CT041 Shows Tolerability and Early Efficacy in Refractory Metastatic Pancreatic Cancer

CT041 had a manageable safety profile and showcased early signals of antitumor activity in heavily pretreated patients with metastatic pancreatic cancer, according to data from a pooled analysis of two phase 1/1b trials (CT041-CG4006, NCT03874897; CT041-ST-01, NCT04581473) published in the Journal of Clinical Oncology.

No predefined dose-limiting toxicities were reported with the claudin 18.2­–targeted CAR T-cell therapy. Discussions with the data safety monitoring committee led to 2.5 x 10⁸ being identified as the dose for exploration in the dose-expansion phase of the research. All patients experienced at least one treatment-emergent adverse effect (TEAE).

At a data cutoff date of February 1, 2023, and with a median follow-up of 17.3 months (95% CI, 13.4-19.4), CT041 induced an investigator-assessed overall response rate of 16.7% (95% CI, 4.7%-37.4%) by RECIST 1.1 criteria in evaluable patients (n = 4/24). Four patients experienced partial responses (PRs) and thirteen achieved stable disease (SD). The disease control rate (DCR) was 70.8% (95% CI, 48.9%-87.4%), and the clinical benefit rate was 37.5% (95% CI, 18.8%-59.4%). The median duration of response (DOR) was 9.5 months (95% CI, 2.6-not reached [NR]); the 6- and 12-month DOR rates were 75.0% (95% CI, 12.8%-96.1%) and 50.0% (95% CI, 5.8%-84.5%), respectively.

The median progression-free survival (PFS) was 3.3 months (95% CI, 1.8-6.2), with a 6-month PFS rate of 36.4% (95% CI, 17.8%-55.2%) and a 12-month PFS rate of 13.6% (95% CI, 3.5%-30,7%). The median overall survival (OS) was 10.0 months (95% CI, 5.5-17.6) with 6- and 12-month OS rates of 66.7% (95% CI, 44.3%-81.7%) and 45.8% (95% CI, 25.6%-64.0%), respectively.

“The data showed that the claudin 18.2[-targeted] CAR T-cell treatment represents exploratory promising anticancer activity in patients with heavily pretreated claudin 18.2–positive pancreatic cancer, pending confirmatory results,” lead study author Changsong Qi, MD, of Peking University Cancer Hospital & Institute, in Beijing, China, and colleagues, wrote in the paper. “The regimen improved OS, PFS, CA19-9 response, and DCR and had an expected safety profile and generally manageable AEs.”

The multicenter, open-label trials enrolled patients with advanced pancreatic cancer, including those who received at least 1 prior therapy. Patients were between the ages of 18 years and 75 years and had claudin 18.2 positivity via an immunohistochemistry staining assay and was defined as an expression intensity of 2 or higher and positive tumor cell proportion of 40% or higher.

Those with a heavy tumor burden or who were determined by investigators to be likely to experience rapid disease progression were permitted to receive bridging therapy, with a recommended regimen of FOLFIRI (leucovorin, fluorouracil, and irinotecan). After the CT041 cells were released, patients were able to receive CAR T-cell therapy infusion within 1 week of completing preconditioning. Those who achieved SD or better, experienced treatment-related adverse effects that recovered to grade 1 or returned to baseline, or who had CAR-claudin 18.2 copies that were undetectable qualified for reinfusion.

The primary end points in both studies were safety and tolerability during the 4 weeks following the first infusion with the product, and secondary end points included 12-month safety and tolerability, pharmacokinetics, and antitumor efficacy.

Patients were enrolled to the trials between October 19, 2019, and December 13, 2021; 10 were enrolled to CT041-CG4006 and 14 were enrolled to CT041-ST-01. Across the trials, the median patient age was 56.0 years (range, 30-74) and 66.7% were male. Half of patients had liver metastases and 33.3% had peritoneal metastases. Tumor locations included the head (29.2%), body (20.8%), tail (29.2%), and other (20.8%). More than half of patients (79.2%) received bridging therapy. Patients had 1 (25.0%), 2 (45.8%), or more than 2 (29.2%) metastatic organs.

In terms of ECOG performance status, 12.5% had a status of 0, and 87.5% had a status of 1. With regard to claudin 18.2 expression, 8.3% had low expression, 33.3% had medium expression, and 58.3% had high expression. The median CA19-9 level was 1,013.800 U/mL at baseline. The majority of patients (79.2%) had undergone surgery. Prior systemic therapies included gemcitabine (75.0%), nab-paclitaxel (Abraxane)/paclitaxel (79.2%), irinotecan/liposomal irinotecan (83.3%), fluorouracil/analogs and derivatives (91.7%), platinum (50.0%), and other (8.3%).

