Lyell adopts dual strategy for CAR-T dose escalation after fatality

Adverse events have led Lyell Immunopharma to adopt a two-pronged strategy in its early CAR-T clinical trial, involving dose modification between different patient groups. A death and other complications necessitated this approach, specifically slowing down dose escalation in patients with lung metastases while pursuing a more aggressive dosage increase in the broader population.

As of Wednesday morning, Lyell's stock had dropped 27%, trading at $1.47.

The ongoing phase 1 trial is investigating LYL797, a CAR-T cell therapy targeting ROR1, in patients with solid tumors. This candidate was designed to overcome T-cell exhaustion, which previously hampered the effectiveness of early ROR1 CAR-T therapies in solid tumors. The trial is structured as a dose-escalation study to evaluate its potential.

The trial data involves 16 patients with triple-negative breast cancer and four with non-small cell lung cancer. Safety concerns emerged for patients with lung involvement, whether due to primary tumors, metastases, or fluid accumulation between the lung and chest wall. Dr. David Spigel, a principal investigator in the trial, presented the safety data on a conference call.

“Safety data in 18 evaluable patients demonstrated that LYL797 has acceptable tolerability in patients who do not have metastases to the lung. However, in those with lung metastases, four cases of grade 3 pneumonitis were reported, all prior to the implementation of dexamethasone prophylaxis,” Spigel said.

The first case of pneumonitis, which is lung inflammation, resulted in a patient dying from respiratory failure. Lyell attributes pneumonitis to local cytokine production associated with underlying lung disease. The biotech company noted that the onset typically occurs 4 to 10 days post-treatment and responds well to early high-dose steroids. As a precaution, Lyell is now administering steroids prophylactically to these patients.

Despite these measures, adverse events prompted Lyell to adjust its dosing strategy based on lung involvement. For patients without lung disease, the dose has been increased to 300 million cells. Meanwhile, those with lung issues are still receiving 75 million cells.

The ultimate impact of increasing the doses will influence both efficacy and durability of the treatment. Lyell observed a dose-dependent rise in clinical benefit rates with higher doses. No patients on the lowest doses exhibited partial or complete responses, whereas two responses were seen in five patients given 150 million cells. Only one patient had been administered 300 million cells by the data cutoff.

Lyell plans to escalate the dose to 450 million cells for patients without lung involvement. Conversely, the next step for patients at risk of pneumonitis will be increasing to 100 million cells. The findings from this dose-escalation study will help determine the appropriate doses for the next trial phase, which will involve 15 breast cancer patients and 15 lung cancer patients.

Additionally, Lyell is extending its research to include ROR1-positive ovarian and endometrial cancers and is preparing another study for patients with multiple myeloma and chronic lymphocytic leukemia. Concurrently, the company has applied to test its second-generation ROR1 CAR-T, LYL119, in human trials and aims to start clinical evaluations this year.