ONC-392/BNT316 Elicits Clinical Activity in Checkpoint Inhibitor–Resistant NSCLC

Kai He, MD, PhD

ONC-392/BNT316 demonstrated early signs of antitumor activity and manageable safety in patients with metastatic, PD-(L)1–resistant non–small cell lung cancer (NSCLC), according to data from the phase 1/2 PRESERVE-001 trial (NCT04140526) that were presented at the 2023 ASCO Annual Meeting.^1,2

Among 27 evaluable patients, 29.6% responded to treatment; 22.2% of these responses were confirmed and 7.4% were unconfirmed. Documented responses at 4 months included complete response and stable disease at the 10-mg/kg dose. Among the remaining 25 patients treated in the expansion cohort, 7 partial responses and 10 cases of stable disease were reported, producing a disease control rate of 70.4%. The study authors noted that all but 1 responder received PD(L)1 inhibition for more than 12 weeks, typifying PD-(L)1-resistant disease.

“Early readout of the expansion cohort shows strong clinical activity in patients with immuno-oncology–resistant NSCLC,” lead study author Kai He, MD, PhD, of The Ohio State University Comprehensive Cancer Center in Columbus, and coauthors, wrote in the poster presentation. “These results support initiation of a pivotal study using ONC-392/BNT316 monotherapy for PD-(L)1–resistant NSCLC.”

Checkpoint inhibitor–based combinations are the standard frontline treatment for patients with advanced NSCLC without targetable gene mutations. However, many patients still develop primary or secondary resistance, and current CTLA-4 inhibitors lack efficacy as monotherapy.

“Metastatic NSCLC has a very poor prognosis with a 5-year survival rate of only 9%. These new data highlight the potential of BNT316/ONC-392 to provide a new approach to leveraging CTLA-4 as an effective target to address advanced, hard-to-treat tumors, further broadening our oncology toolkit,” Professor Özlem Türeci, MD, chief medical officer, and co-founder at BioNTech, said in a press release.¹

ONC-392 is a novel, target-preserving anti–CTLA-4 antibody that selectively depletes regulatory T cells in the tumor microenvironment, delivering an immunotherapeutic effect. Preclinical data have shown that ONC-392 is more effective and better tolerated than other available CTLA-4 inhibitors.

In April 2022, the FDA granted fast track designation to the agent for the treatment of patients with metastatic NSCLC with disease progression on anti–PD(L)1 therapy.³

The ongoing, first-in-human phase 1/2 trial is evaluating the safety, efficacy, and pharmacokinetics of the agent in 3 parts. Part A is a dose-finding rapid titration study of ONC-392 as a single agent in patients with advanced solid tumors; part B is dose finding for the combination of ONC-392 and pembrolizumab (Keytruda; part B); and part C will evaluate expansion cohorts of ONC-392 as a single agent and in combination with pembrolizumab.

Previously, the recommended phase 2 dose of ONC-392 was determined to be 10 mg/kg in patients with advanced solid tumors.²

To be eligible for inclusion in the lung cancer population, patients had to have metastatic, oncogene driver–negative NSCLC following progression on anti–PD-(L)1 therapy. In part A of dose escalation, patients received 10 mg/kg of ONC-392 every 3 weeks (n = 2). In part C, arm 1 of dose expansion, patients received 2 cycles of intravenous ONC-392 at 10 mg/kg followed by 6 mg/kg every 3 weeks (n = 33).

Of the 35 patients enrolled, the median age was 66 years (range, 43-89). Most patients were male (n = 20; 57%), white (n = 33), and had nonsquamous histology (n = 20) and an ECOG performance status of 1 (n = 26; 74%).

At the safety cutoff date of March 10, 2023, 74% (n = 26) of patients experienced treatment-related adverse effects (TRAEs), 43% of which were grade 3/4. Immune-related AEs occurred in 54% (n = 19) of patients; 34% (n = 12) were grade 3/4. TRAEs leading to dose interruption, reduction, or discontinuation occurred in 26% (n = 9), 3% (n = 1), and 20% (n = 7) of patients, respectively.

