Clinical Activity With High-dose HPN217 Warrants Continued Research in R/R Multiple Myeloma

The novel B-cell maturation antigen (BCMA)-targeting T-cell engager HPN217 showed deep and durable responses with a well-tolerated safety profile in patients with heavily pretreated, relapsed/refractory multiple myeloma. According to Al-Ola A. Abdallah, MD, these data position the agent as a candidate for the treatment armamentarium and support its clinical development through continuing dose optimization.

Updated interim results from an ongoing phase 1 trial (NCT04184050) of HPN217 in patients with relapsed/refractory multiple myeloma who have received at least 3 prior therapies were presented at the 2022 ASH Annual Meeting and Exposition.¹ A step-dosing regimen of HPN217 produced an overall response rate (ORR) of 77% in patients receiving higher doses at 12 mg or 24 mg, and the median overall responder time on treatment was 7 months. Three patients who were evaluated for minimal residual disease (MRD) were found to be MRD negative.²

Tolerability of HPN217 was maintained with the step-up dosing regimen. Grade 1 and 2 cytokine release syndrome (CRS) was observed in 29% of patients and in primarily early doses. Moreover, CRS did not increase at the higher dose levels, and no immune effector cell associated neurotoxicity syndrome (ICANS) events were recorded.²

“Our biggest focus [with] BCMA-targeted therapy has to be [increasing] tolerability and efficacy for patients,” Abdallah, an associate professor and physician at University of Kansas Medical Center, said in an interview with OncLive^®. “... [With continued dose-escalation], we're hoping to see a continuous improvement in efficacy and toxicity results.”

In the interview, Abdallah expanded on the rationale for and design of the phase 1 study, detailed updated safety and efficacy data with HPN217 in relapsed/refractory multiple myeloma, and discussed next steps for the investigation as well as sequencing of BCMA-targeted therapies for this patient population.

OncLive^®: What was the rationale for investigating HPN217 in this phase 1 study?

Abdallah: The goal of this phase 1, multicenter, open-label study [was] to focus on the safety, tolerability, pharmacokinetics, and efficacy of this treatment. [We] mainly focused on patients [with] relapsed/refractory multiple myeloma who got at least 3 [prior] lines of therapy and

were known [to be] triple exposed to 3 different classes of therapies. [These] include immunomodulatory drugs, proteasome inhibitors, and CD38 monoclonal antibodies.

How is the mechanism of action for HPN217 unique?

HPN217 is a trispecific T-cell activating construct, or TriTAC, which attaches to 3 different domains. One [arm] attaches to the BCMA, which is present in 95% of plasma cells; that helps [the agent] target myeloma cells. The second [domain] is CD3, which is [found] on T cells. The third domain is the [human serum] albumin, [which] extends the half-life for the TriTAC. The attachment of [HPN217] to BCMA and CD3 [helps] the immune system [attack] tumors.

Please describe the trial design.

The first part [of the study] was a fixed-dose [schedule]. Patients received a small dose [of HPN217] to evaluate the treatment's tolerability and efficacy. The second part increased the dosage [from] 2.15 mg up to 2.86 mg using step-up dosing. If [patients] tolerated that [dosage, investigators] increased the second dose up to 12 mg and 24 mg, [which] was the target dose.

What were the key efficacy data with HPN217?

The efficacy [analysis was] mainly focused [on] patients who got the higher dose [of] 12 mg to 24 mg. These patients [had] a response rate [of] 77%, and 46% of these patients [had a] very good partial response or better. Median follow-up for patients who stayed on the treatment [was] 9 months. We saw a deeper and longer duration of response up to 12 months, and we think that [DOR] is [still] going to improve [as] we enroll and follow-up [with] more patients. [These data are] typical for BCMA-targeted therapy.

What should be taken away from the analysis from a safety perspective?

For the safety [analysis], we looked at hematological and non-hematological [adverse effects (AEs)]. Anemia, fatigue, and CRS were common AEs in patients who got HPN217. Patients who [received] the step-up dosing [had a] CRS [rate] of 29%, which is low compared [with] bispecific antibodies. All patients had grade 1 and 2 [CRS], and the percentage of patients who got tocilizumab [Actemra] was 6%.

We did not see AEs like neurological toxicity, [ICANS], and all other abnormal neurological movements in these patients. The infection rate was 45%, [which included] pneumonia, upper

respiratory infection, and urinary tract infection. [These] safety issues [are] commonly seen [with] BCMA-targeted therapies and were expected.

What are the next steps for this early research?

The next step here is to continue enrollment of patients who are triple-exposed, and [had] prior BCMA-targeted therapy, and [use] a 12- and 24-mg dosage schedule. We believe [that administration] of this treatment is going to change to every other week [because] there's a longer half-life. We [hope to see] lower AEs for these patients.

Where should future research efforts be focused in relapsed/refractory multiple myeloma?

Our biggest focus [with] BCMA-targeted therapy has to be [increasing] tolerability and efficacy for patients. We have 3 different BCMA-targeted therapies that have been FDA approved, and we have to assume that many of patients are going to receive [them in the course of treatment]. We [need to improve] sequencing [of] these newer treatments, including HPN217, [for] patients who [who progressed] on prior BCMA-targeted therapies.

References

1. Abdallah AA, Cowan AJ, Leleu X, et al. Updated interim results from a phase 1 study of HPN217, a half-life extended tri-specific T cell activating construct (TriTAC®) targeting B cell maturation antigen (BCMA) for relapsed/refractory multiple myeloma (RRMM). Blood. 2022;140(suppl 1):7284-7285. doi:10.1182/blood-2022-159665
2. Harpoon Therapeutics presents updated interim results at ASH 2022 for novel T-cell engager HPN217 in relapsed/refractory multiple myeloma. Harpoon Therapeutics. December 7, 2022. Accessed February 6th, 2023. https://ir.harpoontx.com/news-releases/news-release-details