On October 21, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported initial data from the ongoing ORIC-114 Phase 1 dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (clinical poster here) (Press release, ORIC Pharmaceuticals, OCT 21, 2023, View Source [SID1234636214]).

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"We are excited to present the first look at ORIC-114 clinical data, which we believe supports the potential to address the key attributes of a potential best-in-class program for EGFR/HER2 exon 20 mutated NSCLC: minimal EGFR toxicity, minimal off-target toxicity, CNS activity, and systemic activity including post-amivantamab," said Jacob M. Chacko, MD, chief executive officer. "Given the high rate of brain metastases in these patients and the high percentage of patients whose disease progresses in the brain, we believe that a well-tolerated CNS active agent has the potential to be transformative."

"We are pleased with the emerging profile of ORIC-114 in these heavily pretreated patients, which includes clinical activity across multiple dose levels and the first reported intracranial complete response in a patient with EGFR exon 20 lung cancer and documented untreated brain metastases," said Pratik Multani, MD, chief medical officer. "This is the first comprehensive data set for EGFR exon 20 patients with such an exceptionally high rate of CNS disease at baseline and prior exon 20 inhibitor therapy. Based on the encouraging clinical activity and favorable safety profile, we plan to advance this program into dose optimization to select RP2D and, ultimately, into one or more registrational cohorts for potential accelerated approval."

ORIC-114 Phase 1 Study Design

ORIC-114 is being evaluated in a Phase 1 dose escalation clinical trial in patients with advanced solid tumors with EGFR and HER2 exon 20 alterations or HER2 amplifications. Patients previously treated with an exon 20 targeted agent are eligible, including patients with CNS metastases that are either treated or untreated but asymptomatic. Nearly all other clinical studies with EGFR exon 20 inhibitors severely restricted the eligible patient population and excluded patients with active or untreated brain metastases and patients previously treated with an EGFR exon 20 inhibitor, making this data set one of the first and most comprehensive in this population. The primary objectives are to determine the recommended Phase 2 dose (RP2D), and additional objectives include characterization of the safety, tolerability, pharmacokinetic, and preliminary antitumor activity.

ORIC-114 Phase 1 Dose Escalation Data

As of September 26, 2023, 50 patients (21 EGFR exon 20, 24 HER2 exon 20 and 5 HER2+ patients) received ORIC-114 and were heavily pre-treated, with exceptionally high rates of prior exon 20 targeted therapies and brain metastases at baseline.

Of the 21 EGFR exon 20 insertion mutated NSCLC patients, in addition to chemotherapy
81% were treated with ≥1 prior EGFR exon 20 targeted agent, nearly all of whom received prior amivantamab;
19% were treated with multiple prior EGFR exon 20 targeted agents; and
86% presented with CNS metastases at baseline
Of the 24 HER2 exon 20 insertion mutated NSCLC patients
30% were treated with a prior HER2 targeted agent; and
38% presented with CNS metastases at baseline
Preliminary Pharmacokinetic Analysis and Safety

ORIC-114 demonstrated a favorable pharmacokinetic profile with dose proportional increase in exposure, low intra-cohort variability, and a half-life of ~10-15 hours, which supports QD dosing.

ORIC-114 was well-tolerated with mostly Grade 1 and 2 treatment-related adverse events (TRAEs) and little evidence of off-target toxicities. Rash was limited to Grade 1 and 2 events, and there was no Grade 3 or greater treatment related rash. Diarrhea was primarily Grade 1 and 2, with only 6% of patients experiencing Grade 3 diarrhea. There were only 4% discontinuations for TRAEs. The maximum tolerated dose has not been reached.

Preliminary Activity Analysis

Systemic and intracranial activity of ORIC-114 was demonstrated in this heavily pre-treated patient population across multiple dose levels. Preliminary activity data for patients treated at clinically active doses (total daily dose (TDD) ≥45 mg) as of the cut-off date were available for 15 response evaluable NSCLC patients with EGFR exon 20 insertion mutations and 13 response evaluable NSCLC patients with HER2 exon 20 insertion mutations.

EGFR exon 20 patients:

Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses and one ongoing confirmed complete response, including a confirmed complete response in the brain.
Within the 45 mg dose level, a patient had an ongoing confirmed partial response and two of three brain lesions resolved on therapy.
Within the 75 mg dose level, identified as a potential RP2D, of the three patients previously treated with amivantamab
All three patients experienced tumor shrinkage, and
There was an unconfirmed ORR of 67% and a confirmed ORR of 33%, including an ongoing systemic confirmed complete response and the first confirmed CNS complete response reported by an EGFR exon 20 inhibitor in a patient with documented untreated brain metastases at baseline.
HER2 exon 20 patients:

Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses, including an ongoing confirmed partial response with 100% regression of all target lesions, with only persistent non-target lesions preventing a complete response.
Within the 30 mg BID dose level, a patient had an ongoing confirmed partial response and shrinkage of multiple brain lesions on therapy.
Next Steps

The Phase 1 trial of ORIC-114 is ongoing to determine the candidate recommended RP2Ds for dose optimization, and subsequently the selection of the final RP2D. Since the September 26, 2023 data cutoff, the 40 mg BID dose level has cleared the DLT evaluation period, and the study is now evaluating 50 mg BID and 120 mg QD dose levels. The Phase 1 trial will enroll patients with EGFR exon 20 insertion mutations that are EGFR exon 20 inhibitor-naïve, and additional patients who are post-amivantamab. Additionally, enrollment will be expanded to include patients with atypical EGFR mutations based on the promising preclinical activity presented at ESMO (Free ESMO Whitepaper) 2023 (preclinical poster here).

Conference Call and Webcast Details

To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.

About ORIC-114

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.