Early Promise Is Seen With CTX130 for RCC

Targeted Therapies in Oncology, January 2023, Volume 11, Issue 17
Pages: 36

According to findings from the phase 1 COBALT-RCC trial, CTX130 led to an objective response rate of 8%, a stable disease rate of 69%, and a disease control rate of 77% in patients with advanced clear cell renal cell carcinoma.

The investigational allogeneic CRISPR-Cas9 gene-edited, anti-CD70 chimeric antigen recep-tor (CAR) T-cell therapy, CTX130, led to an objective response rate of 8%, a stable disease (SD) rate of 69%, and a disease control rate of 77% in patients with advanced clear cell renal cell carcinoma (RCC). Findings from the phase 1 COBALT-RCC trial (NCT04438083) were presented during the Society for Immunotherapy of Cancer’s 37th Annual Meeting.1

In 13 evaluable patients, 1 had a partial response that became a complete response (CR) by 3 months, with a maintained CR at 18 months. As of 4 months, 4 patients had SD. The therapy had an acceptable safety profile across all dose levels, with no dose-limiting toxicities (DLTs). Of the 14 patients in the study, 50% had grade 1/2 cytokine release syndrome (CRS), 3 of which were related to CTX130. The median time to CRS onset was 1 day, with a median duration of 2 days. Three patients had serious adverse events (AEs) that were infec-tions, all of which were unrelated to CTX130. There was 1 death of pneumonia with grade 4 dyspnea, which was not considered to be related to treatment.

“This first-in-human clinical trial exploring CD70 CAR T-cell therapy in clear cell renal cell carcinoma showed a tolerable safety profile, with no unexpected on-target, off-tumor toxicities and encouraging antitumor activity,” lead study author Sumanta K. Pal, MD, a professor in the Department of Medical Oncology and Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope in Duarte, California, said in a presentation during the meeting. “To our knowledge, this durable [CR] is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed/refractory solid tumors.”

CD70 is a CD27 ligand that has transient expression on activated lymphocytes, and it is found to be highly expressed in clear cell RCC tumor samples. CTX130 is a first-in-class, CD70-targeting allogeneic CAR T-cell therapy that is being evaluated in patients with advanced clear cell RCC. The therapy has targeted disruption of the T-cell receptor α constant (TRAC), β2 microglobulin, and CD70 loci. With the use of an adeno-associated virus vector, an anti-CD70 CAR cassette is inserted into the TRAC locus by homology-directed repair.

The CAR T-cell therapy is manufactured from healthy donor T cells that are then selected and edited prior to expansion and cryopreservation for off-the-shelf use. Preclinical data demonstrated encouraging signals in an RCC xenograft model, Pal noted.

In the open-label, multicenter, international, single-arm COBALT-RCC trial, investigators sought to evaluate the safety and efficacy of CTX130 in patients with advanced clear cell RCC (FIGURE1). The study had 2 parts: a dose-escalation portion (part A) and a cohort expansion portion (part B).

Patients underwent lymphodepletion with fludarabine at 30 mg/m2 plus 500 mg/m2 of cyclophosphamide for 3 days on days –5, –4, and –3. CTX130 infusion began on day +1, with the dose-escalation design: 3 × 107 (dose level 1), 1 ×108 (dose level 2), 3 × 108 (dose level 3), and 9 × 108(dose level 4).

To be eligible for enrollment, patients with unresectable or metastatic RCC with clear cell differentiation had to be at least 18 years old and have a body weight of 42 kg or higher. Prior exposure to a checkpoint inhibitor and VEGF inhibitor were required. Patients also had to have a Karnofsky performance status of at least 80%, as well as adequate renal, liver, cardiac, and pulmonary organ function. Those who had prior treatment with anti-CD70 therapy, CAR T cells, or any other modifi ed T or natural killer cells were excluded from enrollment, as well as those with a history of central nervous system, cardiac, or pulmonary conditions and prior solid organ transplantation or bone marrow transplant.

The primary end point of part A of the trial was incidence of AEs via DLTs; in part B, the primary end point was objective response rate (ORR) per RECIST v1.1 criteria. Secondary end points were best overall response, progression-free survival, and overall survival.

The median age was 64.5 years (range, 54-77), and 85.7% of patients were men. All patients had stage IV metastatic disease and previously received systemic therapy; 64.3% and 92.9% of patients received prior radiotherapy and surgery, respectively.

A total of 57.1% of patients had Inter-national Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease, whereas 42.9% of patients had high-risk disease. An estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 was reported in 42.9% of patients. The median time from diagnosis was 4.9 years (range, 0.7-24.0), and the sum of diameters for target lesions was 64 mm (range, 12-141).

Pal added that typical pharmacokinetics were seen, with peak time to expansion at a median of day 10 and peak concentration of approximately 3500 copies/μg.

REFERENCE
1. Pal SK, Tran B, Haanen JB, et al. CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcino-ma: results from the phase 1 COBALT-RCC study. Presented at: Society for Immunotherapy of Cancer’s 37th Annual Meeting; November 6-10, 2022; Boston, MA. Accessed December 5, 2022. https://bit.ly/3VNBum4