A total of 19 patients received 1 cycle of bridging therapy at the time of the data cutoff date of February 1, 2023; this included FOLFIRI (n = 14), nab-paclitaxel (n = 4), and FOLFOX (leucovorin, fluorouracil, oxaliplatin; n = 1). The median duration from apheresis to first infusion with the CAR T-cell therapy was 28 days (range, 24-76). Moreover, patients received preconditioning treatment with fludarabine/cyclophosphamide plus nab-paclitaxel (n = 22) or fludarabine/cyclophosphamide plus gemcitabine (n = 2). Twelve patients received two cycles of CAR T-cell therapy and two received 3 cycles. The median interval from first infusion to second infusion with CT041 was 77 days (range, 35-242). Most patients (95.8%) had discontinued treatment at the time of data cutoff because of progressive disease.

Additional safety data showed that the most common hematologic AEs reported in evaluable patients who received CT041 (n = 24) included lymphopenia (grade 1/2, 0%; grade 3/4, 100%), leukopenia (41.7%; 58.3%), neutropenia (25.0%; 58.3%), anemia (54.2%; 16.7%), and thrombocytopenia (8.3%; 12.5%). The most common gastrointestinal AEs included nausea (grade 1/2, 70.8%; grade 3/4, 0%), vomiting (62.5%; 0%), upper abdominal pain (29.2%; 0%), constipation (29.2%; 0%), abdominal distension (25.0%; 0%), diarrhea (25.0%; 0%), intestinal obstruction (0%; 8.3%), and erosive gastritis (0%; 4.2%). Grade 1/2 cytokine release syndrome was reported in 83.3% of patients and 1 patient (4.2%) experienced a grade 3/4 event.

Cardiac disorders included sinus tachycardia (grade 1/2, 45.8%; grade 3/4, 0%), sinus bradycardia (8.3%; 4.2%), arrhythmia (0%; 4.2%), and sinus arrhythmia (0%; 4.2%). Respiratory, thoracic, and mediastinal disorders that were grade 1 or 2 occurred in 20.8% of patients; 4.2% experienced grade 3/4 disorders. Grade 1/2 infections and infestations were reported in 8.3% of patients and 4.2% experienced a grade 3/4 event.

Other AEs included pyrexia (grade 1/2, 75.0%; grade 3/4, 16.7%), hypoalbuminemia (66.7%; 0%), increased alanine aminotransferase (54.2%; 4.2%), increased aspartate aminotransferase (41.7%; 8.3%), positive occult blood test (50.0%; 0%), decreased weight (50.0%; 0%), reduced appetite (50.0%; 0%), decreased blood pressure (41.7%; 0%), prolonged activated partial thromboplastin time (37.5%; 0%), asthenia (37.5%; 0%), increased conjugated bilirubin levels (20.8%; 12.5%), chills (33.3%; 0%), hyperglycemia (33.3%; 0%), increased blood bilirubin (20.8%; 8.3%), decreased blood fibrinogen (29.2%; 0%), increased blood pressure (29.2%; 0%), increased lipase (29.2%; 0%), peripheral edema (25.0%; 0%), prolonged prothrombin time (25.0%; 0%), hypokalemia (20.8%; 4.2%), hyponatremia (20.8%; 4.2%), increased unconjugated blood bilirubin (8.3%; 4.2%), increased blood creatine phosphokinase (0%; 4.2%), increased gamma-glutamyl transferase (0%; 4.2%), and tumor pain (4.2%). Skin and subcutaneous disorders (41.7%; 0%) and musculoskeletal and connective tissue disorders (33.3%; 0%) were also reported.

When looking at responses based on baseline claudin 19.2 expression. Of the two patients with low expression, one patient experienced SD and one achieved a PR. Of the eight patients with medium expression, one had a PR, three achieved SD, and four experienced disease progression. Of the fourteen patients with high expression, two had a PR, nine had SD, and three experienced disease progression.

The ORR achieved in those with high expression was similar to that experienced in those with low-/medium-expression, at 14.3% and 20%, respectively; this was also true with regard to DCR, at 78.6% and 60%, respectively. The median PFS in the high-expression subgroup was 3.7 months (95% CI, 1.0-6.2); the median OS was 11.0 months (95% CI, 5.8-NR); in the low-/medium expression subgroup, the median PFS and OS was 3.2 months (95% CI, 0.8-9.3) and 7.7 months (95% CI, 2.3-NR).

“The result of this study provides rationale for investigation of potential biomarkers related to efficacy, and alternative potential enhancing treatment is warranted in the future,” the study authors concluded.

Reference

Qi C, Zhang P, Liu C, et al. Safety and efficacy of CT041 in patients with refractory metastatic pancreatic cancer: a pooled analysis of two early-phase trials. J Clin Oncol. Published online May 24, 2024. doi:10.1200/JCO.23.02314