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, further development in this indication will not be pursued.

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