XENCOR TRIAL RESULTS WEBCAST - XENCOR INC

Explicit Guidance:

• Phase 3 Trial Start: Plans to initiate a pivotal Phase 3 registration-enabling study for XMAB819 (monotherapy) during 2027 in patients with advanced clear cell renal cell carcinoma (RCC) following progression on one PD-1/PD-L1 inhibitor and one VEGFR TKI.
• Target Dose Selection: Selected 400 micrograms per kilogram (mcg/kg) IV as the putative Recommended Phase 3 Dose (RP3D) for XMAB819, citing a clear dose-response relationship and favorable safety profile consistent with lower doses (100 and 200 mcg/kg).
• Control Arm Strategy: Intends to power the Phase 3 study to detect a PFS hazard ratio of 0.7 against the active comparator tivozinib, based on the third-line subgroup data from the TIVO-3 trial (which showed 10.5% ORR and 5.4-month median PFS).
• Accelerated Approval Metrics: Anticipates using a single-arm cohort for an accelerated approval pathway, targeting an objective response rate (ORR) lower bound that exceeds current standard-of-care options; expects a safety analysis set of approximately 100 patients (potentially fewer given data strength) and efficacy metrics focused on ORR and median duration of response (DOR).
• Pipeline Milestones (2027):
  • First Half 2027: Submit End-of-Phase 1 meeting data to the US FDA; present subcutaneous (SC) formulation data; confirm the efficacy and safety of the 400 mcg/kg IV dose cohort (approx. 20 patients).
  • Ongoing: Continue enrollment of additional tumor cohorts (papillary RCC, colorectal, lung) with the expectation of expanding indications.
• Market Projections: Identifies the U.S. addressable market for the third-line setting (>9,000 patients annually) and a global market opportunity exceeding $11 billion by 2030, with potential for "blockbuster" status upon initial approval.

Business-Segment Outlook:

• XMAB819 (Clear Cell RCC): Projected to be the third pivotal study in a T-cell engager portfolio (following ASP2138 with Astellas and Zaloridamig with Amgen) starting in 2027. Aims to become Zencore's first commercial-stage program driven by 2027-2030 milestones.
• Expansion into New Histologies:
  • Papillary RCC, MSS Colorectal Cancer, and Non-Squamous NSCLC: Enrollment for "basket study" cohorts is ongoing. These indications are contingent on ENPP3 expression confirmed by IHC.
  • Readout Expectations: Safety profiles in these new cohorts are expected to mirror the IV 400 mcg/kg cohort (400 mcg/kg target dose with same priming regimen); efficacy readouts are pending but expected to be rapid given the "breakthrough" profile in clear cell RCC.
• Combination Strategies:
  • PD-1 Inhibitor: High confidence in combining XMAB819 with PD-1/PD-L1 inhibitors for first-line settings, citing preclinical data showing amplification of activity and lack of overlapping toxicity (orthogonal toxicity profiles).
  • VEGFR TKI: Strategic preference to avoid VEGFR TKI combinations in early lines to minimize cumulative toxicity and improve quality of life, favoring an immunotherapy-based regimen.
• Formulation Development: Subcutaneous (SC) formulation is in dose escalation; data expected in First Half 2027. Potential strategic paths include using SC for the Phase 3 trial, as a lifecycle convenience play, or exclusively if IV proves superior.

Market and Competitive Outlook:

• Competitive Landscape: XMAB819 aims to replace or augment current monotherapy options (e.g., tivozinib, belzutifan) and combination therapies (e.g., cabozantinib) in the post-IO/VEGFR TKI setting. Claims an ORR of ~45% in heavily pre-treated populations (including HIF-2 inhibitor exposed) versus ~10% for current standards in that setting.
• Market Dynamics: Addresses a "high unmet need" in triple-class exposed patients (progressed on IO, VEGFR TKI, and HIF-2 inhibitors), a segment currently limited to ~30% of the trial population but growing with the approval of Belzutafan/Levatinib combinations.
• First-Line Opportunity: Views the frontline setting (anchored by PD-1/PD-L1 inhibitors) as the largest future market. Plans to leverage early data to engage oncologists specializing in thoracic and GI cancers to expand the label beyond RCC.

