Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials

Author(s): Changsong Qi, MD¹; Panpan Zhang, MD²; Chang Liu, MD²; Jun Zhang, MD³; Jun Zhou, MD⁴; Jiajia Yuan, MD, PhD⁴; Dan Liu, MD²; Miao Zhang, MD²; Jifang Gong, MD⁵; Xicheng Wang, MD, PhD⁴; Jian Li, MD⁵; Xiaotian Zhang, MD⁵; Ning Li, MD⁶; Xiaohui Peng, Master⁷; Zhen Liu, Master⁷; Daijing Yuan, Master⁷; Raffaele Baffa, MD⁷; Yumeng Wang, MD⁷; Lin Shen, MD⁵

Source: https://doi.org/10.1200/JCO.23.02314

Dr. Anjan Patel's Thoughts

CAR-T agent for refractory met-pancreas showing a median duration of response of 9.5 months. These treatments are far from widely available, but the proof of principle is nice to see in a disease that otherwise has not had responses to immunotherapy. Hopefully more agents to come.

PURPOSE

CT041 is a chimeric antigen receptor (CAR)–modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC).

PATIENTS AND METHODS

These two multicenter, open-label phase I/Ib trials (CT041-CG4006, CT041-ST-01) have a similar target population and evaluation schedule. The primary objective was to assess the safety and tolerability of CT041, whereas secondary objectives included efficacy, pharmacokinetics, and immunogenicity.

RESULTS

The combined cohort comprised 24 patients with advanced PC. Among them, five patients (20.8%) had previously received one line of therapy, whereas 19 (79.2%) received ≥2 lines of therapy. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) and GI disorders were most reported grade 1 or 2 adverse events. The overall response rate and disease control rate were 16.7% and 70.8%. The median progression-free survival (mPFS) after infusion was 3.3 months (95% CI, 1.8 to 6.2), and the median overall survival (mOS) was 10.0 months (95% CI, 5.5 to 17.6). The median duration of response (mDoR)was 9.5 months (95% CI, 2.6 to Not reached), with a DoR rate at 12 months of 50% (95% CI, 5.8 to 84.5). The mPFS (6.0 v 1.0 months, P < .001) and mOS (17.6 v 4.0 months, P < .001) were prolonged in patients achieving partial response/stable disease than the progressive disease group. CA19-9 levels had reduced by at least 30% in 17 (70.8%) patients.

CONCLUSION

In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.

Author Affiliations

¹State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China; ²Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China; ³Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; ⁴Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China; ⁵State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China; ⁶Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; ⁷CARsgen Therapeutics Co, Ltd, Shanghai, China

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Somewhat disappointing as this was a negative study, however it is still an option for patients who are not candidates for mFOLFIRINOX.

Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211)

Positive study for the combo of TMZ + cape vs. TMZ alone in met-pNET, confirming a regimen that is already widely used. Patients were first-line, and those with MGMT-def had a better response.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

The NAPOLI-3 study assessed FOLFOX+ liposomal irinotecan vs. gemcitabine + nab-paclitaxel. NALIRIFOX was superior, with an OS of 11.1 vs. 9.2 months. Criticisms of modern gem trials are often that of rigid dosing requirements that differ from modern clinical practice. Additionally, it is unclear whether NALIRIFOX provides any meaningful benefit over FOLFIRINOX, and the cost is always a consideration.