Denileukin Diftitox Combo Shows Promising ORR and CBR in Solid Tumors

Denileukin diftitox plus pembrolizumab yields objective responses and clinical benefit in patients with recurrent solid tumors.

A combined regimen of pembrolizumab (Keytruda) and denileukin diftitox-cxdl (E7777; Lymphir) yielded positive preliminary results in a small cohort of patients with recurrent or advanced metastatic solid tumors, early findings from a phase 1 study (NCT05200559) showed.¹

Data presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting (SITC) showed that the objective response rate (ORR) was 27% (n = 4/15), the clinical benefit rate was 33% (n = 5/15), and the median progression-free survival (PFS) for patients achieving clinical benefit was 57 weeks (range, 30-96).

"We have seen promising results in patients with heavily pre-treated recurrent or metastatic gynecologic tumors and will enroll three additional patients before completing the phase 1 portion of this study. We will further investigate in patients with gynecologic tumors and those with other solid tumor histologies. We want to explore the impact of this therapy on Tregs, host immune-effector cells, and the tumor microenvironment,” Haider Mahdi, MD, lead study author and assistant professor in the department of Obstetrics, Gynecology and Reproductive Services at the University of Pittsburgh, stated in a press release.²

A total of 21 patients were enrolled, and 6 were ineligible for evaluation; 2 were too early to evaluate, 2 withdrew consent after 1 cycle, 1 died from underlying disease before cycle 2, and 1 was removed due to a potential rheumatoid arthritis diagnosis.

Of the 15 patients eligible for evaluation, progression of disease was found in 7; partial responses (PRs) at the first scan were observed in 4; durable, stable disease was achieved by 1 for at least 6 months, and 2 patients had stable disease for fewer than 6 months.

To be eligible for participation, patients were required to have recurrent or advanced metastatic solid tumors, adequate organ function, an ECOG score of 0 or 1, at least 1 prior line of therapy, and measurable disease.

Additionally, 10 patients received previous anti–PD-1/L1 therapy. Of the 4 patients with PRs, 2 occurred in patients with past exposure to anti–PD-1/L1 therapy.

Patients were administered 200 mg of pembrolizumab intravenously on day 1 every 21 days and either 3, 6, 9, or 12 mcg/kg of denileukin diftitox intravenously on days 1 to 3 in a dose escalation every 21 days for 8 cycles. No correlation was drawn between denileukin diftitox dosage and efficacy.

Maintenance pembrolizumab was given to 5 patients with a clinical benefit after all 8 cycles of the regimen were completed. Four of the patients had PRs, and 1 had stable disease for 6 months or longer.

Most adverse effects (AEs) were associated with each respective patient’s underlying disease. Probable capillary leak syndrome (CLS) was seen in 1 patient at the 12 mcg denileukin diftitox dose level on the first cycle. There were 0 definitive immune-related AEs of grade 3 or higher documented.

Tumor types included in the study are as follows: 10 patients had ovarian, 6 had endometrial, 2 had endometrium, 1 had cervical, 1 had vulvar, and 1 had squamous cell with basaloid features.

Expansion to a phase 2 trial would see the dosage amounts changed to 200 mg of pembrolizumab intravenously on day 1 and denileukin diftitox at the phase 2 recommended dose (P2RD) every 21 days. Future plans involve adding 3 patients into the phase 1 part of the trial, then advancing to phase 2.

References

1. Mahdi H, Cooper K, Mitch K, et al. T-regulatory cell depletion with E7777 (denileukin diftitox-cxdl) combined with pembrolizumab in patients with recurrent solid tumors: phase I trial. Presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting (SITC); November 6-10, 2024; Houston, TX. Abstract 614.
2. Citius Pharmaceuticals, Inc. and Citius Oncology, Inc. announce promising preliminary results of an investigator-initiated phase I clinical trial of pembrolizumab (KEYTRUDA®) and LYMPHIR™ in cancer patients with recurrent solid tumors. News Release. Citius Pharmaceuticals, Inc. November 11, 2024. Accessed November 12, 2024. https://tinyurl.com/yc895fkk