1333P A global phase 1b study of ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, in patients with advanced solid tumors harboring EGFR Exon 20 or HER2 alterations

Insertion mutations within exon 20 of both EGFR and HER2 are oncogenic drivers and are most commonly found in NSCLC. EGFR exon 20 insertion mutations occur in 4-10% of all EGFR-mutated NSCLC. Brain metastases are present in approximately one-third or more of these cases but are not addressed by available therapies directed against these mutations. ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, making it a promising therapeutic candidate to address the unmet medical need of having both meaningful systemic as well as CNS antitumor activity. ORIC-114-01 (NCT05315700) is an ongoing i3+3 dose escalation (Part I), followed by dose optimization (Part II), and dose expansion (Part III) study in patients with advanced solid tumors harboring an EGFR or HER2 alteration who have exhausted available treatment options, including patients with active brain metastases. Primary objectives are safety/tolerability and pharmacokinetics of ORIC-114. Part I will determine the provisional RP2Ds and/or MTD for optimization in Part II and, subsequently, the optimal RP2D for Part III. Secondary endpoints will evaluate antitumor activity by RECIST v1.1, including intracranial responses in patients presenting with brain metastases at baseline. As of 03 April 2023, 32 patients received ORIC-114 across 8 dose levels administered QD or BID. The most common TRAEs reported in ≥10% of pts were rash (34%), stomatitis (28%), paronychia (25%), diarrhea (19%), dermatitis acneiform (16%), mucosal inflammation (13%), and pruritis (13%). The vast majority of these events were mild (G1) to moderate (G2) in severity with no MTD reached. Grade 3 TRAEs occurred in 6 patients, all of which resolved with dose modifications; there were no Grade ≥4 TRAEs. Early evidence of both systemic and intracranial antitumor activity was observed. ORIC-114 has demonstrated an acceptable safety profile and preliminary antitumor activity, including in the CNS, at doses predicted to be active. Enrollment is ongoing and updated data will be presented.