An ongoing Phase I clinical trial evaluating the combination of pembrolizumab (Keytruda) and denileukin diftitox-cxdl (Lymphir) in patients with recurrent solid tumors has shown positive preliminary results. The study, presented at the Society for Immunotherapy of Cancer (SITC) 2024, suggests that this chemotherapy-free regimen may offer a new treatment option for patients with limited alternatives.
The open-label trial (NCT05200559) employed a dose-escalation approach, administering denileukin diftitox-cxdl 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. The primary objective was to assess the safety and preliminary efficacy of the combination in patients with various recurrent or metastatic solid tumors, including ovarian, endometrial, and cervical cancers. The trial utilized the Time-to-Event Continual Reassessment Method (TITE-CRM) to determine the recommended Phase II dose (RP2D).
Safety and Tolerability
The trial enrolled 21 patients with recurrent or metastatic solid tumors who had received at least one prior line of therapy. The most common adverse events included hypoalbuminemia, fever/chills, acute hypersensitivity reactions, anemia, nausea/vomiting, asthenia (fatigue), and anorexia. Notably, vascular leak syndrome, previously associated with denileukin diftitox-cxdl, was not reported in this trial. One dose-limiting toxicity (DLT), capillary leak syndrome, was observed at the highest dose level (12 mcg/kg), but the patient was able to continue treatment safely. No significant immune-related adverse events were observed.
Efficacy Outcomes
Among the evaluable participants, four patients achieved a partial response, and one patient demonstrated durable stable disease lasting over six months. Of 12 patients evaluable for efficacy, 3 patients had a partial response (25% RR), and 3 patients had durable stable disease (25% SD) for a clinical benefit rate of 50%. The median number of prior therapies was 3. Preliminary results showed that one patient had progressed on prior therapy, including pembrolizumab combined with lenvatinib. The overall response rate (ORR) was 27% (4/15), and the clinical benefit rate was 33% (5/15) among evaluable patients. Median progression-free survival (PFS) for patients achieving clinical benefit was 57 weeks, ranging from 30 to 96 weeks.
Mechanism of Action and Clinical Significance
Denileukin diftitox-cxdl is a recombinant interleukin-2 receptor (IL-2R) fusion protein that selectively targets and depletes immunosuppressive regulatory T lymphocytes (Tregs) in the tumor microenvironment. By combining it with pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, the regimen aims to enhance the anti-tumor immune response. Two of the four patients who achieved partial remission had received prior checkpoint inhibitors, highlighting the potential of this combination to overcome resistance to anti-PD-1/L1 therapy.
Investigator Commentary
Dr. Haider Mahdi, Assistant Professor at the University of Pittsburgh, who conducted the study, stated, "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 I portion of this study. We will further investigate in patients with gynecologic tumors and those with other solid tumor histologies to explore the impact of this therapy on Tregs, host immune-effector cells, and the tumor microenvironment."
Myron S. Czuczman, MD, Chief Medical Officer of Citius Pharmaceuticals and Citius Oncology, noted, "The preliminary results from this Phase I 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-cxdl may have the ability to improve and prolong the anti-tumor activity of immune checkpoint inhibitors."
