ORIC® ENOZERTINIB PROGRAM UPDATE CALL - ORIC PHARMACEUTICALS INC

Financial Performance:

• No specific financial metrics (revenue, earnings, cash flow, debt) were disclosed in this clinical update call as the company is pre-revenue.
• Cash Runway: Management confirmed that the previously stated cash runway through the second half of 2028 remains unchanged; this guidance already includes the projected costs for initiating the Redwood 1 Phase 3 trial (EnoZertinib) in H1 2027 and the Himalayas 1 Phase 3 trial (RINDSY).

Guidance and Future Outlook:

• Trial Initiation: Plan to initiate "Redwood 1," a global Phase 3 trial for first-line EGFR atypical non-small cell lung cancer (NSCLC), in the first half of 2027.
• Regulatory Path: Completed End-of-Phase 1 meetings with the FDA; trial design, dose (80mg QD), endpoints, and control arm have been aligned.
• Exon 20 Strategy: Currently evaluating three potential Phase 3 regimens for EnoZertinib in EGFR exon 20 mutations (monotherapy, chemo combination, amivantamab combination); expect to share data on all three cohorts in mid-2027.
• Long-term Goals: Aiming for best-in-class status with a potential global market opportunity exceeding $5 billion; plans to seek accelerated approval via ORR and full approval via PFS.

Business Segments and Product Lines:

• EnoZertinib (EGFR Atypicals): Updated Phase 1b data in first-line PACC/L861Q mutations (N=26) shows an 84% confirmed systemic ORR, 70% confirmed intracranial ORR, and 88% 6-month landmark PFS.
• Patient Population Context: Trial enrolled a highly challenging cohort with 65% baseline CNS metastases (double the competitor average) and 46% with untreated brain mets.
• EnoZertinib (EGFR Exon 20): Ongoing dose exploration in monotherapy and combination settings (with chemo and amivantamab); data expected mid-2027.
• Safety Profile: No treatment-related discontinuations; Grade 3 AEs in 23% (all manageable with dose modification); no significant off-target toxicities (cardiac, hepatic, hematologic).
• Preclinical Differentiation: Demonstrated high cell potency across diverse EGFR mutants, extreme selectivity sparing wild-type kinases, and strong brain penetrance.

Market and Competitive Landscape:

• Market Size: Estimated U.S. annual addressable market of >$2.5 billion and global >$5 billion for first-line EGFR atypical NSCLC.
• Competitive Gap: Current options (afatinib, osimertinib, amivantamab-lazertinib) lack a combined profile of high systemic efficacy, robust CNS activity, and tolerability.
• Key Competitors:
  • Firmiletinib (Firmo): Recent Phase 3 (VIRBIN) in Exon 20 was negative against chemo; limited data in atypicals.
  • Silvertinib: High toxicity rates (84% dose reductions/interruptions) and limited CNS data.
  • Amivantamab + Lazertinib: High efficacy but complex dosing and toxicity; not a pure TKI monotherapy.
• Market Research: Blinded oncologist feedback indicated a differentiated best-in-class profile could capture ~60% market share.

Risks and Challenges:

• Clinical Risk: Unmet need suggests high scrutiny; need to prove superiority in Phase 3 against the standard of care (Osimertinib/Afatinib).
• Competitive Risk: Competitors in Exon 20 space have faced setbacks (negative Phase 3 results); the pipeline's success relies on identifying the optimal regimen (mono vs. combo).
• Regulatory Risk: Must satisfy FDA strict criteria for CNS activity (untreated mets) to secure accelerated approval.
• Operational Risk: Global trial initiation requires complex coordination across 10 countries and regulatory submissions.

Management Commentary and Tone:

• Tone: Highly confident and optimistic; described data as a "new benchmark" and "best-in-class."
• Key Message: Emphasized that EnoZertinib's brain penetrance addresses the primary site of progression in EGFR atypical patients, where current therapies fail.
• Strategic Focus: Rapid progression to Phase 3 to capture the market before competitors; treating patients with "active untreated" CNS disease to prove true CNS activity.
• Team Confidence: Highlighted the physician-led enrollment of high-burden patients as a validation of the drug's preclinical profile and efficacy.

Analyst Questions and Answers:

• Enrollment Strategy: Confirmed high CNS burden enrollment was physician-driven based on preclinical/early clinical data, not a specific enrollment target.
• PFS Durability: Management expects PFS differentiation to follow the pattern of CNS-active TKIs (e.g., Alectinib/Lorlatinib), where CNS control drives overall PFS even if systemic ORR is similar to competitors.
• CNS Assessment: Reiterated the use of modified RANO-BM criteria and BICR to validate intracranial responses, specifically in patients with untreated lesions to avoid confounding from prior radiation.
• Phase 3 Control Arm: The control arm will be physician's choice of Osimertinib or Afatinib, stratified by geographic mutation prevalence; no cap on selection to reflect real-world usage.
• L861Q Subgroup: Small cohort (3 patients) showed complete responses; will be stratified in Phase 3 due to high activity observed.
• Exon 20 Strategy: Recent negative competitor data reinforces the need to rigorously evaluate all three EnoZertinib regimens (mono/combo) before selecting a Phase 3 path.
• Dose Management: 39% of patients required dose reductions in Phase 1b, but responses were maintained; 80mg is sufficient with ample reduction room to 60mg.

Other Key Points:

• Patient Vignettes: Two cases highlighted deep responses in patients with 5+ untreated brain mets, achieving complete intracranial responses.
• Safety Mechanism: Toxicity profile aligns with EGFR wild-type inhibition (rash, diarrhea, peronychia) rather than off-target effects, suggesting high tolerability for community oncologists.
• Global Footprint: Phase 1b conducted at 39 academic centers across North America, Europe, and Asia Pacific, facilitating the global Phase 3 launch.
• Project BARRIERS: Trial design incorporates FDA's initiative to support accelerated approval via ORR with a follow-up for full approval via PFS.