Macro / Industry Outlook:

• Regulatory Pathway: Aiming for accelerated approval (conditional) based on single-arm data with strong response rates in unmet need populations, followed by a confirmatory randomized controlled trial (RCT) for full approval.
• Development Model: Emphasizes a "2+1" format platform (XMAP) enabling higher selectivity and safety compared to 1+1 bispecifics, positioning Zencore as a leader in solid tumor T-cell engagers.
• Healthcare Delivery: Plans to reduce hospitalization requirements during the priming period (targeting reduced monitoring/outpatient delivery) based on successful precedents from peers (e.g., Amgen's tarlatamab), facilitating community-based administration.

Strategic Initiatives:

• Platform Leverage: Utilizing the XMAP platform for multiple assets:
  • ASP2138 (Astellas): Currently in Phase 3 (CD3 bispecific, same 2+1 format) combined with Pembrolizumab/Chemo in gastric cancer.
  • Zaloridamig (Amgen): Active Phase 3 program in prostate cancer.
  • Other Candidates: Phase 1b data for Plumodimab (RA) and XMAB412 (TLN1A/IL-23) expected in two weeks (ACR conference). Phase 1 data for XMAB412 and Phase 2b data for XMAB942 (ulcerative colitis) expected through 2027.
• Manufacturing: Utilizing commercially validated CDMOs in the U.S. with a high-titer cell bank capable of scaling to 2,000L; drug product stability confirmed for 60 months.
• Partnerships: Awaiting updates from J&J regarding Pasiridamig (XMAB platform) combined with J&G 9401 (CD28 bispecific).

Risks and Headwinds to Outlook:

• Regulatory Uncertainty: Accelerated approval is conditional; confirmatory studies (Phase 3) must validate clinical benefit, and failure to do so could result in withdrawal.
• Tolerability in New Indications: While safety in RCC is favorable, efficacy and safety in new histologies (NSCLC, Colorectal) are unproven and could be lower due to different tumor biology (e.g., T-cell distribution).
• Subcutaneous Formulation Risk: The SC development is still in dose escalation; if data does not meet expectations or matches IV exposure profiles poorly, it may be deprioritized.
• Dose Selection Confirmation: The 400 mcg/kg dose is "putative" RP3D; final confirmation relies on the full enrollment of the 400 mcg/kg expansion cohort (~20 patients) and maturity of follow-up data.
• Market Access: While the market is large, adoption in later lines depends on pricing and reimbursement negotiations against existing standard of care.

Management Tone on the Future:

• High Confidence: Management expresses strong enthusiasm, describing the data as a "high watermark" for Phase 1 trials in RCC and citing "breakthrough potential."
• Strategic Focus: 2027 is characterized as a "pivotal year" for clinical milestones that will establish XMAB819 as Zencore's first commercial program.
• Momentum: The tone indicates a shift from "proof of concept" to "execution of late-phase development," with plans to aggressively engage health authorities for an accelerated pathway.
• Differentiation: Emphasizes the unique "2+1" selectivity and lack of cumulative toxicity as key differentiators against VEGFR TKIs and other TCEs.

Miscellaneous:

• Patient Characteristics: The studied population was heavily pre-treated, with 35-40% having received four or more prior lines and ~30% exposed to HIF-2 inhibitors, validating the drug's efficacy in the most refractory patients.
• Durability: Median time on treatment is 7 months, with responses deepening over time (some continuing >2.5 years); 75% of responses occur within the VEGFR TKI-like timeframe (rapid onset) while 25% show delayed deepening (immune-mediated).
• Toxicity Management: CRS and rash are predominantly low-grade and transient, occurring during the priming period. Mitigation strategies include pre-medications (acetaminophen, diphenhydramine, saline, dexamethasone, tocilizumab for priming) and prophylactic antihistamines for rash.
• Safety Profile: No treatment discontinuations due to toxicity in the 400 mcg/kg cohort; dose reductions were minimal (4.5% for rash, 15% for transaminitis, which were self-limited).