HPN328 Elicits Antitumor Activity in Small Cell Lung Cancer and Other NETs

HPN328, a novel half-life extended DLL3-targeting T-cell engager, demonstrated clinical activity and tolerability in patients with pretreated small cell lung cancer (SCLC) and other neuroendocrine tumors, according to findings from a phase 1/2 study (NCT04471727) presented at the 2022 ASCO Annual Meeting.¹

The results demonstrated that 39% of patients (n = 7/18) experienced a reduction in the sum of their target lesion diameter; this included 5 patients with SCLC, 1 with neuroendocrine prostate cancer, and 1 with thymic atypical carcinoid. One case of a confirmed partial response was reported in a patient with SCLC in the second line who continues to receive treatment at 32 weeks.

“Already HPN328 is demonstrating durable antitumor activity in this heavily treated relapsed/refractory population, and we are seeing responses deepen over time,” lead study author Melissa Johnson, MD, of Sarah Cannon Research Institute, said.

HPN328 is a TriTAC that binds to human and non-human primate DLL3, CD3ε, and albumin with similar affinities. On March 7, 2022, the FDA granted an orphan drug designation to HPN328 for the treatment of patients with SCLC.²

The open-label study consisted of a dose-escalation and -expansion phase. In the dose-escalation phase, 1 patient received a fixed dose of HPN328. If the patient experienced a grade 2 or higher adverse effect (AE), they proceeded to the 3+3 design. Between 3 and 6 patients were enrolled per cohort, and step-up dosing was used.

The trial enrolled patients with relapsed SCLC following platinum-based chemotherapy and patients with other malignancies with high-grade neuroendocrine features who had relapsed or were refractory to standard of care (SOC) or had no SOC available.

The objectives of the trial included the assessment of safety and tolerability, determination of the recommended phase 2 dose and/or maximum tolerated dose (MTD), characterization of pharmacokinetic (PK) and pharmacodynamic activity, and evaluation of preliminary antitumor activity.

HPN328 was administered as a once-weekly intravenous infusion. Premedication with dexamethasone, acetaminophen, and histamine receptor blockers were given at initial doses.

Imaging was performed every 9 weeks per RECIST v1.1 criteria, and immunohistochemistry was used to retrospectively analyze tumor tissue for DLL3 expression.

Eighteen patients were enrolled across 8 cohorts. Most patients had SCLC (n = 11; 61%); 11% (n = 2) had neuroendocrine prostate cancer, and 28% (n = 5) had other neuroendocrine neoplasms. Half of patients had baseline liver metastases (n = 9; 50%) and 39% (n = 7) had brain metastases at baseline.

Most patients had received 1 or 2 prior therapies (n = 5; 28% each) but 17% received 3 or 4 each (n = 3 each) and 11% (n = 2) received 5 prior therapies. Additionally, most patients received a prior checkpoint inhibitor (n = 14; 78%), including all patients with SCLC.

Treatment duration was “clinically meaningful,” Johnson said, and ranged from 4.1 weeks to 41.4 weeks. As of April 21, 2022, 5 patients remained on treatment, with durations of 14.1, 22.1, 29.0 33.1, and 41.4 weeks. Approximately one-third of patients (n = 6/18; 33%) were on treatment for at least 20 weeks.

The MTD was not reached, and no dose-limiting toxicities occurred. “The tolerable safety profile enabled a rapid dose escalation up to 12 mg, which was the highest administered dose” Johnson said.

Additional results indicated that 27% patients with SCLC (n = 3/11) had a greater than 30% reduction in the sum of their target lesion diameter across all doses. Most patients with SCLC (n = 4/6; 67%) who received at least 1.215 mg/week of HPN328 had a reduction in the sum of their target lesion diameter.

In terms of safety, any treatment-emergent AE (TEAE) occurred in 100% of patients; grade 3 or greater effects occurred in 56% (n = 10) of patients. Any-grade and grade 3 or greater treatment-related AEs occurred in 83% (n = 15) and 6% (n = 1) of patients, respectively.

TEAEs occurring in at least 15% of patients included dysgeusia (any grade, 39%), fatigue (any grade, 39%), hypotension (any grade, 39%; grade ≥3, 6%), constipation (any grade, 33%), hyponatremia (any grade, 33%; grade ≥3, 6%), nausea (any grade, 33%), vomiting (any grade, 33%), anemia (any grade, 28%; grade ≥3, 11%), chills (any grade, 28%), pyrexia (any grade, 28%), alanine aminotransferase increase (any grade, 22%; grade ≥3, 6%), aspartate aminotransferase increase (any grade, 22%; grade ≥3, 6%), cytokine release syndrome (CRS; any grade, 22%), diarrhea (any grade, 17%), dry skin (any grade, 17%), dyspnea (any grade, 17%), headache (any grade, 17%), neutrophil count decrease/neutropenia (any grade, 17%; grade ≥3, 11%), and weight decrease (any grade, 17%).

Grade 1 and 2 CRS occurred in 22% of patients (n = 4); no grade 3 or greater CRS or immune effector cell–associated neurotoxicity syndrome was reported.

Notably, no patients discontinued treatment because of AEs.

Further analysis demonstrated linear PK with HPN328, with dose-proportional increases in exposures at doses between 0.135 mg and 12 mg. The median half-life was 71 hours.

“HPN328 is clinically active and well tolerated, validating the TriTAC platform in the treatment of advanced solid tumors that express DLL3, and dose escalation continues,” Johnson concluded.

References

1. Johnson ML, Dy GK, Mamdani H, et al. Interim results of an ongoing phase 1/2a study of HPN328, a tri-specific, half-life extended, DLL3-targeting, T-cell engager, in patients with small cell lung cancer and other neuroendocrine cancers. J Clin Oncol. 2022;40(suppl 16):8566. doi:10.1200/JCO.2022.40.16_suppl.8566
2. Harpoon Therapeutics granted orphan drug designation for HPN328 for treatment of small cell lung cancer. News release. Harpoon Therapeutics, Inc.; March 7, 2022. Accessed June 21, 2022. https://bit.ly/3n3NqR9