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Retsevmo ^® ^▼ (selpercatinib)

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How to manage increased hepatic enzymes with Retsevmo® (selpercatinib)

Alanine aminotransferase and aspartate aminotransferase increases were very common in selpercatinib-treated patients. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase.

UK_cFAQ_SEL403_HEPATIC_ENZYMES

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Hepatic enzymes information from the Retsevmo Summary of Product Characteristics

Increases in hepatic enzymes such as ALT or AST are one of the most common serious side effects of selpercatinib. Section 4.8 of the summary of product characteristics (SmPC) provides further information on the incidences and the time to onset.

ALT and AST should be monitored as described in section 4.4 of the SmPC. Dose modifications are necessary in patients with increases in ALT or AST grade 3 or 4 (see section 4.2 of the SmPC).

Please review the Retsevmo Summary of Product Characteristics for complete information, particularly the sections

4.2 Posology and method of administration
4.4 Special warnings and precautions for use
4.8 Undesirable effects

Below is further information from the clinical trials with a focus on incidences, severity, onset, and management in the clinical trials.

A full description of the clinical trials mentioned below is available in section 5.1 of the SmPC.

Content overview

Increased ALT and AST with selpercatinib in clinical trials

Treatment-emergent adverse events of increased ALT and AST with selpercatinib

Serious adverse events of increased ALT and AST with selpercatinib

Time to onset of increased ALT and AST in selpercatinib trials

Dosage modifications for increased ALT and AST in selpercatinib studies

Additional hepatic enzyme abnormalities in LIBRETTO-001

Dosage modifications for other hepatic abnormalities in selpercatinib trials

Hepatic function criteria in selpercatinib clinical trials

ALT and AST adverse event criteria

References

Increased ALT and AST with selpercatinib in clinical trials

The composite term of ALT increased included the preferred terms of ALT increased and ALT abnormal. The composite term of AST increased included the preferred terms of aspartate aminotransferase increased and aspartate aminotransferase abnormal.1

Treatment-emergent adverse events of increased ALT and AST with selpercatinib

Treatment-Emergent Adverse Events of Increases in ALT and AST in Selpercatinib Clinical Trials presents increases in ALT and AST across selpercatinib trials.

**Treatment-Emergent Adverse Events of Increases in ALT and AST in Selpercatinib Clinical Trials1-3**
Hepatic enzyme, severity, %	LIBRETTO-001a (N=796)	LIBRETTO-431b		LIBRETTO-531b
Hepatic enzyme, severity, %	LIBRETTO-001a (N=796)	SEL (N=158)	Control (N=98)	SEL (N=193)	CAB or VANDE (N=97)
ALT increasedc
All grades	29	60	40	26	34
Grade ≥3	9	22	3	10	2
AST increasedd
All grades	29	61	40	24	38
Grade ≥3	6	13	1	5	2

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CAB = cabozantinib; SEL = selpercatinib; VANDE = vandetanib.

aJune 2021 data cutoff.

bMay 2023 data cutoff.

cComposite term includes preferred terms ALT abnormal and ALT increased.

dComposite term includes preferred terms AST abnormal and AST increased.

Serious adverse events of increased ALT and AST with selpercatinib

In LIBRETTO-001, 12 patients (2%) experienced a serious adverse event (SAE) of ALT increased with 9 patient cases considered related to selpercatinib. Similarly, 12 patients (2%) experienced an SAE of AST increased with 9 patient cases considered related to selpercatinib.1

In LIBRETTO-431, 1 patient (<1%) experienced an SAE of ALT increased, and 1 patient (<1%) experienced an SAE of AST increased. Both events were considered related to selpercatinib.1

In LIBRETTO-531, there were no SAEs of ALT or AST increased reported.1

Time to onset of increased ALT and AST in selpercatinib trials

The time to onset of ALT and AST increases was similar across selpercatinib trials (Time to Onset of Increased Alanine Aminotransferase and Aspartate Aminotransferase in Selpercatinib Trials).

**Time to Onset of Increased Alanine Aminotransferase and Aspartate Aminotransferase** **in Selpercatinib Trials1**
Time to Onset, weeks (range)	LIBRETTO-001a (N=796)	LIBRETTO-431b (N=256)	LIBRETTO-531b (N=290)
ALT	5.8 (0.1-131.7)	5.1 (0.1-110.9)	5.6 (0.1-85.1)
AST	6.0 (0.1-174.7)	5.3 (0.7-88.1)	5.7 (0.1-85.1)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase.

aJune 2021 data cutoff.

bMay 2023 data cutoff.

Dosage modifications for increased ALT and AST in selpercatinib studies

Dose modifications due to increased AST and increased ALT are summarized in Dosing Schedule Changes Due to Increased Alanine Aminotransferase and Aspartate Aminotransferase in Selpercatinib Clinical Trials.

