STIFEL 2026 HEALTHCARE CONFERENCE - BLACK DIAMOND THERAPEUTICS INC

Explicit Guidance:

• Timeline: Phase 3 trial initiation in non-small cell lung cancer (NSCLC) expected in Q2 2024.
• Data Readouts:
  • Interim PFS data from Glioblastoma (GBM) phase 2 trial expected in H1 2028.
  • Preliminary data from the leptomeningeal disease cohort expected in 2029.
  • Final data for accelerated approval (CNS-ORR endpoint) expected in 2029 upon final patient enrollment completion.
• Capital Strategy: Management aims to secure additional capital (dilutive or non-dilutive) to fund Phase 3 endpoints and approval milestones.
• Commercial Pathway: Anticipates utilization via NCCN Compendia inclusion for the non-brain metastasis single-arm cohort without requiring a standalone randomized PFS study for that specific sub-population.

Business-Segment Outlook:

• NSCLC Indication (Non-Classical Mutations):
  • Target Population: Aims to capture the entire population of non-classical EGFR mutations (approx. 25% of EGFR+ NSCLC), including Exon 20 insertions and the "alphabet soup" of rare mutations, moving away from the current fragmented approach.
  • Trial Design: Phase 3 randomized (1:1) trial (300 patients) with a primary focus on CNS-ORR (86% vs. ~35% benchmarks) and PFS (12.2 months observed vs. 5.1–6.1 months benchmarks).
  • Cohorts: Includes a randomized portion for patients with brain metastases and a single-arm cohort (80 patients) for patients without brain metastases (current Phase 2 PFS: 23.5 months; 0/24 patients developed brain mets in 16 months).
  • Control Arm: Global trial utilizing a mix of Afatinib and Osimertinib as standard of care based on regional usage.
• Glioblastoma (GBM) Indication:
  • Trial Design: Randomized Phase 2 (Silibertinib + Temozolomide vs. Temozolomide alone) with an IDMC reviewing interim PFS.
  • Trigger: Positive interim PFS will trigger conversion to a Phase 3 trial with Overall Survival (OS) as the endpoint.
  • TAM: Approximately 50,000 patients globally with EGFR alterations in GBM.
  • Leptomeningeal Disease: New FDA-suggested small cohort initiated to address this high-unmet-need population.

Market and Competitive Outlook:

• Differentiation: Silibertinib is positioned as the "most brain-penetrant" EGFR TKI, addressing the primary failure mode of current therapies (Osimertinib/Afatinib) which is CNS progression.
• Competitive Landscape: Competitors are restricted to specific subsets (e.g., PAC mutations) or focus solely on systemic ORR. Silibertinib targets all non-classical mutations under a unified definition agreed to by the FDA.
• Pricing/Positioning: Anticipated to become the standard of care for non-classical mutations, potentially reducing the need for radiation in patients with brain metastases due to superior intracranial control.

Macro / Industry Outlook:

• Regulatory: FDA has provided a clear path to accelerated approval based on CNS-ORR (RENO-BM criteria) and full approval based on PFS. FDA specifically suggested the inclusion of leptomeningeal disease and non-brain metastasis cohorts.
• Global Expansion: Trial setup active outside US/Canada; specific regulatory preparations underway in Japan.
• Partnerships: Potential for ex-US rights partnerships and international collaborations to capitalize on the global market.

Strategic Initiatives:

• Dose Optimization: Pivotal dose confirmed at 150 mg (down from 200 mg) to reduce dose reduction rates and adverse events (rash, diarrhea) in the frontline setting without compromising efficacy.
• Trial Execution: Enrollment at 150 mg has commenced (since August) to generate sufficient safety data for FDA acceptance prior to Phase 3 start.
• Manufacturing: Registration batches produced; stability and ADME studies (including radio-labeled studies in healthy volunteers) completed; program deemed "big pharma phase 3 ready."
• Pipeline Expansion: Active pursuit of partnerships for international commercialization.

Risks and Headwinds to Outlook:

• Trial Complexity: Managing a global trial with mixed control arms (Afatinib vs. Osimertinib) across different regions (US vs. Asia/Europe/South America).
• Dose Reduction Dependency: The 150 mg dose relies on early dose reductions (first 4-6 weeks) to be tolerable; insufficient data on this specific regimen could delay trial initiation.
• Regulatory Uncertainty: While CNS-ORR is a strong accelerated path, final full approval remains contingent on PFS confirmation in Phase 3.
• Capex: Significant additional capital required to complete Phase 3 trials and GBM milestones; potential dilution or partnership terms will be necessary.
• Clinical Enrollment: Risk of physician preference for radiation in symptomatic patients potentially complicating enrollment, though trial design accommodates radiation for symptomatic lesions.

Management Tone on the Future:

• Confidence Level: High. Management expresses strong confidence in the "very clear path to accelerated approval" and the "home run" potential of the single definition for non-classical mutations.
• Hedges: Acknowledges the difficulty of the GBM market but frames the drug as addressing every failure point of previous EGFR inhibitors (paradoxical activation, potency).
• Strategic Clarity: Emphasizes the "one-trial approach" to capture the entire non-classical population, signaling a strategic shift from niche targeting to broad market dominance in this segment.
• Forward-Looking Optimism: Describes the GBM opportunity as a "call option" and the CNS-ORR data (86%) as a significant de-risking factor compared to current standards (mid-30s).

Miscellaneous:

• Safety Data: Current Phase 2 data shows 23.5 months PFS in patients without baseline brain metastases (n=24) with zero brain metastasis events over 16 months of median follow-up, contrasting with the 5.1-month PFS of Osimertinib in similar populations (where 50% received radiation).
• Drug Formulation: Pill strengths available (75mg, 100mg, 175mg, 275mg) allow for flexible dosing (e.g., two 75mg pills for 150 mg dose) facilitating the dose reduction strategy.
• Surveillance Protocol: Strict 6-week surveillance MRI protocol utilized in Phase 2 to detect CNS progression early.