ONC-392 Monotherapy Shows Efficacy in in Advanced Solid Tumors

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The PRESERVE-001 study has shown efficacy from ONC-392, a new anti-CTLA-4 antibody, as a monotherapy in patients with non–small cell lung cancer and ovarian cancer.

A study of ONC-392 (NCT04140526) has shown efficacy, tolerability and safety in patients with advanced solid tumors, according to preclinical data from OncoC4.1 ONC-392 is an anti–CTLA-4 monoclonal antibody that enhances antitumor activity at the same time that it promotes CTLA-4’s protective function against autoimmune diseases.

Targeting the CTLA-4 checkpoint has been established as a paradigm of cancer immunotherapy, but previous clinically tested anti–CTLA-4 antibodies have exhibited high toxicities and limited efficacy.2 ONC-392 is intended to selectively reduce regulatory T cells to impact the tumor, while preserving the CTLA-4 checkpoint by avoiding lysosomal degradation of CTLA-4 during treatment.

The PRESERVE-001 phase 1a/1b trial investigated the use of ONC-392 as a monotherapy and in combination with a PD-1 inhibitor in treating advanced solid tumors and non–small cell lung cancer (NSCLC).1 In the monotherapy arm, 10 patients received ONC-392 intravenously. An escalating dosage was used to determine the recommended dose for phase 2 monotherapy was 10 mg/kg once every 3 weeks.

Based on CT scan data, beneficial clinical activity was detected in 6 of 10 patients. Of 6 patients who received 10 mg/kg of ONC-392, 1 patient with NSCLC and 1 patient with ovarian cancer achieved a complete response. Of 4 patients who received a dose of 3 mg/kg, 1 patient with NSCLC and 1 patient with ovarian cancer had stable disease for more than 7 months.

Investigators observed preliminary evidence of clinical benefit among 3 out of 4 patients with metastatic ovarian cancer, including 1 with complete response, pending confirmation.

“Ovarian cancer is largely refractory to other checkpoint inhibitors and [patients with] stage IV ovarian cancer who failed platinum-based systemic therapy have very poor prognosis,” said Pan Zheng, MD, PhD, chief medical officer of OncoC4. “These data demonstrate the significant potential of ONC-392 to be a safe and effective monotherapy treatment option for this difficult to treat disease.”

Of the 10 patients who received ONC-392 monotherapy, 3 patients had stage IV NSCLC with resistance to PD-1, and all 3 showed indications of clinical benefit, including 1 with complete response and 2 with stable disease. This could provide a new late-line treatment option for patients whose disease has been resistant to PD-1 or PD-L1 inhibitors.

ONC-392’s efficacy in patients with PD-1 resistant disease is also crucial for ovarian cancer. “Treating PD-L1/PD-1-refractory cancer is one of the most substantial challenges in cancer immunotherapy. We are very encouraged with these initial data and believe ONC-392 as monotherapy warrants further clinical evaluation,” Zheng said.

The PRESERVE-001 study also investigated safety and tolerability of ONC-392. Grade 3 adverse events (AEs) were only observed after 3 or 4 cycles of 10 mg/kg, the highest dosage given. The AEs were seen only in patients who also showed a clinical benefit, and they were responsive to standard therapies.

ONC-392’s mechanism of action is meant to recycle instead of removing CTLA-4, providing both efficacy and reduced toxicity. “CTLA-4-targeting immunotherapy has been limited by its toxicity.” said Yang Liu, PhD, chief executive officer and chief scientific officer of OncoC4. “These data are promising and suggest that our unique treatment approach has the potential to fundamentally change the risk/benefit ratio of CTLA-4 targeting therapy with broad implications for multiple tumor types.”

Monotherapy cohorts will be expanded to test for efficacy in other indications, and a phase 2/3 trial is planned for monotherapy. Besides the monotherapy, there are 2 other arms of the trial investigating ONC-392 as combination therapy. One is with pembrolizumab (Keytruda) in patients with NSCLC, melanoma, and Merkel cell carcinoma, and the other is ONC-392 in combination with osimertinib (Tagrisso) in patients with NSCLC with EGFR mutations.

Four abstracts on ONC-392 will be presented at the Society for Immunotherapy of Cancer’s (SITC) 36th Annual Meeting, describing the clinical data, mechanism of action, pharmacokinetics, and clinical trial designs.


1. OncoC4, Inc. Reports Phase Ia Data on Safety and Clinical Activities of ONC-392 (Nextgen Anti-CTLA-4) Monotherapy for Stage IV Solid Tumors. OncoC4. November 9, 2021. Accessed November 10, 2021. https://bit.ly/3D6V4kb

2. Rolfo CD, Bentzen S, Devenport M, et al. First-in-human phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy.J Clin Oncol. 2020;38(suppl 15):TPS3159. doi:10.1200/JCO.2020.38.15_suppl.TPS3159