Lyell begins Phase 3 CAR-T trial with 93% response rate data
Head-to-head study positions ronde-cel against approved therapies as biotech targets BLA submission in 2027
Lyell Immunopharma has commenced dosing patients in a first-of-its-kind Phase 3 clinical trial that pits its experimental CAR-T therapy directly against two already-approved treatments, marking a critical inflection point for the South San Francisco biotechnology company.
The PiNACLE-H2H trial, which began enrolling patients in February, will evaluate rondecabtagene autoleucel (ronde-cel) head-to-head against investigator's choice of either lisocabtagene maraleucel or axicabtagene ciloleucel in patients with relapsed or refractory large B-cell lymphoma in the second-line setting, according to the company announcement. The trial design represents an unusually ambitious approach for a mid-stage biotech, requiring Lyell to demonstrate superiority or non-inferiority against therapies already generating billions in annual sales.
The trial's launch follows clinical data from the company's Phase 1/2 study showing a 93% overall response rate and 76% complete response rate among 29 evaluable patients in the third-line or later setting, Lyell reported at the American Society of Hematology meeting in December. Perhaps more notably, 72% of patients who achieved complete responses maintained them at six months or longer, with a median progression-free survival of 18 months.
"The initiation of our Phase 3 PiNACLE-H2H trial marks an important milestone for Lyell and for patients with large B-cell lymphoma," the company stated in its earnings release. "We believe the head-to-head design of this trial will provide a robust data set to support regulatory approval."
Lyell reported its Q4 and full-year 2025 financial results this week, showing a narrowing net loss of $140.7 million compared to $191.9 million in the prior year. The company ended the period with $247.2 million in cash and received an additional $50 million in March, providing runway into the second quarter of 2027. That timeline positions Lyell to fund operations through its anticipated Biologics License Application submission targeted for mid-2027.
The safety profile from earlier trials has shown no Grade 3 or greater cytokine release syndrome, a common and potentially severe side effect of CAR-T therapies, with manageable rates of lower-grade immune effector cell-associated neurotoxicity syndrome. Those results, combined with the response durability data, have helped sustain analyst optimism despite the company's pre-revenue status and accumulated losses.
Shares of Lyell, which have traded in a 52-week range of $7.65 to $45.00, closed at $24.77 on Thursday. The company's market capitalization stands at approximately $545 million. Analyst price targets average $30.75, with two buy ratings offsetting one strong sell recommendation, according to market data.
The CAR-T market for large B-cell lymphoma represents one of the most lucrative opportunities in oncology, with approved therapies from Gilead Sciences, Bristol Myers Squibb, and Novartis generating multi-billion dollar franchises. However, the head-to-head trial design carries significant risk, as showing superiority against established therapies with years of real-world experience remains a high bar even for companies with promising early-stage data.
Lyell also reported progress in a separate program, adding seven new patients to its LYL273 trial in metastatic colorectal cancer without observing dose-limiting toxicity. That program, while earlier stage, provides potential optionality beyond the company's core focus on blood cancers.
The PiNACLE-H2H trial represents the culmination of Lyell's T-cell reprogramming technology platform, which the company has developed to address persistent challenges in cellular therapy durability. As the study progresses through 2026 and into 2027, investors will be watching not just efficacy endpoints but also manufacturing timelines and competitive dynamics in a rapidly evolving CAR-T landscape.