CAR-T death drives Lyell to take 2-track approach to dose escalation

A death and other adverse events have forced Lyell Immunopharma to take a two-track approach to its early-phase CAR-T clinical trial, holding back dose escalation in people with lung metastases while racing ahead in the wider population. 

Lyell’s stock was trading down 27% at $1.47 as of 10.05 am ET on Wednesday morning.

The phase 1 trial is assessing the ROR1-targeted CAR-T cell therapy LYL797 in solid tumor patients. Lyell designed the candidate to overcome T-cell exhaustion, a phenomenon that limited the impact of early ROR1 CAR-T cell therapies on solid tumors. The biotech put the prospect to the test in a dose-escalation study. 

Lyell’s dataset includes 16 people with triple-negative breast cancer and four patients with non-small cell lung cancer. The safety signal concerns people whose lungs are affected by disease, either because they have primary tumors, metastases or a build up of fluid between the lung and the chest wall. David Spigel, M.D., a lead investigator in the phase 1 trial, discussed the safety data on a conference call with analysts. 

“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 patient with pneumonitis, a medical term for lung inflammation, died of respiratory failure. Lyell believes pneumonitis is related to local cytokine production that happens because of the underlying lung disease. The biotech said the onset is predictable, happening 4 to 10 days after treatment, and is treated effectively with early high-dose steroids. Lyell is giving steroids prophylactically to patients. 

Even so, the adverse events have driven Lyell to proceed at different speeds in different populations. In patients without lung involvement, the biotech has dialed up dosing to 300 million cells. Patients with lung involvement are still receiving 75 million cells.

How high Lyell can take the dose will influence efficacy and durability. The biotech saw dose-dependent increases in the clinical benefit rate as it increased the dose. No patients on the two lower doses had partial or complete responses. Lyell saw two responses in the five patients on the 150 million cell dose. Only one patient had received 300 million cells as of the data cutoff. 

Lyell is planning to go up to 450 million cells in patients without lung involvement but the next step up in patients at risk of pneumonitis is 100 million cells. The dose-escalation study will inform the selection of doses for the next stage of the trial, which will assess the recommended phase 2 doses in 15 people with breast cancer and 15 lung cancer patients. 

Lyell is expanding development to include ROR1-positive ovarian or endometrial cancers and planning to start another study in patients with multiple myeloma and chronic lymphocytic leukemia. In parallel, the biotech has filed to study its second-generation ROR1 CAR-T, LYL119, in humans and expects to enter the clinic this year.