Lyell Immunopharma (LYEL) Study Update summary

Initial clinical results and study design

• Phase I trial of LYL797, a ROR1-targeted CAR T-cell with anti-exhaustion technology, enrolled patients with relapsed/refractory triple-negative breast cancer and non-small cell lung cancer, using a dose-escalation/expansion design.

• Dose escalation included four levels, with the highest cleared dose at 150 million cells; a 40% objective response rate and 60% clinical benefit rate were observed at this dose.

• Dose-dependent clinical activity was demonstrated, with a 38% clinical benefit rate across all dose levels.

• The study uses a modified toxicity probability interval (mTPI-2) design, with separate dose escalation for patients with and without lung involvement; higher doses, including 300 million cells, are under evaluation.

• Enrollment is expanding to include ROR1+, platinum-resistant ovarian or endometrial cancers, with new trials planned in multiple myeloma and CLL.

Translational and mechanistic findings

• LYL797 incorporates c-Jun overexpression and Epi-R manufacturing to resist T-cell exhaustion and promote stem-like, persistent T-cells.

• CAR T cells showed robust expansion, tumor infiltration, and evidence of tumor lysis, with lower exhaustion marker expression and a memory/stem-like phenotype.

• CAR T-cells were detected in all evaluable tumor biopsies, with persistence up to four months post-infusion.

• Transcriptomic analysis showed LYL797 T-cells resembled low-exhaustion CD19 CAR T-cells, not exhausted tumor-infiltrating lymphocytes.

• Manufacturing success rate for LYL797 was 100%.

Safety and adverse events

• No dose-limiting toxicities in patients without lung involvement; most common grade 3+ events were pneumonitis, hypoxia, and cytopenia.

• Pneumonitis occurred only in patients with lung metastases, managed with early steroid intervention and now with prophylactic dexamethasone.

• Cytokine release syndrome was mild and manageable; no ICANS attributed to LYL797.

• Grade ≥3 pneumonitis (17%) and hypoxia (11%) occurred only in patients with lung metastases; one Grade 5 respiratory failure reported.

• Safety monitoring and protocol adjustments are ongoing to optimize dosing and minimize risk.