Tarlatamab-dlle (Imdelltra) demonstrated a manageable security profile and early antitumor exercise in sufferers with DLL3-expressing neuroendocrine prostate most cancers (NEPC), in line with early knowledge from a section 1b examine (NCT04702737) offered throughout the2024 ASCO Annual Assembly.1
Findings from the first evaluation confirmed that 22.2% (95% CI, 6.4%-47.6%) of sufferers within the total inhabitants (n = 40) achieved an total response with tarlatamab. The median length of therapy (DOT) was 1.4 months, and the median length of response (DOR) was 7.3 months (95% CI, 3.7-not evaluable). Notably, 1 affected person remained on therapy on the knowledge cutoff date of January 24, 2024, and continued to reply at 25.8+ months. Furthermore, sufferers skilled a median radiographic progression-free survival (rPFS) of two.1 months (95% CI, 1.7-3.7) and a median total survival (OS) of seven.9 months (95% CI, 4.4-13.2).
Amongst these with DLL3-positive tumors, the general response charge (ORR) was 10.5% (95% CI, 2.9%-24.8%). The median DOT on 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) on this inhabitants.
“These findings present preliminary assist for the exercise of tarlatamab in DLL3-positive prostate most cancers, in addition to spotlight the necessity to optimize affected person choice methods for this high-risk subset of metastatic castration-resistant prostate most cancers,” lead examine creator Rahul Aggarwal, MD, affiliate director for Scientific Sciences on the College of California, San Francisco (UCSF) Helen Diller Household Complete Most cancers Heart and an affiliate professor of hematology/oncology at UCSF, acknowledged in an oral presentation of the info.
Tarlatamab is a bispecific T-cell engager concentrating on DLL3, a protein expressed within the majority of high-grade neuroendocrine cancers, together with NEPC. Sufferers with DLL3-positive prostate most cancers typically expertise poor survival outcomes and lack efficient therapeutic options to plain chemotherapy. Notably, tarlatamab has proven promising medical exercise and a manageable security profile in pretreated extensive-stage small cell lung most cancers, with findings from the section 2 DeLLphi-301 trial (NCT05060016) supporting the agent’s accelerated approval by the FDA for this indication in Might 2024.2
“Each de novo and treatment-emergent NEPC, which will be present in as much as 15% to twenty% of metastatic CRPC biopsies, characterize very high-risk subsets of this illness, with restricted standard-of-care therapy choices past platinum-based chemotherapy,” Aggarwal defined throughout the presentation.1 “[Therefore,] we performed a potential section 1b examine of tarlatamab in sufferers with NEPC.”
The examine enrolled sufferers with metastatic de novo or treatment-emergent NEPC, outlined as histological small cell prostate most cancers; neuroendocrine differentiation by immunohistochemistry (IHC); or having at the very least 2 alterations in TP53, RB1, and/or PTEN by IHC or genomic evaluation. Sufferers additionally will need to have demonstrated development on 1 or extra prior strains of systemic remedy, together with platinum-based chemotherapy or an androgen receptor–signaling inhibitor.
All sufferers acquired a 1-mg step dose of intravenous tarlatamab on day 1 of cycle 1, adopted by 100 mg of the agent on days 8 and 15 of cycle 1, and twice-weekly administration thereafter. Aggarwal famous that this was the very best dose of tarlatamab decided to be secure and tolerable, as established within the section 1 DeLLphi-300 trial (NCT03319940).
The first finish level of the examine was security and tolerability, with key secondary finish factors together with antitumor exercise and pharmacokinetics. Affected person choice biomarkers served as an exploratory finish level.
On the knowledge cutoff, 40 sufferers had been enrolled onto the examine and acquired at the very least 1 dose of tarlatamab. Within the total inhabitants, the median age of sufferers was 64.5 years (vary, 43-83) and 95% of sufferers had an ECOG efficiency standing of 0 or 1. Sufferers acquired a median of three prior therapy strains (vary, 2-4), and 78% had beforehand been uncovered to platinum-based chemotherapy. The median baseline prostate-specific antigen (PSA) stage was 0.2 ng/mL (vary, 0.0-5000). Liver and bone metastases had been reported in 40% and 65% of sufferers, respectively.
When it comes to histological options, 86% of sufferers (n = 37) had tumor samples evaluated for DLL3, 46% had small cell histology, 40% had adenocarcinoma with neuroendocrine options, and 14% had adenocarcinoma with genetic markers. Retrospective DLL3 IHC evaluation confirmed that 56% of biopsy-evaluable sufferers (n = 32) had DLL3-positive tumors.
Concerning security, Aggarwal reported that, “Tarlatamab, at a goal dose of 100 mg IV each 2 weeks, demonstrated a manageable security profile.”
All sufferers skilled treatment-related antagonistic results (TRAEs), the vast majority of which had been low grade. Grade 3 and 4 TRAEs had been reported in 32.5% and 10.0% of sufferers, respectively; no grade 5 TRAEs had been noticed. Twenty % of sufferers skilled TRAEs resulting in dose interruption or discount, and seven.5% skilled TRAEs that led to therapy discontinuation.
Any-grade cytokine launch syndrome (CRS) and immune effector cell–related neurotoxicity syndrome or different related neurological AEs had been reported in 75% and 12.5% of sufferers, respectively. CRS occasions had been widespread, transient, and primarily grade 1. Grade 2 and three CRS occasions occurred in 17.5% and a couple of.5% of sufferers, respectively. There have been no grade 4 CRS occasions. Grade 2 or 4 ICANS occasions had been noticed in 5.0% and a couple of.5% of sufferers, respectively.
“We utilized a broad composite definition of NEPC, and didn’t require DLL3 positivity for affected person choice, which appeared to restrict the noticed exercise within the total cohort,” Aggarwal famous throughout the presentation. “Nevertheless, extra strong exercise was noticed within the DLL3-positive subset, significantly those that had true small cell histologic transformation.”
He concluded that additional analysis of tarlatamab is deliberate in sufferers with DLL3-positive prostate most cancers, and can embrace strategies to optimize affected person choice.
Disclosures: Dr Aggarwal experiences serving in a consulting or advisory function for Alessa Therapeutics, Amgen, AstraZeneca, Bayer, BioXcel Therapeutics, Boxer Capital, EcoR1 Capital, Exelixis, Janssen, Jubilant Prescribed drugs, Merck, Novartis, OncLive., PCCTC, Pfizer, Tersera; receiving institutional analysis funding from Amgen, AstraZeneca, Janssen, Merck, Novartis, Xynomic Pharma, Zenith Epigenetics; offering skilled testimony for the College of Utah Well being; and having journey lodging and bills paid for by DAVA Oncology.
References
- Aggarwal RR, Rottey S, Bernard-Tessier A, et al. Part 1b examine of tarlatamab in de novo or treatment-emergent neuroendocrine prostate most cancers (NEPC). J Clin Oncol. 2024, 42(16):5012.doi:10.1200/JCO.2024.42.16_suppl.5012
- FDA grants accelerated approval to tarlatamab-dlle for in depth stage small cell lung most cancers. FDA. Might 16, 2024. Accessed July 10, 2024. https://www.fda.gov/medicine/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
