Denileukin Diftitox Combo Yields Activity in R/R Gynecologic Cancers

Denileukin diftitox-cxdl (Lymphir) in combination with pembrolizumab (Keytruda) demonstrated preliminary clinical activity and a manageable safety profile in patients with relapsed or refractory gynecologic cancers, including ovarian and endometrial malignancies, according to topline results from an investigator-initiated phase 1 trial (NCT05200559) announced by Citius Oncology, Inc.¹

The study evaluated the safety and efficacy of the interleukin-2 (IL-2)–based immunotherapy paired with the PD-1 inhibitor in a patient population that has traditionally had limited options following the failure of platinum-based chemotherapy.

“We are encouraged by the favorable safety profile and sustained disease control observed in this heavily pretreated patient population. Evidence from the study suggests augmented anti-tumor activity when [denileukin diftitox] is combined with [pembrolizumab] and warrants further exploration in phase 2 settings,” said Myron Czuczman, MD, executive vice president and chief medical officer of Citius Oncology and Citius Pharma, in the press release.¹

Efficacy and Safety With the Denileukin Diftitox Combo

Among 21 evaluable patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer, the combination regimen produced an objective response rate (ORR) of 24%. Additionally, the study reported a clinical benefit rate (CBR) of 48%, which included those with a complete response, partial response, or stable disease for 6 months or more.

Among 25 patients evaluable for safety data, no unexpected safety signals or serious immune-related adverse events were observed at any dose level.

Full safety and clinical efficacy results are anticipated to be shared at an international cancer conference later in 2026.

“The efficacy signal shown by this combination is incredibly exciting considering the minimal impact immuno-oncology has made in ovarian cancer thus far. If these findings are confirmed in subsequent studies, we may have a transformational therapy on our hands,” added Alexander B. Olawaiye, MD, principal investigator of the study, and professor in the Department of Obstetrics at the University of Pittsburgh and director of Gynecologic Cancer Research at Magee-Women’s Hospital of the University of Pittsburgh Medical Center.¹

Trial Breakdown and Eligibility

The phase 1 study utilized a dose-escalation and expansion design to determine the safety and recommended phase 2 dose of the combination.² The treatment regimen consisted of 200 mg of intravenous pembrolizumab administered on day 1 of a 21-day cycle. Denileukin diftitox was administered intravenously at dose levels of either 3, 6, 9, or 12 mcg/kg on days 1 to 3 of each 21-day cycle. Those who completed 8 cycles of combination therapy continued to receive pembrolizumab monotherapy until disease progression.

Patient eligibility required participants to have histologically confirmed solid tumors, including ovarian or endometrial cancer. All patients must have progressed after receiving or were refractory to standard-of-care therapies for their disease. The protocol required measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Patients also had adequate hematologic and end-organ function, as well as a life expectancy of at least 6 months.

Those with a history of prior immune checkpoint inhibitor therapy, prior allogeneic stem cell or solid organ transplant, concurrent second primary malignancy within 3 years of screening, and HIV were excluded from enrollment.

Notably, the investigators highlighted that the use of denileukin diftitox was outside of its FDA-approved indication, and that the phase 1 study was not designed or powered to evaluate clinical efficacy.

The primary end points of the phase 1 trial were the recommended phase 2 dose, as well as changes in T-regulatory cells, CD8-positive T cells, and myeloid cells in tumor and peripheral blood. Secondary end points included ORR, progression-free survival, and overall survival.

References

1. Citius Oncology announces positive topline results from investigator-initiated phase 1 study of LYMPHIR in combination with pembrolizumab in relapsed or refractory gynecologic cancers. News release. Citius Oncology, Inc. March 10, 2026. Accessed March 10, 2026. https://tinyurl.com/46f46bdx
2. T-regulatory cell depletion with E7777 combined with pembrolizumab in recurrent or metastatic solid tumors. ClinicalTrials.gov. Updated December 5, 2024. Accessed March 10, 2026. https://tinyurl.com/y6rmbvwc