“The rate of severe immune-related AEs in the dose expansion cohort (30%) is relatively lower than what was reported for drugs of the similar class at comparable doses,” the authors wrote.

Gastrointestinal disorders included diarrhea (all grade, 14%; grade 3, 3%), colitis (all grade, 11%; grade 3, 9%), nausea (all grade, 6%; grade 3, 3%), and vomiting (all grade, 9%; grade 3, 3%). General disorders and administration site conditions included fatigue (all grade, 11%; grade 3, 3%), chills (all grade, 11%), and pyrexia (all grade, 9%). Skin and subcutaneous tissue disorders included pruritus (all grade, 6%) and rash (all grade, 6%). Other reported AEs included infusion-related reactions (all grade, 20%), aspartate transaminase/alanine transaminase increase (all grade, 17%; grade 3, 3%; grade 4, 3%), and muscular weakness (grade 3, 9%).

One case each of grade 3 treatment-related immune pancreatitis, intestinal perforation, adrenal insufficiency, tubulointerstitial nephritis, and immune hepatitis also occurred.

“The clinical activity and safety profile validate the improved therapeutic index of BNT316/ONC-392,” Pan Zheng, MD, PhD, chief medical officer and co-founder at OncoC4, stated in the press release. “We are especially encouraged by the readouts from the PD-(L)1-resistant NSCLC. Responses were observed regardless of PD-L1 status, and among those who failed multiple lines of immunotherapy and chemotherapy, including PD-1 and CTLA-4 combination therapy.”

Representative cases of the agent’s activity were included in the poster. The first was of a 75-year-old man who had received a diagnosis of stage IV lung adenosquamous carcinoma in January 2019. The man received 4 cycles of frontline pembrolizumab (Keytruda), carboplatin, and paclitaxel, followed by pembrolizumab maintenance until May 2022. Stereotactic body radiation therapy was administered in the left lung in January 2022, prior to systemic cancer progression with metastatic lesions in the adrenal glands and brain in May 2022. Stereotactic radiosurgery was performed in June 2022, and ONC-392 was started in July 2022. By September, the right adrenal lesion had resolved.

The second case was a 64-year-old man who had received a diagnosis of squamous cell carcinoma of the lung in August 2021. The man received weekly paclitaxel and carboplatin plus radiation therapy, completing the course in November 2021 before showing metastases in the spleen and liver in December 2021. The cancer continued to progress after 2 cycles of ipilimumab (Yervoy), nivolumab (Opdivo), carboplatin, and paclitaxel. ONC-392 was started March 2022 and led to tumor shrinkage on imaging in July and October assessments. As of May 2023, the patient remains on treatment.

Patients in the trial will continue to be monitored for survival in ongoing follow-up.

References

1. BioNTech and OncoC4 present positive phase 1/2 data for antibody candidate BNT316/ONC-392 in hard-to-treat NSCLC at ASCO. News release. BioNTech SE. June 2, 2023. Accessed June 27, 2023. https://www.globenewswire.com/news-release/2023/06/02/2681039/0/en/BioNTech-and-OncoC4-Present-Positive-Phase-1-2-Data-for-Antibody-Candidate-BNT316-ONC-392-in-Hard-to-Treat-NSCLC-at-ASCO.html
2. Safety and clinical activity of target-preserving anti-CTLA-4 antibody ONC-392 as monotherapy in NSCLC patients who progressed on PD(L)1-targeted immunotherapy. J Clin Oncol. 2023;41(suppl 16):9024. doi:10.1200/JCO.2023.41.16_suppl.9024
3. OncoC4 announces fast track designation granted by the U.S. FDA for ONC-392 monotherapy in PD(L)1-resistant NSCLC. News release. OncoC4. April 26, 2022. Accessed June 28, 2023. https://www.globenewswire.com/en/news-release/2022/04/26/2429043/0/en/OncoC4-Announces-Fast-Track-Designation-Granted-by-the-U-S-FDA-for-ONC-392-Monotherapy-in-PD-L-1-Resistant-NSCLC.html