Tarlatamab

No interaction studies have been performed. Initiation of tarlatamab treatment causes transient release of cytokines that may suppress CYP450 enzymes and may result in increased exposures of concomitant CYP substrates. Patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, should be monitored for known adverse events. The dose of the concomitant medicinal product should be adjusted as needed.

Tarlatamab has not been studied in patients with severe renal impairment. No dose recommendations can be made for patients with severe renal impairment to end-stage renal disease.

Limited data is available in patients with moderate hepatic impairment. IMDYLLTRA has not been studied in patients with severe hepatic impairment. No dose recommendations can be made for patients with moderate or severe hepatic impairment.

There are no available data from the use of tarlatamab in pregnant women.

A reproductive toxicity study conducted in mice using the murine surrogate molecule muS757 showed transplacental transport of muS757. Based on its mechanism of action and potential development of adverse reactions (like CRS) following tarlatamab exposure, tarlatamab may cause foetal harm when administered to a pregnant woman.

Tarlatamab is not recommended during pregnancy and in women of child bearing potential not using contraception.

Pregnancy status for females of child-bearing potential should be verified prior to starting treatment with tarlatamab.

It is unknown whether tarlatamab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with tarlatamab and for at least 2 months after the last dose.

Women of child bearing potential/contraception

Women of child bearing potential have to use effective contraception during and for 2 months after treatment with tarlatamab.

Fertility

There are no clinical trials to evaluate the effect of tarlatamab on fertility.

Due to the potential for ICANS associated neurological events following tarlatamab infusion, tarlatamab may have major influence on the ability to drive and use machines. In the event of any neurologic symptoms, patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until they resolve.

Summary of the safety profile

The safety of tarlatamab was evaluated in 473 patients with small cell lung cancer (SCLC) who received the tarlatamab target dose of 10 mg as monotherapy in clinical trials.

The most common adverse reactions are: CRS (56.7%), decreased appetite (36.4%), pyrexia (31.9%), dysgeusia (31.3%), constipation (30.4%), anaemia (30.0%), fatigue (29.8%), nausea (24.9%), asthenia (19.0%), neutropenia (16.9%), hyponatraemia (16.7%), headache (16.3%), lymphopenia (15.6%).

The most common serious adverse reactions are CRS (19.7%) and pyrexia (4.7%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials are listed by system organ class and by frequency. The frequencies of adverse reactions is based on pooled data from one phase 1, one phase 2, and one phase 3 clinical trials with 473 patients. The median duration of exposure was 18.0 weeks (range: 0.1 to 175.1 weeks).

Adverse reactions are listed according to the MedDRA system organ classification and by frequency. Frequency categories are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

^a Includes neutrophil count decreased.
^b Includes lymphocyte count decreased.
^c Additional information is provided in "Descriptions of selected adverse reactions".

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In clinical trials with pooled safety data from 473 patients with SCLC receiving the tarlatamab 1 mg as first dose and 10 mg second and later dose, CRS occurred in 56.7% of patients, with grade 1 in 39.3%, grade 2 in 15.4% of patients, grade 3 in 1.7% of patients and grade 4 events in 0.2% of patients. Serious events of CRS were reported in 19.7% of patients. After the first dose of tarlatamab, 41.4% of patients experienced any grade CRS, with 34.0% of patients experiencing any grade CRS after the second dose. The majority of CRS events occurred after the first two doses, with 8.5% of patients experiencing CRS following third dose or later. Following the day 1 infusion, 13.7% of patients experienced ≥ grade 2 CRS. Following the day 8 infusion, 4.4% of patients experienced ≥ grade 2 CRS. The median time from the most recent dose of tarlatamab to the first onset of CRS was 15.9 hours (range: 9.0 to 26.5 hours). For those grade 1 events that progressed to grade 2 or greater, the median time from grade 1 event to grade 2 or greater events was 22.1 hours (interquartile range: 8.5 - 31.6 hours). Cytokine release syndrome led to treatment interruption and/or dose modification in 2.1% of patients and to discontinuation of tarlatamab in 0.6% of patients.

Fatal CRS cases have been reported in the post-marketing setting.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Tarlatamab can cause ICANS, including life-threatening or fatal events.

In clinical trials with pooled safety data from 473 patients with SCLC receiving tarlatamab at 10 mg, ICANS was reported in 4.7% of patients. The median time from the first dose of tarlatamab to the first onset of ICANS was 9.0 days (interquartile range: 2 to 13 days). The median time to resolution of ICANS was 4 days (interquartile range: 2 to 8 days).

Neutropenia

In clinical trials with pooled safety data from 473 patients with SCLC receiving tarlatamab at 10 mg, neutropenia occurred in 16.9% of patients including 8.2% of patients experiencing grade 3 or grade 4 events. The median time from the first dose of tarlatamab to the first onset of neutropenia was 43 days (range: 29 to 109 days). Neutropenia leading to dose interruption occurred in 3.2% patients with none leading to treatment discontinuation. Treatment with G-CSF was required in 6% of patients.