An ongoing Phase I clinical trial combining LYMPHIR™ (denileukin diftitox-cxdl) with pembrolizumab is showing promising preliminary results in patients with recurrent solid tumors, particularly gynecological malignancies. The trial, led by Dr. Haider Mahdi at the University of Pittsburgh, aims to determine an optimal dose and assess the impact of the combination on the tumor immune microenvironment.
The data, presented at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting, revealed a 27% objective response rate (ORR) and a 33% clinical benefit rate (CBR) among evaluable patients. Notably, the median progression-free survival (PFS) for patients achieving clinical benefit was 57 weeks, ranging from 30 to 96 weeks.
Efficacy and Safety
The trial enrolled 21 patients with recurrent or metastatic solid tumors, with 15 patients evaluable for response. Four patients achieved partial remission, and one patient demonstrated durable stable disease lasting over six months. Importantly, two of the four patients who achieved partial remission had previously received checkpoint inhibitors, suggesting potential efficacy in patients who have failed prior anti-PD-1/L1 therapy.
The combination regimen was generally well-tolerated, with most adverse events related to the patients' underlying disease. Only one case of dose-limiting toxicity (capillary leak syndrome) was reported at the highest dose level (12 mcg/kg), and no significant immune-related adverse events were observed.
Mechanism of Action and Clinical Significance
LYMPHIR is a targeted immune therapy that depletes immunosuppressive regulatory T lymphocytes (Tregs), potentially enhancing the anti-tumor activity of immune checkpoint inhibitors like pembrolizumab. Pembrolizumab, a PD-1 inhibitor marketed as KEYTRUDA® by Merck, works by blocking the PD-1 protein on T cells, enabling the immune system to recognize and attack cancer cells.
Dr. Myron Czuczman, Chief Medical Officer of Citius Pharmaceuticals and Citius Oncology, stated, "This efficacy data strongly suggests that LYMPHIR may have the ability to improve and prolong the anti-tumor 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."
Trial Design and Patient Population
The Phase I trial is an open-label, dose-escalation study evaluating the safety and efficacy of pembrolizumab in combination with LYMPHIR in patients with recurrent or metastatic solid tumors. LYMPHIR was administered at four dose levels (3, 6, 9, and 12 mcg/kg) in combination with pembrolizumab (200 mg) on a 21-day cycle for eight cycles, followed by pembrolizumab monotherapy as maintenance. The study utilized the Time-to-Event Continual Reassessment Method (TITE-CRM) to assess dose-limiting toxicities and determine the recommended Phase II dose (RP2D).
The trial enrolled patients with various recurrent or metastatic solid tumors, including ovarian, endometrial, and cervical cancers. These cancers represent significant health burdens, with hundreds of thousands of new cases diagnosed annually worldwide.
Future Directions
Citius Pharmaceuticals and Citius Oncology are optimistic about the potential of LYMPHIR to boost a patient's response to pembrolizumab. They plan to expand the research in a Phase II study to further evaluate the combination's benefits across a broader range of solid tumor types.
