ORIC® ENOZERTINIB PROGRAM UPDATE CALL - ORIC PHARMACEUTICALS INC

Explicit Guidance:

• Commercial Timing: Aims to initiate the global Phase 3 "Redwood 1" trial in the first half of 2027 for first-line EGFR atypical non-small cell lung cancer (NSCLC).
• Cash Runway: Maintains cash runway through the second half of 2028, explicitly accounting for the initiation of Redwood 1 alongside the RINDSY Metastat (RIN-CY) trial.
• Data Readout Timing: No specific top-line data readout dates provided for ORR (accelerated approval) or PFS (full approval); management states guidance on timing will be refined after trial initiation.
• Phase 3 Dose: Confirmed Recommended Phase 3 Dose (RP3D) of 80 mg once daily following end-of-phase 1 interactions with the FDA.

Business-Segment Outlook:

• EGFR Atypical (L861Q/PACC): Projected to capture substantial share of a $2.5+ billion U.S. annual and $5+ billion global first-line addressable market; blinded market research suggests potential ~60% market share for a best-in-class profile.
• EGFR Exon 20: Planning to evaluate three potential Phase 3 regimens (monotherapy, plus amivantamab, plus chemotherapy); expects to share concurrent data on all three cohorts in mid-2027 to determine the optimal development path for the "Redwood 2" trial.
• Product Positioning: Aiming for a best-in-class profile defined by strong systemic efficacy, robust CNS activity (including in untreated brain metastases), and a tolerable safety profile with no significant off-target toxicity.

Market and Competitive Outlook:

• Demand Trends: Highlights a high unmet need in the EGFR atypical population (approx. 15% of EGFR-mutant NSCLC), where current therapies (afatinib, osimertinib) lack sufficient CNS penetration or durability.
• Competitive Positioning: Anticipates rapid market share acquisition similar to osimertinib, alectinib, and lorlatinib, despite being a later entrant; expects differentiation against amivantamab+lazertinib and firmonertinib based on safety and CNS activity.
• Therapeutic Landscape: Competitors like firmonertinib and seribertinib face challenges with high toxicity (grade 3+ AEs requiring dose reduction in ~84% of patients) or negative Phase 3 outcomes (e.g., Virbin Phase 3 failure).
• Market Share Drivers: Oncologist preference research indicates a strong willingness to switch to a CNS-active agent with superior safety, even if it enters the market after competitors.

Macro / Industry Outlook:

• Regulatory Strategy: Aligned with FDA on Phase 3 design utilizing Project BOLT (dual endpoints): ORR for accelerated approval followed by PFS data for conversion to full approval.
• Global Expansion: Redwood 1 is a global trial (North America, Europe, Asia Pacific) with ongoing interactions planned with ex-US regulatory agencies to support the study design.
• Enrollment Philosophy: Investigators are expected to enroll patients with active, untreated brain metastases (historically >30% baseline rate; trial cohort had 65%) due to the "clinical paradigm" shift toward systemic therapy for CNS disease.

Strategic Initiatives:

• Redwood 1 Trial: Global, randomized, Phase 3 in treatment-naive EGFR atypical NSCLC (L861Q/PACC); compares enozertinib (80mg QD) vs. physician's choice of osimertinib or afatinib.
• Trial Endpoints: Dual primary endpoints of ORR (by BICR) and PFS (by BICR); key secondary endpoints include OS and intracranial ORR.
• Control Arm Composition: Stratified by physician's choice of osimertinib vs. afatinib, with geographic variations expected but no cap on the proportion of agents used.
• Exon 20 Pipeline: Continued evaluation of combination therapies (enzozertinib + amivantamab or chemotherapy) to address recent competitor setbacks (e.g., Firminertinib Phase 3 negative).

Risks and Headwinds to Outlook:

• Trial Design Risks: Success depends on demonstrating superiority over osimertinib (which has CNS activity but lower potency against atypical mutations) and afatinib (which lacks CNS activity).
• Toxicity Management: While current safety profile is manageable (diarrhea, onycholysis), long-term tolerability and the potential need for dose reductions (observed in 39% of patients in Phase 1b) could impact adherence or efficacy if not managed.
• Competitor Activity: Monitoring of other late-stage programs (e.g., filivertinib, zilvertinib, sublisertinib) which currently have limited or immature data that could alter the competitive landscape.
• Regulatory Uncertainty: While FDA alignment is secured, final approvals depend on the successful readout of Redwood 1 and subsequent regulatory interactions globally.

Management Tone on the Future:

• Confidence Level: Highly confident; repeatedly described data as "stellar," "best-in-class," and setting a "new benchmark."
• Forward Momentum: Expressed urgency to move "rapidly" to Phase 3 to address a "significant unmet need."
• Differentiation: Strong emphasis on the drug's ability to treat patients with untreated brain metastases, a key differentiator where competitors struggle.
• Strategic Caution: Maintains a balanced view on Exon 20 development, acknowledging the need to "thoroughly evaluate" all three regimen options before selecting a path, reflecting a disciplined approach despite market excitement.

Miscellaneous:

• Data Cutoffs: Phase 1b data presented is as of September 4, 2026.
• Clinical Data Highlights: Phase 1b cohort (26 patients) showed 84% confirmed systemic ORR, 70% confirmed intracranial ORR, 88% 6-month landmark PFS, and 0% treatment-related discontinuations.
• Patient Demographics: High disease burden in trial cohort (65% baseline CNS mets; 46% untreated) compared to ~30-35% in general population/competitor trials.