CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors
Rachel E Sanborn1, Omid Hamid2, Elisabeth Ge de Vries3
1Department of Medical Oncology, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA Rachel.Sanborn@providence.org.
Background:
Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.
Methods:
Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).
Results:
Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.
Conclusions:
The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.
Insights
The first-in-human study of pacmilimab (CX-072) and ipilimumab in advanced solid tumors found the recommended phase 2 dose to be active with a favorable safety profile. This combination shows promise for cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Probody therapeutics, like CX-072 (pacmilimab), are engineered for tumor-specific activation, reducing off-tumor toxicity.
- CX-072 is a Probody immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1).
- This study investigates the combination of pacmilimab with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of pacmilimab in combination with ipilimumab.
- To evaluate the safety and tolerability of this combination therapy in patients with advanced solid tumors.
- To assess the preliminary efficacy, including objective response rate, of the combination therapy.
Main Methods:
- A multicenter, open-label, phase 1/2 study enrolled 27 adult patients with advanced solid tumors naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors.
- A standard 3+3 dose-escalation design was used to determine the MTD of pacmilimab and ipilimumab.
- Treatment involved intravenous administration every 3 weeks for four cycles, followed by pacmilimab monotherapy.
Main Results:
- The MTD and recommended phase 2 dose was determined to be pacmilimab 10 mg/kg + ipilimumab 3 mg/kg every 3 weeks.
- Dose-limiting toxicities were observed in three patients, leading to the identification of the MTD.
- The overall response rate was 19%, with one complete response and four partial responses, some lasting over 12 months.
Conclusions:
- The combination of pacmilimab (10 mg/kg) and ipilimumab (3 mg/kg) is active and demonstrates a favorable tolerability profile.
- The identified MTD and recommended phase 2 dose support further clinical investigation of this combination.
- This Probody-based immunotherapy approach shows potential for managing advanced solid tumors.
