Tarlatamab

Tarlatamab 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 causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells. Tarlatamab 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 10 mg and 100 mg (10 times the highest approved recommended dosage).

There is an exposure-response relationship between tarlatamab 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 dosage of 0.3 mg and above. Peak elevation of cytokines was generally observed 24 hours following the initial dose of tarlatamab 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 pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified. The exposure of tarlatamab 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 steady state exposures were achieved by Cycle 2 Day 15. Pharmacokinetic exposures are summarized for the recommended dosage of IMDELLTRA in the following table.

Pharmacokinetic parameters of tarlatamab:

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

Distribution

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

Metabolism

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

Elimination

Tarlatamab’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 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 are unknown.

Effects of Tarlatamab on CYP450 Substrates

Tarlatamab 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.