**Dosing Schedule Changes** **Due to Increased Alanine Aminotransferase and Aspartate Aminotransferase in Selpercatinib Clinical Trials1**
Dosing Schedule Change, %	LIBRETTO-001a (N=796)		LIBRETTO-431b (N=256)		LIBRETTO-531b c (N=290)
Dosing Schedule Change, %	ALT	AST	ALT	AST	ALT	AST
Interruption	12	11	12d	5	7	4
Reduction	8	7	10	4	7	4
Discontinued	1	1	<1	0	0	<1

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase.

aJune 2021 data cutoff.

bMay 2023 data cutoff.

cDose modification includes dose omission and reduction.

dInterruption includes dose delay and omission.

Additional hepatic enzyme abnormalities in LIBRETTO-001

The incidence and severity of additional hepatic enzyme abnormalities deemed to be study drug related in LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531 are summarized in Related Hepatic Enzyme Abnormalities Other Than ALT and AST That Occurred in Selpercatinib Trials.

In LIBRETTO-001, there were 3 patients (<1%) who experienced serious adverse events (SAE) of blood bilirubin increased and 4 patients (1) who experienced SAEs of ascites that were considered related to selpercatinib.1

In LIBRETTO-431 and LIBRETTO-531, there were no related SAEs of blood alkaline phosphatase (ALP) increased, blood bilirubin increased, or hypoalbuminemia reported.1

**Related Hepatic Enzyme Abnormalities Other Than ALT and AST That Occurred in Selpercatinib Trials**1
Preferred Term, %	LIBRETTO-001a (N=796)		LIBRETTO-431b (N=256)		LIBRETTO-531b (N=290)
Preferred Term, %	Any Grade	Grade ≥3	Any Grade	Grade ≥3	Any Grade	Grade ≥3
Blood ALP increased	8	<1	11	<1	8	<1
Blood bilirubin increased	8	<1	23	<1	7	<1
Hypoalbuminemia	0	1	11	<1	2	0

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

aJune 2021 data cutoff.

bMay 2023 data cutoff.

Dosage modifications for other hepatic abnormalities in selpercatinib trials

In LIBRETTO-001, dose modifications due to other hepatic enzyme changes included discontinuation (<1%), dose reduction (<1%), and drug omission (2%) due to blood bilirubin increased. Dose modifications due to blood ALP increased included reduction (<1%) and drug omission (2%). Drug omission (<1%) occurred due to hypoalbuminemia.1

In the LIBRETTO-431 dose modifications due to other hepatic enzyme changes included discontinuation (<1%) and drug omission (2.5%) due to blood bilirubin increased.1

In LIBRETTO-531, dose modifications due to other hepatic enzyme changes included dose reduction (1%) and dose omission (1%) for blood bilirubin increased.1

Hepatic function criteria in selpercatinib clinical trials

Inclusion criteria included having adequate hepatic functioning defined as

ALT and AST ≤2.5 times the upper limit of normal (ULN) or ≤5 times the ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor), and
total bilirubin ≤1.5 times the ULN or ≤3 times the ULN with documented liver involvement (patients with Gilbert’s Disease could be enrolled with prior Sponsor approval).1

In the phase 1/2 study, some but not all patients were previously treated with immune checkpoint inhibitors (ICIs). Prior ICI therapy may be a contributing factor in these patients.1

ALT and AST adverse event criteria

Based on selpercatinib information available to date, increased ALT and AST were identified as adverse events of special interest.1

Increases in ALT and AST were locally graded by Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03) as

>ULN to 3 times ULN (grade 1)
>3 to 5 times the ULN (grade 2)
>5 to 20 times the ULN (grade 3), and
>20 times the ULN (grade 4).

These fold-increases refer to multiples of the ULN established by the local laboratory facility running the test.4

References

1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2Hadoux J, Elisei R, Brose M, et al; LIBRETTO-531 Trial Investigators. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389:1851-1861. https://dx.doi.org/10.1056/NEJMoa2309719

3Zhou C, Solomon BJ, Loong K, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion–positive NSCLC. N Engl J Med. 2023. https://dx.doi.org/10.1056/NEJMoa2309457

4US Department of Health and Human Services; National Institutes of Health and National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed January 30, 2020.

Links to references and third-party websites are provided solely for your convenience and to facilitate easy access to the sources cited.

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: 21 November 2023

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Retsevmo ® ▼ (selpercatinib)

How to manage increased hepatic enzymes with Retsevmo® (selpercatinib)

Alanine aminotransferase and aspartate aminotransferase increases were very common in selpercatinib-treated patients. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase.

Hepatic enzymes information from the Retsevmo Summary of Product Characteristics

Content overview

Increased ALT and AST with selpercatinib in clinical trials

Treatment-emergent adverse events of increased ALT and AST with selpercatinib

Serious adverse events of increased ALT and AST with selpercatinib

Time to onset of increased ALT and AST in selpercatinib trials

Dosage modifications for increased ALT and AST in selpercatinib studies

Additional hepatic enzyme abnormalities in LIBRETTO-001

Dosage modifications for other hepatic abnormalities in selpercatinib trials

Hepatic function criteria in selpercatinib clinical trials

ALT and AST adverse event criteria

References

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Retsevmo ^® ^▼ (selpercatinib)