Lyell’s ROR1-Targeted CAR-T LYL797 Attains 60% Clinical Benefit Rate at High Dose Level in Phase 1 Solid Tumor Trial

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Notably, 1 patient treated in the trial died of respiratory failure, but it is not clear whether the death was related to LYL797.

Lyell Immunopharma’s LYL797, an autologous investigational ROR1-targeted chimeric antigen receptor (CAR) T-cell therapy, has demonstrated a clinical benefit rate (CBR) of 60% a subset of 5 patients with triple-negative breast cancer (TNBC) who were treated in a phase 1 clinical trial (NCT05274451) for patients with ROR1-expressing solid tumors.1 Notably, 1 patient treated in the trial died of respiratory failure, but it is not clear whether the death was related to LYL797.

Among the 5 patients who were treated at the highest dose level (150x106) administered in the study thus far, the objective response rate (ORR) was 40%, with 2 patients having achieved partial responses that were maintained as of 90 days posttreatment. The CBR, which was defined as a best response of stable disease, partial response, or complete response, was 60% for this group.

The trial treated 20 patients in total, with 16 having relapsed/refractory (r/r) TNBC and the other 4 having r/r non–small cell lung cancer (NSCLC). Among the 16 patients evaluable for efficacy across multiple dose levels, including 50x106 cells, 100x106 cells, 150x106 cells, the CBR was 38%, indicating a dose-dependent response to the therapy.

“We are encouraged to see clinical responses and a clear dose-dependent indication of antitumor clinical activity from treatment with LYL797 in patients with advanced triple-negative breast cancer,” Lynn Seely, MD, the president and CEO of Lyell, said in a statement.1 “Our translational data provide, to our knowledge, the first demonstration of persistent CAR T cell infiltration into solid tumors associated with evidence of cancer cell killing. This early validation of our anti-exhaustion technology gives us the conviction to expand our trial to include patients with ROR1+ ovarian or endometrial cancers, while continuing to enroll patients with triple-negative breast or non-small lung cancers, and also to initiate a new clinical trial for patients with multiple myeloma and chronic lymphocytic leukemia. This compelling early clinical data from LYL797 gives us a high degree of confidence to advance LYL119, our next generation ROR1-targeted product candidate with even more powerful anti-exhaustion technology. We have submitted an IND for LYL119 and expect to enter the clinic this year.”

In terms of safety, which was based on 18 evaluable patients, 61% of patients experienced cases of cytokine release syndrome (CRS), 22% of patients experienced cases of pneumonitis, and 17% of patients experienced cases of headaches. Along with cytopenia, which was expected from lymphodepletion, the aforementioned adverse events (AEs) constituted the most common treatment-related AEs reported. Lyell noted that the CRS cases were generally mild and were treated with tocilizumab and steroids. With regard to treatment-related AEs assessed as grade 3 or higher, the most common were cytopenia (78%), pneumonitis (17%), and hypoxia (11%). Notably, 1 patient died from a case of respiratory failure 41 days after receiving LYL797. Lyell did not provide any additional details about this patient’s death, so it is not clear at this time whether it was related to the CAR-T.

Because the grade 3 or higher cases of pneumonitis occurred exclusively in patients with TNBC who had lung metastases, Lyell altered the trial’s protocol to divide patients into separate dose escalation cohorts based on the presence of lung involvement. The protocol has also been updated to include administration of prophylactic dexamethasone for all participants, with the intention of addressing potential pneumonitis cases. Furthermore, Lyell stated that patients without lung involvement are now being treated at a higher dose: 300x106 cells. Meanwhile, patients with lung involvement are being treated at a dose of 75x106 cells.

All 20 patients treated thus far were enrolled with metastatic disease and had previously received a mean of 6 prior therapies for metastatic disease. Lyell stated that the trial had a 100% success rate for manufacturing of the CAR-T product.

“These are promising initial clinical findings demonstrating that LYL797 ROR-1-targeted CAR T cells had dose-dependent antitumor clinical activity and have the potential to deliver even more meaningful and durable benefit to patients as we continue to dose escalate,” lead investigator David R. Spigel, MD, the chief scientific officer at the Sarah Cannon Research Institute, and a medical oncologist, added to the statement.1 “Pneumonitis is a known complication of radiotherapy and several approved cancer therapies, including immune checkpoint blockade and several antibody-drug conjugate therapies. We have implemented a protocol using steroids, the standard of care for treatment of patients with pneumonitis, that I believe will enable us to successfully monitor and manage these events.”

LYL797 incorporates Gen-R technology, which is a form of genetic reprogramming intended to overcome T-cell exhaustion, and Epi-R technology, a form of epigenetic reprogramming which is intended to generate T-cells with properties of durable stemness via an optimized manufacturing process.2 Improved functional activity compared to ROR-1-targeted CAR-T therapies without the 2 forms of reprogramming was demonstrated in preclinical studies in models of ROR1+ TNBC and NSCLC tumors.

The investigational new drug application for the current phase 1 trial was cleared by the FDA in December 2021.3 A poster detailing the design of the multicenter, single-arm, open-label, dose-escalation and dose-expansion trial was previously presented by Lyell at the European Society for Medical Oncology (ESMO) 2022 Congress, September 9-13, 2022 in Paris, France.2

“While CAR T-cell therapies have proven effective in hematologic malignancies, patients with solid tumors have seen limited benefit from these approaches due to a tumor microenvironment that leads to T-cell exhaustion and a loss of durable stemness,” Tina Albertson, MD, PhD, chief medical officer and head of development at Lyell, said in a December 2021 statement.3 “LYL797 is the first program to clinically evaluate our 2 T-cell reprogramming technologies which are designed to overcome these barriers, with the goal of developing more effective therapies for patients with solid tumor cancers.”

REFERENCES
1. Lyell Immunopharma Reports Dose-dependent Clinical Activity from Phase 1 Trial of LYL797, a ROR1-targeted CAR-T Cell Product Candidate Enhanced with its Proprietary Anti-exhaustion Technology. News release. Lyell Immunopharma, Inc. June 26, 2024. Accessed June 27, 2024. https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-reports-dose-dependent-clinical-activity
2. Spigel DR, Murthy HS, Chumsri S, et al.Phase I study of LYL797, a ROR1-targeted CAR T-cell therapy with genetic and epigenetic reprogramming for the treatment of advanced solid tumors. Presented at: 2022 ESMO Congress. September 9-13, 2022; Paris, France. Abstract 777TiP
3. Lyell Immunopharma announces FDA clearance of its IND for LYL797, a CAR T-cell therapy incorporating novel reprogramming technologies for solid tumors. News release. Lyell Immunopharma, Inc. December 16, 2021. Accessed June 27, 2024. https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-announces-fda-clearance-its-ind-lyl797-car-t
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