Tarlatamab

Risk Summary

Based on its mechanism of action, tarlatamab may cause fetal harm when administered to a pregnant woman. There are no available data on the use of tarlatamab in pregnant women to inform a drug-associated risk.

In an animal reproduction study, a murine surrogate molecule administered intravenously to pregnant mice crossed the placental barrier.

Tarlatamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance.

Human immunoglobulin G (IgG) and proteins comprising IgG-derived fragment crystallizable (Fc) domains are known to cross the placental barrier; therefore, tarlatamab has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with tarlatamab. In an embryo-fetal developmental toxicity study, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause maternal toxicity, embryo-fetal toxicity or teratogenicity.

There are no data on the presence of tarlatamab in human milk or the effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to tarlatamab are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with tarlatamab and for 2 months after the last dose.

No carcinogenicity or genotoxicity studies have been conducted with tarlatamab.

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

Clinical trials experience

Extensive Stage Small Cell Lung Cancer

The pooled safety population described in the WARNINGS AND PRECAUTIONS and below reflects exposure to intravenous tarlatamab, as a single agent, at the recommended dosage of tarlatamab 1 mg on Cycle 1 Day 1 followed by 10 mg on Days 8 and 15, and then every 2 weeks until disease progression or intolerable toxicity in 187 patients with extensive stage small cell lung cancer enrolled in Study DeLLphi300 and Study DeLLphi-301. Among 187 patients who received tarlatamab, 31% were exposed for 6 months or longer and 14% were exposed for greater than one year.

The most common (>20%) adverse reactions were cytokine release syndrome (55%), fatigue (51%), pyrexia (36%), dysgeusia (36%), decreased appetite (34%), musculoskeletal pain (30%), constipation (30%), anemia (27%) and nausea (22%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (57%), decreased sodium (16%), increased uric acid (10%), decreased total neutrophils (6%), decreased hemoglobin (5%), increased activated partial thromboplastin time (5%), decreased potassium (5%), increased aspartate aminotransferase (3.2%), decreased white blood cells (3.8%), decreased platelets (3.2%) and increased alanine aminotransferase (2.1%).

The demographic characteristics of patients who received tarlatamab were: median age 66 years (range: 35 to 82); 65% male; 70% White, 26% Asian, 2.1% Black or African American; and 2.1% Hispanic or Latino.

Serious adverse reactions occurred in 58% of patients who received tarlatamab. Serious adverse reactions in >3% of patients included cytokine release syndrome (24%), pneumonia (6%), pyrexia (3.7%) and hyponatremia (3.6%). Fatal adverse reactions occurred in 2.7% of patients who received tarlatamab including pneumonia 0.5%, aspiration (0.5%), pulmonary embolism (0.5%), respiratory acidosis (0.5%), and respiratory failure (0.5%).

Permanent discontinuation of tarlatamab due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of tarlatamab in >1% of patients included cytokine release syndrome (1.6%) and tumor lysis syndrome (1.1%).

Dosage interruptions of tarlatamab due to an adverse reaction occurred in 27% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included fatigue (3.2%), cytokine release syndrome (2.7%) and respiratory tract infection (2.1%).

Table 1 summarizes adverse reactions observed in Study DeLLphi-300 and Study DeLLphi-301.

Table 1. Adverse Reactions (≥15%) in Patients with ES-SCLC Who Received Tarlatamab in Study DeLLphi-300 and Study DeLLphi-301:

^a Graded using CTCAE Version 4.0 and Version 5.0.
^b Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019.
^c Includes fatigue and asthenia.
^d Includes myalgia, arthralgia, back pain, pain in extremity, neck pain, musculoskeletal chest pain, non-cardiac chest pain and bone pain.
^e Includes dyspnea and exertional dyspnea.

Table 2 summarizes laboratory abnormalities in Study DeLLphi-300 and Study DeLLphi-301.

Table 2. Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES – SCLC in Study DeLLphi-300 and Study DeLLphi-301:

^a The denominator used to calculate the rate varied from 41 to 187 based on the number of patients with a baseline value and at least one post-treatment value.
^b All Grade lab abnormalities occurring at a frequency less than 20% included decreased neutrophils.