NATIONAL HARBOR, MD – PRS-343, a 4-1BB/HER2 bispecific molecule, has demonstrated safety and antitumor activity in patients with heavily pretreated, HER2-positive solid tumors, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
In a phase 1 trial of 18 evaluable patients, PRS-343 produced partial responses in 2 patients and enabled 8 patients to maintain stable disease. PRS-343 was considered well tolerated at all doses and schedules tested.
“PRS-343 is a bispecific construct targeting HER2 as well as 4-1BB,” said, of Memorial Sloan Kettering Cancer Center in New York. “The HER2 component of the molecule localizes it into the tumor microenvironment of any HER2-positive cells. If the density of the HER2 protein is high enough, that facilitates cross-linkage of 4-1BB.
“4-1BB is an immune agonist that’s present in activated T cells, and cross-linkage helps to improve T-cell exhaustion and is also critical for T-cell expansion. The idea is that, by localizing 4-1BB activation to the tumor microenvironment, we can avoid some of the systemic toxicities associated with naked 4-1BB antibodies,” Dr. Ku added.
The ongoing, phase 1 trial of PRS-343 () has enrolled 53 patients with a range of HER2-positive malignancies. To be eligible, patients must have progressed on standard therapy or have a tumor for which no standard therapy is available.
The most common diagnosis among enrolled patients is gastroesophageal cancer (n = 19), followed by breast cancer (n = 14), gynecologic cancers (n = 6), colorectal cancer (n = 5), and other malignancies.
The patients’ median age at baseline was 61 years (range, 29-92 years), and a majority were female (62%). Most patients (79%) had received three or more prior lines of therapy, including anti-HER2 treatments. Breast cancer patients had received a median of four anti-HER2 treatments, and gastric cancer patients had received a median of two.
The patients have been treated with PRS-343 at 11 dose levels, ranging from 0.0005 mg/kg to 8 mg/kg, given every 3 weeks. The highest dose, 8 mg/kg, was also given every 2 weeks.
Treatment-related adverse events (TRAEs) included infusion-related reactions (9%), fatigue (9%), chills (6%), flushing (6%), nausea (6%), diarrhea (6%), vomiting (5%), and noncardiac chest pain (4%).
“This was an extremely well-tolerated drug,” Dr. Ku said. “Out of 111 TRAEs, only a tiny proportion were grade 3, and toxicities mostly clustered around infusion-related reactions, constitutional symptoms, as well as gastrointestinal symptoms.”
Grade 3 TRAEs included infusion-related reactions (2%), fatigue (1%), flushing (3%), and noncardiac chest pain (1%). There were no grade 4-5 TRAEs.
At the data cutoff (Oct. 23, 2019), 18 patients were evaluable for a response at active dose levels (2.5 mg/kg, 5 mg/kg, and 8 mg/kg).
Two patients achieved a partial response, and eight had stable disease. “This translates to a response rate of 11% and a disease control rate of 55%,” Dr. Ku noted.
Both responders received PRS-343 at 8 mg/kg every 2 weeks. One of these patients had stage 4 gastric adenocarcinoma, and one had stage 4 gynecologic carcinoma.
Of the eight patients with stable disease, three received PRS-343 at 8 mg/kg every 2 weeks, two received 8 mg/kg every 3 weeks, one received the 5 mg/kg dose, and two received the 2.5 mg/kg dose.
Dr. Ku noted that the average time on treatment significantly increased in patients who received PRS-343 at 8 mg/kg every 2 weeks. Additionally, both responders and patients with stable disease had a “clear increase” in CD8+ T cells.
“[PRS-343] has demonstrated antitumor activity in heavily pretreated patients across multiple tumor types, and the treatment history, specifically the receipt of prior anti-HER2 therapy, indicates this is a 4-1BB-driven mechanism of action,” Dr. Ku said. “Based on these results, future studies are planned for continued development in defined HER2-positive indications.”
The current study is sponsored by Pieris Pharmaceuticals. Dr. Ku disclosed relationships with Arog Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck, Zymeworks, and Pieris Pharmaceuticals.
SOURCE: Ku GY et al. SITC 2019,