IMDELLTRA Solution for injection Ref.[110074] Active ingredients: Tarlatamab

Tarlatamab-dlle is a bispecific T-cell engager that binds to DLL3 expressed on the surface of cells, including tumor cells, and CD3 expressed on the surface of T-cells. Tarlatamab-dlle causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells. Tarlatamab-dlle had anti-tumor activity in mouse models of SCLC.

Exposure-Response Relationships

There are no clinically significant exposure-response relationships for efficacy over the exposure range observed between tarlatamab-dlle 10 mg and 100 mg (10 times the highest approved recommended dosage).

There is an exposure-response relationship between tarlatamab-dlle exposure and neutropenia or neurologic toxicity including ICANS with a higher risk of any grade neutropenia or neurologic toxicity including ICANS at higher exposure.

Serum Cytokines

Transient elevation of serum cytokines IL-2, IL-6, IL-8, IL-10, and IFN-γ were observed at a tarlatamab-dlle dosage of 0.3 mg and above. Peak elevation of cytokines was generally observed 24 hours following the initial dose of IMDELLTRA at 1 mg on Cycle 1 Day 1 and generally returned to baseline levels prior to the next infusion on Cycle 1 Day 8.

Tarlatamab-dlle pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified. The exposure of tarlatamab-dlle increased dose proportionally in the evaluated dose range of IMDELLTRA 1 mg to 100 mg every 2 weeks (10 times the highest approved recommended dosage). Tarlatamab-dlle steady state exposures were achieved by Cycle 2 Day 15. Pharmacokinetic exposures are summarized for the recommended dosage of IMDELLTRA in Table 15.

Table 15. Pharmacokinetic Parameters of Tarlatamab-dlle:

^a Parameters are reported as geometric mean (CV%).

Distribution

Tarlatamab-dlle steady state volume of distribution is 8.6 L (18.3%).

Metabolism

Tarlatamab-dlle is expected to be metabolized into small peptides by catabolic pathways.

Elimination

Tarlatamab-dlle’s median terminal elimination half-life (min, max) is 11.2 (4.3 to 26.5) days and the estimated systemic clearance is 0.65 L/day (44%) in patients with SCLC.

Specific Populations

No clinically significant differences in the pharmacokinetics of tarlatamab-dlle were observed based on age (32 to 82 years), body weight (35 to 149 kg), sex, race (White and Asian), mild or moderate renal impairment (eGFR ≥30 to <90 mL/min), or mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN).

The effects of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min), or moderate to severe hepatic impairment (total bilirubin >1.5 x ULN, any AST) on the pharmacokinetics of tarlatamab-dlle are unknown.

Effects of Tarlatamab-dlle on CYP450 Substrates

Tarlatamab-dlle causes transient release of cytokines that may suppress CYP450 enzymes and may result in an increased exposure of concomitant CYP substrates during and up to 14 days after occurrence of cytokine release syndrome [see Clinical Pharmacology (12.2)].

No carcinogenicity or genotoxicity studies have been conducted with tarlatamab-dlle.

No studies have been conducted to evaluate the effects of tarlatamab-dlle on fertility.

14.1 Small Cell Lung Cancer

The efficacy of IMDELLTRA was evaluated in Study DeLLphi-301 [NCT05060016], an open-label, multicenter, multi-cohort clinical trial. Eligible patients were required to have relapsed/refractory SCLC with disease progression after receiving previous treatment with platinum-based chemotherapy and at least one other line of prior therapy, an ECOG Performance Status of 0 or 1, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) The trial excluded patients with symptomatic brain metastases, evidence of interstitial lung disease or noninfectious pneumonitis, and active immunodeficiency.

A total of 99 patients received IMDELLTRA intravenously 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 until disease progression or unacceptable toxicity.

The study population characteristics were: median age 64 years (range: 35 to 82); 48% of patients ≥65 years and 10% of patients ≥75 years; 72% male; 58% White, 41% Asian; 1% Hispanic or Latino; and 74% have ECOG 1.

Ninety-seven percent of patients had metastatic disease at baseline; 22% had brain metastases at baseline; and 92% were former/current smokers. All patients received prior platinum-based chemotherapy (median two lines); 74% received prior anti-PD-(L)1 therapy (including 59% who received anti-PD[L]1 therapy in combination with platinumbased chemotherapy in the frontline setting); 51% received prior topoisomerase I inhibitor (including 20% who received topotecan). Platinum sensitivity status, defined by time to progression after first line platinum therapy, was known for 69/99 patients.

Twenty-seven patients (27%) had platinum-resistant SCLC, defined as time to progression <90 days after first line platinum therapy, while 42 patients (42%) had platinum-sensitive SCLC. Tumor assessments were performed every 6 weeks for the first 48 weeks and every 12 weeks thereafter. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as evaluated by Blinded Independent Central Review (BICR) according to RECIST v1.1.

Efficacy results are presented in Table 16.

Table 16. Efficacy Results for Study DeLLphi-301:

^a Assessed by Blinded Independent Central Review, CI= Confidence Interval
^b Median based on Kaplan-Meier estimate.
^c Based on observed duration of response.

Of the 69 patients with available data regarding platinum sensitivity status, the ORR was 52% (95% CI 32, 71) in 27 patients with platinum-resistant SCLC and 31% (95% CI 18, 47) in 42 patients with platinum-sensitive SCLC.