IMDYLLTRA Powder for solution for infusion Ref.[116661] Active ingredients: Tarlatamab

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX33

Mechanism of action

Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of tumour cells and CD3 expressed on the surface of T-cells. The bispecific binding of tarlatamab to T-cells and DLL3-positive tumour cells triggers T-cell activation, production of inflammatory cytokines, and release of cytotoxic proteins, which results in redirected lysis of tumour cells.

Pharmacodynamic effects

The pharmacodynamic response after a single infusion of tarlatamab was characterised by T-cell redistribution and activation, and transient cytokine elevation. Peripheral T-cell redistribution (i.e., T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred within 24 hours after the initial dose of tarlatamab at 1 mg on day 1. T-cell counts declined within 6 hours post infusion and returned to baseline levels in the majority of the patients prior to the next infusion on day 8.

Serum cytokines IL-2, IL-6, IL-8, IL-10, IFN-γ and TNF-α were transiently elevated following the initial dose of tarlatamab at 1 mg on day 1. Cytokine levels peaked within the first 2 days following the start of tarlatamab infusion and generally returned to baseline levels prior to the next infusion on day 8. In subsequent treatments, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial infusion on day 1.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited. Clinical efficacy and safety Study DeLLphi-304 The efficacy of IMDYLLTRA was studied in a phase 3 multicentre, randomised, open-label trial (Study DeLLphi-304). Eligible patients were required to have SCLC with disease progression following 1 platinum-based regimen. In regions where standard of care (SOC) first-line systemic treatment for patients diagnosed with extensive-stage disease included platinum-based chemotherapy in combination with PD-(L)1 inhibitor, patients were required to have failed PD-(L)1 inhibitor as part of their first-line systemic treatment or to be ineligible to receive PD-(L)1 inhibitor therapy. Additionally, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and at least one measurable lesion as defined by response evaluation criteria in solid tumours (RECIST v1.1). The trial excluded patients with symptomatic brain metastases or active immunodeficiency.

A total of 509 patients were enrolled and randomised 1:1 to receive either IMDYLLTRA or SOC chemotherapy. 254 patients were randomised to IMDYLLTRA at an initial dose of 1 mg on Cycle 1 day 1 followed by 10 mg on days 8, 15, and every 2 weeks thereafter in a 28-day cycle until disease progression or unacceptable toxicity. SOC chemotherapies included topotecan (n=185), lurbinectedin (n=47) or amrubicin (n=23). Randomisation was stratified by prior anti-PD-(L)1 exposure (yes vs no), platinum sensitivity status (chemotherapy-free interval ≥180 days, <180 to ≥90 days, or <90 days), presence (previous or current) of brain metastases (yes vs no) and standard of care (topotecan/amrubicin vs lurbinectedin). Treatment continued until disease progression or unacceptable toxicity. Tumour assessments were performed every 6 weeks for the first 48 weeks and every 12 weeks thereafter.

The baseline demographics and disease characteristics of the study population were: median age of 65 years (range: 20 to 86 years); 41.3% age 65 to 74; 10.8% age 75 or older; 69% male; 57.2% White and 40.1% Asian; 32% ECOG PS of 0 and 67.2% ECOG PS of 1; 91% patients had metastatic disease at baseline; 44.8% had brain metastases at baseline; 35.2% had liver metastases at baseline. 68.8% patients were former smokers; 20.6% were current smokers, 10.6% were never smokers. All patients received at least 1 line of prior platinum-based chemotherapy (range: 1 to 3 lines); 97.6% of patients had received 1 prior treatment line; 70.7% received prior anti-PD-(L)1 therapy; 223 patients (43.8%) had chemotherapy-free interval <90 days after end of first-line platinum therapy, while 286 patients (56.2%) had chemotherapy-free interval ≥90 days.

The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy outcomes were progression-free survival (PFS) based on investigator assessment per response evaluation criteria in solid tumours (RECIST v1.1) and select patient-reported outcomes. Additional endpoints included overall response rate (ORR) based on investigator assessment per RECIST v1.1.

Patients received a median of 5 cycles of IMDYLLTRA treatment (range: 1 to 19 cycles), and a median of 4 cycles of SOC treatment (range: 1 to 21 cycles).

Efficacy results are summarised in table 9 and figure 1. The median (95% CI) follow-up time for OS was 11.2 months (10.4, 12.1) in the tarlatamab group and 11.7 months (10.6, 12.3) in the SOC chemotherapy group. The median (95% CI) follow-up time for PFS was 11.0 (8.5, 11.2) months for tarlatamab and 9.7 (8.4, 11.1) months for SOC chemotherapy.

Table 9. Efficacy results for patients with SCLC in Study DeLLphi-304:

^a per Kaplan-Meier estimates.
^b Hazard ratio based on the stratified Cox proportional hazard model.
^c PFS, ORR based on investigator assessment per RECIST v1.1.
CI = Confidence interval; N = number; NE = not estimable

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with tarlatamab in all subsets of the paediatric population in treatment of small cell lung cancer (see section 4.2 for information on paediatric use).