week-on/2-week-off schedule was optimal. Moreover, no dose-limiting toxicities were observed, and all treatment-related adverse events (TRAEs) were of grade 1 or 2. The most frequently reported TRAEs were thrombocytopenia (n = 2), acneiform dermatitis (n = 2), rash (n = 2), and constipation (n = 2).
Regarding pharmacokinetics, the inhibitor was absorbed within 2.16 hours and was mostly eliminated within 48 hours, leading to a mean terminal half-life of 7.44 hours (n = 15). The preliminary pharmacodynamic data show that TGFβ is required to maintain skin Langerhans cells in the epidermis, and interruption leads to maintain skin Langerhans cell migration in preclinical models; this suggests that TGFβ is modulated in some patients.
The drug exposures increased with escalating dose levels up to the highest dose range of 50 mg twice daily. Moreover, plasma exposures in patients receiving this dose were comparable with exposure levels from preclinical in vivo target inhibition and efficacy models.
Across all cohorts, there was one partial responsein the 50-mg cohort—six cases of stable disease, 11 patients with progressive disease, and 12 with non-evaluable disease. The overall response rate was 3.3% (n = 1), and the disease-control rate was 23.3% (n = 7).
Additionally, an 85.7% tumor reduction, assessed by Response Assessment in Neuro-Oncology criteria, was reported in one patient with EGFR-mutant, CDK4-amplified, IDH1/2 wild-type, and MGMT-methylated glioblastoma. The patient was treated at 50 mg twice daily and has remained on treatment for more than 11 months.
Moreover, tumor regression was observed in 5 patients comprising glioma (n = 2), and oligoastrocytoma, astrocytoma, and glioblastoma (n = 1 each).
Detailed pharmacodynamic biomarker studies are the next steps following this research, Dr. Yap concluded. Additionally, an expansion cohort assessing patients with glioblastoma is ongoing.
Yap T, Baldini C, Massard C, et al. First-in-human phase 1 dose-escalation trial of the potent and selective next generation transforming growth factor-β receptor type 1 (TGF-βR1) inhibitor LY3200882 in patients with advanced cancer. In: Proceedings from the 2018 SITC Annual Meeting; November 7-11, 2018; Washington, DC. Abstract 030.