Phase I extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours

Abstract

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al., NEJM 2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19 th Feb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median DoR and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ ALT, fatigue, nausea and constipation the most common AEs reported in 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusion cancer is detected in a broad range of tumor types. Larotrectinib is an effective tumor-agnostic treatment for TRK fusion cancer with a favorable safety profile. Screening patients for NTRK gene fusions in solid tumors should be actively considered.

Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications

“…It shows manageable side effects in interim analysis of a phase I trial in which this agent was evaluated in combination with denosumab in 5 patients. Dysgeusia (62%), fatigue (37%), weight loss (37%), back pain (37%) and headache (37%) were the most frequent AEs [128]. An ongoing trial is evaluating ETC-159 in endometrial cancer alone or in combination with pembrolizumab (NCT02521844).…”

Casein Kinase 1α as a Regulator of Wnt-Driven Cancer

“…Although remarkable effort has been made in the identification and development of Wnt pathway inhibitors, the on-target toxicity of these drugs, including the disruption of bone and intestine tissues, has limited their clinical utility. However, the use of additional drugs that ameliorate these on-target toxicities has extended the potential of currently available Wnt-inhibiting drugs [130][131][132]. For example, a recent phase I trial result has shown that the co-administration of the PORCN inhibitor ETC-159 along with bone protective treatment in patients harboring solid tumors is safe [132].…”

“…However, the use of additional drugs that ameliorate these on-target toxicities has extended the potential of currently available Wnt-inhibiting drugs [130][131][132]. For example, a recent phase I trial result has shown that the co-administration of the PORCN inhibitor ETC-159 along with bone protective treatment in patients harboring solid tumors is safe [132]. We have discussed here that CK1α activators show significant efficacy in treating Wnt-driven cancers, without exhibiting on-target toxicity in normal tissue homeostasis at therapeutic doses.…”

Lineage reversion drives WNT independence in intestinal cancer

“…Due to the paucity of pre-and post-treatment clinical samples, we exploited engineered murine organoids to interrogate the genetics of WNT dependence and WNT-targeted therapy response, but this work has obvious implications for clinical application of WNT therapies. To date, WNT-targeted drugs have performed poorly in early phase clinical studies, owing to on-target dose-limiting toxicity, including bone fractures (51). Recent work has shown that combination of RANKL and PORCN inhibitors provide potent WNT pathway suppression while avoiding adverse bone-related effects (23).…”