Pembrolizumab Plus Denileukin Diftitox Shows Promise in Solid Tumors

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A regimen of pembrolizumab (Keytruda) and denileukin diftitox-cxdl (Lymphir; E7777) was well-tolerated, including at the highest dosage, when used for the treatment of patients with recurrent solid tumors, according to preliminary findings from an ongoing investigator-initiated phase 1 trial (NCT05200559).¹

According to data presented in a poster presentation at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting, pembrolizumab given with denileukin diftitox led to an overall response rate (ORR) of 27%.^1,2 The clinical benefit rate was 33% and the median progression-free survival (PFS) was 57 weeks (range, 30-96).

Four of the evaluable patients achieved a partial response, 2 of whom had received prior checkpoint inhibitors. Additionally, 1 patient demonstrated stable disease that lasted for more than 6 months. These results show the potential of denileukin diftitox plus immune checkpoint inhibitors in patients who fail prior anti–PD-1/L1 therapy.

“We have seen promising results in patients with heavily pretreated recurrent or metastatic gynecologic tumors and will enroll three additional patients before completing the phase 1 portion of this study," said Haider Mahdi, MD, assistant professor, Department of Obstetrics, Gynecology & Reproductive Sciences, at the University of Pittsburgh, in a press release.¹ "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.”

For safety, this chemotherapy-free immunomodulatory regimen was manageable. There was 1 dose-limiting toxicity (DLT) of capillary leak syndrome at 12 mcg/kg. No immune-related adverse events (AEs) of grade 3 or greater were documented, and grade 3 or greater AEs were mostly related to underlying disease.

"The preliminary results from this phase 1 trial of patients with recurrent gynecological cancers are highly encouraging. This novel chemo-free immunomodulatory combination regimen has been well tolerated, including at the highest dosage. This efficacy data strongly suggests that [denileukin diftitox] may have the ability to improve and prolong the antitumor activity of immune checkpoint inhibitors. To date, this unique regimen has not been associated with significant immune-related adverse events. Moreover, of the 15 evaluable patients, one third experienced a clinical benefit with a median of more than 12 months of progression-free survival," stated Myron Czuczman, chief medical officer of Citius Pharmaceuticals and Citius Oncology, in a press release.

About the Phase 1 Trial of Pembrolizumab/Denileukin Diftitox

A total of 21 patients with recurrent or metastatic solid tumors, including ovarian cancer, endometrial cancer, and cervical cancer, were enrolled in the open-label, phase 1 study.³ Patients were required to have an ECOG performance status of 0 or 1, measurable disease, and adequate organ function. Further, those with recurrent or metastatic solid tumors who received 1 or more prior lines of therapy were eligible for enrollment.

This study includes 2 phases: a dose-escalation phase and a dose-expansion phase. In the dose-escalation phase, eligible patients will have solid tumors for which pembrolizumab is either approved or deemed appropriate by the treating physician, based on prior trials showing encouraging efficacy. Eligible tumor types include (but are not limited to) renal cell carcinoma, melanoma, ovarian cancer, microsatellite instability–high (MSI-H) cancers, endometrial cancer, non–small cell lung cancer, hepatocellular carcinoma, cervical cancer, and urothelial cancer.

The dose-expansion phase focuses initially on ovarian cancer and MSI-H cancer, with the possibility of additional cohorts added later. The TITE-CRM method will be used for dose assignment and patients will be treated until disease progression, unacceptable toxicities, and/or dose-limiting toxicities. Denileukin diftitox will be administered for 8 cycles, after which pembrolizumab may continue.

In phase 1 of this study, denileukin diftitox is given in escalating dose levels—3 µg/kg (dose level 1), 6 µg/kg (dose level 2), 9 µg/kg (dose level 3), and 12 µg/kg (dose level 4)—on days 1 through 3 of each cycle, for up to 8 cycles, with DLTs assessed during only the first 2 cycles. Pembrolizumab is given at a fixed dose of 200 mg intravenously (IV) on day 1 of each 21-day cycle.

Phase 2 is giving denileukin diftitox to patients at the phase 2 recommended dose (RP2D) determined from phase 1 of the study on days 1 through 3, again for up to 8 cycles. Pembrolizumab will continue to be administered at 200 mg IV on day 1 of each 21-day cycle.

Primary end points of the study include determining the RP2D and evaluating changes in specific immune cell populations within both the tumor and peripheral blood over a period of up to 5 years. These end points include monitoring changes in T-regulatory cells within the tumor microenvironment, as well as in peripheral blood, to assess the impact of the treatment on immune regulation. Additionally, shifts in CD8+ T cell levels and changes in myeloid cells are being assessed.

Secondary end points being evaluated include objective response, PFS, and overall survival.

REFERENCES:

1. 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 11, 2024. https://tinyurl.com/ut5trt22

2. 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: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 614.

3. T-regulatory cell depletion with E7777 combined with pembrolizumab in recurrent or metastatic solid tumors. ClinicalTrials.gov. Updated November 9, 2023. Accessed November 11, 2024. https://clinicaltrials.gov/study/NCT05200559