Patient death prompts Lyell to revise ROR1 CAR-T dosing

Shares in Lyell Immunopharma dropped by 35% on Wednesday after the company announced that its Phase I trial of the experimental CAR-T therapy LYL797, despite showing potential in solid tumors, faces significant safety challenges, particularly for patients with lung involvement.

David Spigel, a leading investigator in the study, noted that pneumonitis is a known complication of several cancer therapies and radiotherapy. Consequently, the trial has incorporated a protocol for using steroids, the standard care for pneumonitis, to monitor and manage these events effectively.

LYL797 is a CAR T-cell therapy targeting ROR1 and employs Lyell's genetic and epigenetic reprogramming tools to prevent T cells from becoming exhausted. This therapy functions by overexpressing the protein c-Jun, which helps correct an imbalance in the AP-1 family of transcription factors found in exhausted T cells.

In the initial dataset, 20 patients were treated, including 16 with triple-negative breast cancer (TNBC) and four with non-small-cell lung cancer (NSCLC), all with relapsed/refractory metastatic disease. Four different dose levels have been explored thus far.

However, the trial encountered significant safety issues, particularly with pneumonitis and hypoxia. The most common severe side effects (Grade ≥3) were pneumonitis (17%) and hypoxia (11%), along with cytopenia due to lymphodepletion (78%). Importantly, there were no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) linked to LYL797. Unfortunately, one patient died from respiratory failure on day 41. Lyell indicated that severe pneumonitis was only seen in patients with TNBC and lung metastases, leading the company to divide dose escalation into two cohorts based on lung involvement. Patients without lung involvement are currently being evaluated at the highest dose level, 300 x 10^6 cells, while those with lung metastases or primary lung tumors are treated more cautiously at the 75 x 10^6 cell dose level.

Despite these setbacks, the trial presented some encouraging efficacy signals. Among five patients with TNBC treated at the 150 x 10^6 cell dose level, two had confirmed partial responses by day 90, resulting in an objective response rate (ORR) of 40%. The clinical benefit rate (CBR) was 60% at the 150 x 10^6 cell dose level and 38% across all dose levels.

CEO Lynn Seely expressed optimism, stating, "We are encouraged to see clinical responses and a clear dose-dependent indication of anti-tumor clinical activity in patients with advanced triple-negative breast cancer." She further highlighted that the translational data demonstrated persistent CAR T cell infiltration into solid tumors and evidence of cancer cell killing, marking a significant milestone.

The study also showed an increase in the number of LYL797 CAR T-cells in blood samples by day 60 for all 11 patients studied so far, with peak expansion occurring between days 8 and 11. Patients who received 150 x 10^6 cells exhibited three times more CAR T-cells at their peak than those who received 50 x 10^6 cells. Additionally, a low proportion of CAR T-cells showed the exhaustion marker TIGIT by day 11, supporting the effectiveness of c-Jun overexpression in preventing cell exhaustion.

Seely announced plans to expand the trial to include patients with ROR1+ ovarian or endometrial cancers and to initiate a new clinical trial for patients with multiple myeloma and chronic lymphocytic leukemia. Moreover, Lyell intends to advance its next-generation ROR1-targeted product, LYL119, which incorporates more powerful anti-exhaustion technology, into the clinic later this year.