FDA Grants Fast Track Designation to ERAS-801 in EGFR-altered Glioblastoma

Jonathan E. Lim, MD

The FDA has granted a fast track designation to ERAS-801 for the treatment of adult patients with glioblastoma harboring EGFR gene alterations.¹

ERAS-801 is an oral, small molecule EGFR inhibitor that exhibited substantial central nervous system (CNS) penetration in preclinical animal studies. ERAS-801 monotherapy is being evaluated in patients with recurrent glioblastoma as part of the ongoing phase 1 THUNDERBBOLT-1 trial (NCT05222802).

“Receiving fast track designation from the FDA underscores the serious unmet medical need in patients with glioblastoma and reinforces the promise that ERAS-801 may offer as a differentiated treatment option,” Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, stated in a news release. “Glioblastoma is an aggressive malignancy with high rates of relapse and a 5-year survival rate below 10%. While over half of glioblastoma cases are driven by EGFR alterations and/or amplifications, there are no approved EGFR inhibitors for the treatment of glioblastoma due to the lack of sufficient brain penetration to treat primary brain tumors, as well as lack of activity against EGFR alterations observed in glioblastoma, such as EGFR variant III.

“To help overcome these limitations, ERAS-801 was specifically designed to have high CNS penetration and broad activity against both oncogenic and wild-type EGFR,” Lim added. “We look forward to working closely with the FDA to expedite clinical development of ERAS-801 for these patients and anticipate reporting initial monotherapy data from the phase 1 THUNDERBBOLT-1 trial in recurrent glioblastoma in the second half of 2023.”

Findings from preclinical animal models showed that ERAS-801 displayed a brain-to-plasma partition coefficient (Kp) of 3.7 and a corresponding unbound partition coefficient (Kp,uu) of 1.2, which was up to 4 times higher than what has been observed with approved EGFR inhibitors. These findings suggested that approximately 100% of the free drug in plasma could cross the blood–brain barrier.

The non-randomized, open-label, multicenter THUNDERBBOLT-1 study is enrolling patients who are at least 18 years of age with recurrent IDH wild-type glioblastoma as defined by the World Health Organization 2021 criteria. Patients must also have adequate organ function.²

Prior treatment with an EGFR inhibitor for glioblastoma is not permitted. Other key exclusion criteria include current enrollment in another therapeutic study, history of clinically significant cardiovascular disease, gastrointestinal conditions that may affect the administration or absorption of oral medication, or an active infection requiring systemic therapy.

In the dose-escalation portion of the trial, the recommended dose for dose expansion will be determined. Treatment with oral ERAS-801 will occur in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.

The primary end points of the trial are to identify dose-limiting toxicities, the maximum-tolerated dose, the recommended dose, and adverse effects. Secondary end points consist of pharmacokinetics, objective response rate, duration of response, and time to response.

Additional sub-studies of THUNDERBBOLT-1 could explore ERAS-801 in combination with other agents and in broader patient types.¹

Initial data from THUNDERBBOLT-1 are expected to read out in the second half of 2023.

References

1. Erasca granted FDA fast track designation for CNS-penetrant EGFR inhibitor ERAS-801 in patients with glioblastoma. News release. Erasca. May 1, 2023. Accessed May 2, 2023. https://investors.erasca.com/news-releases/
2. A study to evaluate ERAS-801 in patients with recurrent glioblastoma (THUNDERBBOLT-1). ClinicalTrials.gov. Updated November 15, 2022. Accessed May 2, 2023. https://clinicaltrials.gov/ct2/show/NCT05222802