Q4 2026 Silevertinib Program Update Webcast - BLACK DIAMOND THERAPEUTICS INC

Explicit Guidance:

• Timeline for Phase 3 Initiation: Planned initiation of the pivotal Phase 3 trial for silibvertinib (NSCLC) in the second quarter of 2027.
• Timeline for Safety Data Submission: Expectation to submit safety data from the 150 mg dose cohort (Cohort 4) to the FDA prior to Phase 3 initiation, with anticipated completion and submission in the second quarter of 2027.
• Timeline for NSCLC Phase 3 Enrollment: Enrollment duration expected to take approximately 18 months following initiation in Q2 2027.
• Timeline for NSCLC Preliminary Data: Anticipation of preliminary data from Phase 3 open-label cohorts (patients without brain metastasis) in 2028.
• Timeline for NSCLC Primary Endpoint (CNS-ORR): Expected readout for CNS Overall Response Rate (accelerated approval endpoint) in 2029.
• Timeline for GBM Interim Data: Expectation of interim Progression-Free Survival (PFS) data from the Phase 2 Glioblastoma (GBM) trial in the first half of 2028.
• Dose Confirmation: FDA acknowledged the 150 mg dose as the pivotal dose; current enrollment is proceeding at this level.

Business-Segment Outlook:

• NSCLC Program: Positioning silibvertinib as a potential "drug of choice" for all frontline patients with Non-Classical (NCM) EGFR mutations, a market segment representing approximately 25% of EGFR-mutated NSCLC cases (triple the size of the Exon 20 insertion market).
• Target Population Expansion: Potential to expand beyond NCMs to include classical mutations (e.g., L858R) and the adjuvant setting, leveraging preclinical potency data (10x more potent vs. Osimertinib on L858R) and robust CNS activity.
• Glioblastoma (GBM) Program: Developing a precision medicine approach for EGFR-altered GBM; trial currently enrolling in the randomized Phase 2 part (150 mg dose) with potential to convert to a registrational Phase 3 based on interim PFS results.
• Specific Sub-population Opportunity: FDA suggested adding a cohort for patients with Leptomeningeal Disease, addressing a group with poor prognosis and no current treatment options.

Market and Competitive Outlook:

• Competitive Advantage: Silibvertinib is the only EGFR TKI to demonstrate high levels of unbound drug in brain tumors, allowing deep penetration of the blood-brain barrier; competitors (Afatinib, Osimertinib) show limited CNS activity (historical CNS-ORR of 35-36% vs. 86% for silibvertinib).
• Trial Design Differentiation: The FDA-accepted primary endpoint for accelerated approval is CNS-ORR per RANO-BM criteria, a unique path distinguishing the company from competitors pursuing systemic ORR endpoints (which face a higher hurdle, e.g., 66% for Afatinib in comparator trials).
• Enrollment Feasibility: Confidence in enrollment driven by the "investigator's choice" control arm (Afatinib vs. Osimertinib), accommodating regional variations in standard of care (e.g., Afatinib dominance in Asia, Osimertinib off-label use in US).
• Adoption Potential: Anticipates wide clinical uptake and inclusion in NCCN guidelines based on single-arm data from patients without brain metastases, where silibvertinib shows 23.5 months median PFS vs. 9.8 months for Osimertinib.

Macro / Industry Outlook:

• Regulatory Environment: Describes the FDA End-of-Phase II meeting as "highly collaborative" and a "home run," with full regulatory alignment on patient definition (all NCMs), endpoint (CNS-ORR), and dosing.
• Global Standard of Care: Notes that global trials (US/Canada) are necessary to ensure data applicability, as early Asia-centric data often fails to hold up in global trials; silibvertinib is already validated in a real-world patient population.

Strategic Initiatives:

• Phase 3 Trial Design: Enrollment of 300 patients with NCMs:
  • Randomized Arm: For patients with brain metastases, comparing silibvertinib vs. investigator's choice (Afatinib/Osimertinib). Primary accelerated approval endpoint: CNS-ORR.
  • Single-Arm Open-Label Cohort: For the ~60% of patients without brain metastasis, evaluating response rate and PFS.
• Dose Optimization: Moving to a lower pivotal dose (150 mg) compared to Phase 2 to improve tolerability (reducing dose reduction rates from 82%) while maintaining efficacy exposure.
• GBM Expansion: Advancing the GBM program with a randomized Phase 2 (silivertinib + temozolomide vs. temozolomide alone) in patients with EGFR variant 3 and MGMT unmethylated status.
• Pipeline Synergy: Leveraging CNS activity data to potentially target adjuvant settings and other patient populations beyond the current frontline indication.

Risks and Headwinds to Outlook:

• Competitor Superiority: Competitors face significant risk if they cannot demonstrate efficacy superior to Afatinib (66% systemic ORR) in systemic endpoints, whereas silibvertinib faces a lower hurdle via CNS endpoints.
• Efficacy Variability: Potential risk that CNS-ORR data could decline in the Phase 3 trial (starting at 86% vs. 35% benchmark), though management states the study is well-powered to detect a difference even if the experimental arm performance drops slightly.
• Trial Complexity: Dependence on the 18-month enrollment timeline and the successful generation of "sufficient follow-up" for durability of benefit by the time of enrollment completion to support the accelerated approval filing.
• Regulatory Conditions: FDA requires submission of safety data from a sufficient number of patients at the 150 mg dose prior to trial enrollment; while the number is unspecified, failure to demonstrate tolerability improvements could delay initiation.

Management Tone on the Future:

• Confidence Level: High confidence and optimism; CEO describes the FDA meeting as a "home run" and data as "unprecedented" and "highly compelling."
• Strategic Clarity: Clear differentiation from competitors, emphasizing the unique ability to treat the entire NCM population without a complex "alphabet soup" of mutations.
• Growth Expectations: Belief that the drug has the potential to be the "drug of choice" for the entire NCM frontline market, capturing a segment three times larger than the Exon 20 market.

Miscellaneous:

• Safety Profile: No new safety signals identified; median dose intensity maintained at 126 mg/day; 150 mg dose expected to provide adequate exposure with improved tolerability.
• Surveillance Rigor: Emphasis on rigorous monitoring (brain MRIs every 6 weeks) in the Phase 2 trial, which detected no brain progression in 24 patients without baseline metastases over 16 months.
• Geographic Scope: Phase 3 trial includes sites in the US, Canada, Asia, South America, and Mexico to ensure global relevance and represent real-world practice.