ERAS-801 Receives ODD From FDA for Malignant Glioma/Glioblastoma

The FDA cleared the investigational new drug application for ERAS-801 in December 2021, and later granted the agent fast track designation in May 2023.

Orally bioavailable, small molecule EGFR inhibitor ERAS-801 has received FDA orphan drug designation for malignant glioma including glioblastoma, according to a press release from Erasca.¹

Thus far, the highly potent, selective, reversible agent has demonstrated promising central nervous system (CNS) penetration, according to pre-clinical animal models. Investigators believe that initial findings on single-agent ERAS-801 in the phase 1 THUNDERBBOLT-1 study (NCT05222802) will be read in the second half of 2023.

“[Glioblastoma] is an aggressive malignancy [affecting] approximately 37,000 patients annually in the United States and Europe. Currently, approved EGFR inhibitors are limited by insufficient CNS penetration to treat [glioblastoma] and minimal activity [glioblastoma]–specific EGFR amplifications, mutations, and other molecular alterations, which contribute to high rates of relapse and a 5-year survival rate below 10%,” Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, said in the press release. “Receiving ODD recognizes both the importance of innovation for patients with [glioblastoma] and the therapeutic potential of ERAS-801 to provide a targeted treatment option for these patients, who have a poor prognosis.”

In animal models, ERAS-801 yielded a brain-to-plasma partition coefficient Kp of 3.7, as well as an unbound partition coefficient K_p,uu of 1.2. Investigators reported that this was 4 times higher than that of FDA-approved EGFR inhibitors, which means that it’s possible all free drugs in the plasma will be able to cross the blood-brain barrier.

Moreover, survival benefit was observed in 93% (n = 13/14) of those in the EGFR-mutant and/or amplified model. Both survival and brain penetrance were notably higher with ERAS-801 vs other FDA-approved EGFR inhibitors such as osimertinib (Tagrisso), lapatinib (Tykerb), and erlotinib (Tarceva).

The THUNDERBBOLT-1 trial is assessing the use of ERAS-801 in a population of patients diagnosed with recurrent glioblastoma with the goals of determining the agent’s safety and tolerability, maximum tolerated dose, antitumor activity, and pharmacokinetic profile. The trial has an estimated enrollment of 90 patients who will receive ERAS-801 in sequential ascending doses until progression, unacceptable toxicity, or withdrawal of consent in the dose escalation portion. Additionally, in the dose expansion portion of the study, patients with recurrent, EGFR-altered disease will receive ERAS-801 at the recommended dose.

The trial’s primary end points include determining the dose-limiting toxicities, maximum tolerated dose, recommended dose, and adverse effects. Investigators cited several secondary end points such as objective response rate, duration of response, and time to response.

The FDA cleared the investigational new drug (IND) application for the agent in December 2021,² and later granted the ERAS-801 fast track designation in May 2023.³

“We are pleased with the pace at which our ERAS-801 program is advancing. Filing this IND a quarter ahead of schedule and receiving FDA clearance allows us to begin potentially helping patients sooner,” Lim said at the time of the fast track designation.

References

1. Erasca granted FDA orphan drug designation for CNS-penetrant EGFR inhibitor ERAS-801 for the treatment of MALIGNANT GLIOMA. News release. Erasca. June 22, 2023. Accessed June 26, 2023. https://bit.ly/3XoLUug
2. Erasca announces FDA clearance of IND application for ERAS-801 in glioblastoma multiforme and collaboration with GCAR for potential inclusion in GBM AGILE clinical trial. News release. Erasca. December 17, 2021. Accessed June 26, 2023. https://bit.ly/3CK7Oii
3. Erasca granted FDA fast track designation for CNS-penetrant EGFR inhibitor ERAS-801 in patients with glioblastoma. News release. Erasca. May 1, 2023. Accessed June 26, 2023. https://bit.ly/3pkpdLp