Development of FHD-286 Monotherapy Will Not Continue in Metastatic Uveal Melanoma

Although the highly potent, selective, allosteric, oral, small molecule BRG1/BRM inhibitor FHD-286 elicited signs of clinical activity and safety as monotherapy in patients with metastatic uveal melanoma in the dose-escalation portion of a phase 1 trial (NCT04879017), further development in this indication will not be pursued, according to an announcement from Foghorn Therapeutics.¹

Data showed that among 47 of 73 patients who had target lesions available for evaluation, 1 patient experienced a durable partial response, remaining on treatment for 16 months. Additionally, 9 patients experienced stable disease. Reductions in tumor target lesions were also reported in 8 patients.

Notably, reductions in circulating tumor DNA were observed. Preliminary data on immune modulation markers in the tumor microenvironment also support potential investigation of FHD-286 in combination with immune checkpoint inhibitors, according to the announcement.

Regarding safety, the most common any-grade treatment-related adverse effects (TRAEs) included dysgeusia, fatigue, increased aspartate aminotransferase, nausea/vomiting, dry mouth, and rash. The most common grade 3 or higher TRAEs consisted of anemia, asthenia, increased alkaline phosphatase, hypokalemia, muscular weakness, and rash.

“The clinical data further support the safety and tolerability of FHD-286 and build on the previously disclosed acute myeloid leukemia [AML]/myelodysplastic syndrome [MDS] data. In the study, 9 patients had stable disease and 1 patient had a durable partial response,” Adrian Gottschalk, president and chief executive officer of Foghorn Therapeutics, stated in a news release. “However, Foghorn does not plan to pursue this indication on its own. We plan to initiate dosing the FHD-286 combination study in relapsed/refractory AML during the third quarter of 2023 and continue to invest in our promising pre-clinical programs such as selective-BRM, CBP, EP300, and ARID1B.”

A phase 1 trial (NCT04891757) is also investigating the use of FDH-286 in patients with relapsed/refractory AML or MDS. The FDA placed a full clinical hold on the study in August 2022 due to suspected cases of fatal differentiation syndrome believed to be associated with FHD-286.² However, the clinical hold was lifted on June 5, 2023, and the company plans to commence a phase 1 study of FHD-286 in combination with decitabine or cytarabine in patients with relapsed and/or refractory AML in the third quarter of 2023.³

The phase 1 trial in uveal melanoma enrolled patients at least 18 years of age with histologically or cytologically confirmed metastatic disease who were newly diagnosed and had not yet received liver-directed or systemic treatment; were ineligible for any available therapy likely to convey clinical benefit; or had disease progression after treatment with available therapies and/or were intolerant to those treatments. Other key inclusion criteria included measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 to 2.⁴

Patients with thrombocytopenia or another bleeding disorder, active brain metastases and/or leptomeningeal disease, or known and possible risk for QT prolongation were excluded from the study.

Enrolled patients had received a median of 2 prior lines of therapy. Patients were treated with FHD-286 at continuous daily doses of 2.5 mg (n = 2), 5.0 mg (n = 12), 7.5 mg (n = 17), and 10.0 mg (n = 9), or intermittently with 1-week-on/1-week-off schedules at 10.0 mg (n = 10), 15.0 mg (n = 9), 17.5 mg (n = 3), 20.0 mg (n = 5), and 22.5 mg (n = 6).¹

AEs and dose-limiting toxicities served as the co-primary end points of the study. Secondary end points included overall response rate, duration of response, time to response, time to progression, progression-free survival, overall survival, and pharmacokinetics.⁴

References

1. Foghorn Therapeutics announces clinical data from phase 1 study of FHD-286 in metastatic uveal melanoma. News release. Foghorn Therapeutics. June 28, 2023. Accessed June 29, 2023. https://ir.foghorntx.com/news-releases/news-release-details/foghorn-therapeutics-announces-clinical-data-phase-1-study-fhd
2. Foghorn Therapeutics provides further update on FHD-286 phase I study in relapsed/refractory AML/MDS. News release. Foghorn Therapeutics. August 23, 2022. Accessed June 29, 2023. https://ir.foghorntx.com/news-releases/news-release-details/foghorn-therapeutics-provides-further-update-fhd-286-phase-i
3. Foghorn Therapeutics announces FDA has lifted clinical hold on phase 1 study of FHD-286 in relapsed and/or refractory AML/MDS patients. News release. Foghorn Therapeutics. June 5, 2023. Accessed June 29, 2023. https://ir.foghorntx.com/news-releases/news-release-details/foghorn-therapeutics-announces-fda-has-lifted-clinical-hold
4. FHD-286 in subjects with metastatic uveal melanoma. ClinicalTrials.gov. Updated March 16, 2023. Accessed June 29, 2023. https://clinicaltrials.gov/study/NCT04879017