Tarlatamab Monotherapy Is Safe, Active in DLL3+ Neuroendocrine Prostate Cancer

Tarlatamab-dlle (Imdelltra) demonstrated a manageable safety profile and early antitumor activity in patients with DLL3-expressing neuroendocrine prostate cancer (NEPC), according to early data from a phase 1b study (NCT04702737) presented during the 2024 ASCO Annual Meeting.¹

Findings from the primary analysis showed that 10.5% (95% CI, 2.9%-24.8%) of patients in the overall population (n = 40) achieved an overall response with tarlatamab. The median duration of treatment (DOT) was 1.4 months, and the median duration of response (DOR) was 7.3 months (95% CI, 3.7-not evaluable). Moreover, patients experienced a median radiographic progression-free survival (rPFS) of 2.1 months (95% CI, 1.7-3.7) and a median overall survival (OS) of 7.9 months (95% CI, 4.4-13.2).

Among those with DLL3-positive tumors, the overall response rate (ORR) was 22.2% (95% CI, 6.4%-47.6%). Notably, 1 patient remained on treatment at the data cutoff date of January 24, 2024, and continued to respond at 25.8+ months. The median DOT in this subset was 3.6 months. The median rPFS was 3.7 months (95% CI, 1.9-7.4) and the median OS was 9.8 months (95% CI, 4.4-15.2) in this population.

“These findings provide preliminary support for the activity of tarlatamab in DLL3-positive prostate cancer, as well as highlight the need to optimize patient selection strategies for this high-risk subset of metastatic castration-resistant prostate cancer,” lead study author Rahul Aggarwal, MD, associate director for Clinical Sciences at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center and an associate professor of hematology/oncology at UCSF, stated in an oral presentation of the data.

Tarlatamab is a bispecific T-cell engager targeting DLL3, a protein expressed in the majority of high-grade neuroendocrine cancers, including NEPC. Patients with DLL3-positive prostate cancer often experience poor survival outcomes and lack effective therapeutic alternatives to standard chemotherapy. Notably, tarlatamab has shown promising clinical activity and a manageable safety profile in pretreated extensive-stage small cell lung cancer, with findings from the phase 2 DeLLphi-301 trial (NCT05060016) supporting the agent’s accelerated approval by the FDA for this indication in May 2024.²

“Both de novo and treatment-emergent NEPC, which can be found in up to 15% to 20% of metastatic CRPC biopsies, represent very high-risk subsets of this disease, with limited standard-of-care treatment options beyond platinum-based chemotherapy,” Aggarwal explained during the presentation.¹ “[Therefore,] we conducted a prospective phase 1b study of tarlatamab in patients with NEPC.”

The study enrolled patients with metastatic de novo or treatment-emergent NEPC, defined as histological small cell prostate cancer; neuroendocrine differentiation by immunohistochemistry (IHC); or having at least 2 alterations in TP53, RB1, and/or PTEN by IHC or genomic analysis. Patients also must have demonstrated progression on 1 or more prior lines of systemic therapy, including platinum-based chemotherapy or an androgen receptor–signaling inhibitor.

All patients received a 1-mg step dose of intravenous tarlatamab on day 1 of cycle 1, followed by 100 mg of the agent on days 8 and 15 of cycle 1, and twice-weekly administration thereafter. Aggarwal noted that this was the highest dose of tarlatamab determined to be safe and tolerable, as established in the phase 1 DeLLphi-300 trial (NCT03319940).

The primary end point of the study was safety and tolerability, with key secondary end points including antitumor activity and pharmacokinetics. Patient selection biomarkers served as an exploratory end point.

At the data cutoff, 40 patients were enrolled onto the study and received at least 1 dose of tarlatamab. In the overall population, the median age of patients was 64.5 years (range, 43-83) and 95% of patients had an ECOG performance status of 0 or 1. Patients received a median of 3 prior treatment lines (range, 2-4), and 78% had previously been exposed to platinum-based chemotherapy. The median baseline prostate-specific antigen (PSA) level was 0.2 ng/mL (range, 0.0-5000). Liver and bone metastases were reported in 40% and 65% of patients, respectively.

In terms of histological features, 86% of patients (n = 37) had tumor samples evaluated for DLL3, 46% had small cell histology, 40% had adenocarcinoma with neuroendocrine features, and 14% had adenocarcinoma with genetic markers. Retrospective DLL3 IHC analysis showed that 56% of biopsy-evaluable patients (n = 32) had DLL3-positive tumors.

Regarding safety, Aggarwal reported that, “Tarlatamab, at a target dose of 100 mg IV every 2 weeks, demonstrated a manageable safety profile.”

All patients experienced treatment-related adverse effects (TRAEs), the majority of which were low grade. Grade 3 and 4 TRAEs were reported in 32.5% and 10.0% of patients, respectively; no grade 5 TRAEs were observed. Twenty percent of patients experienced TRAEs leading to dose interruption or reduction, and 7.5% experienced TRAEs that led to treatment discontinuation.

Any-grade cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome or other associated neurological AEs were reported in 75% and 12.5% of patients, respectively. CRS events were common, transient, and primarily grade 1. Grade 2 and 3 CRS events occurred in 17.5% and 2.5% of patients, respectively. There were no grade 4 CRS events. Grade 2 or 4 ICANS events were observed in 5.0% and 2.5% of patients, respectively.

“We utilized a broad composite definition of NEPC, and did not require DLL3 positivity for patient selection, which appeared to limit the observed activity in the overall cohort,” Aggarwal noted during the presentation. “However, more robust activity was observed in the DLL3-positive subset, particularly those who had true small cell histologic transformation.”

He concluded that further evaluation of tarlatamab is planned in patients with DLL3-positive prostate cancer, and will include methods to optimize patient selection.

Disclosures: Dr Aggarwal reports serving in a consulting or advisory role for Alessa Therapeutics, Amgen, AstraZeneca, Bayer, BioXcel Therapeutics, Boxer Capital, EcoR1 Capital, Exelixis, Janssen, Jubilant Pharmaceuticals, Merck, Novartis, OncLive., PCCTC, Pfizer, Tersera; receiving institutional research funding from Amgen, AstraZeneca, Janssen, Merck, Novartis, Xynomic Pharma, Zenith Epigenetics; providing expert testimony for the University of Utah Health; and having travel accommodations and expenses paid for by DAVA Oncology.

References

1. Aggarwal RR, Rottey S, Bernard-Tessier A, et al. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2024, 42(16):5012.doi:10.1200/JCO.2024.42.16_suppl.5012
2. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed July 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer