Retsevmo ® ▼ (selpercatinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information.For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).

Could hepatic enzymes be altered using Retsevmo® ▼ (selpercatinib)?

Alanine aminotransferase (38%) and aspartate aminotransferase (37%) increases were observed in the LIBRETTO-001 population. Temporary increases in total bilirubin and alkaline phosphatase were also seen.

UK_cFAQ_SEL403_HEPATIC_ENZYMES
UK_cFAQ_SEL403_HEPATIC_ENZYMES
en-GB

Warnings and Precautions: Selpercatinib and Increased Hepatic Enzymes

Grade ≥3 increased alanine aminotransferase (ALT) and grade ≥3 increased aspartate aminotransferase (AST) were reported in patients receiving selpercatinib.  Both ALT and AST should be monitored

  • prior to the start of selpercatinib therapy
  • every 2 weeks during the first 3 months of treatment
  • monthly for the next 3 months of treatment, and
  • otherwise as clinically indicated.1

 Based on the level of ALT or AST elevations, selpercatinib may require dose modification.1

Dosing Modifications for Increased AST and/or ALT

Close monitoring of patients with impaired hepatic function is important.  No dose adjustment is required for patients with mild (Child‑Pugh class A) or moderate (Child‑Pugh class B) hepatic impairment.1

Patients with severe (Child‑Pugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily.1

Dosing modifications specific to grade ≥3 increased AST and ALT are presented in Dosing Modifications for Increased AST and/or ALT.

Dosing Modifications for Increased AST and/or ALT1

Gradea

Dose Modification

3 and 4 

 

  • Suspend dose until toxicity resolves to baseline. Resume at a dose reduced by 2 levels.
  • If after at least 2 weeks selpercatinib is tolerated without recurrent increased ALT or AST, increase dosing by 1 dose level.
  • If selpercatinib is tolerated without recurrence for at least 4 weeks, increase to dose taken prior to the onset of grade 3 or 4 increased AST or ALT.
  • Permanently discontinue selpercatinib if grade 3 or 4 ALT or AST increases recur despite dose modifications.

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events.

a Grade defined by CTCAE criteria.

Increased Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001

As of June 2021 data cutoff (N=796), ALT increases were reported in in 284 patients (36%) and AST increases were reported in 292 patients (37%) in LIBRETTO-001. The majority of events were grade 1 and 2. No grade 5 events were reported.  (Increases in Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001 (N=796)).2,3

The composite term of ALT increased included the preferred terms of alanine aminotransferase increased and alanaine amintertransferase abnormal. The composite term of AST increased included the preferred terms of aspartate aminotransferase increased and aspartate aminotransferase abnormal.3

Increases in Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001 (N=796)2,3

 

Any Causality

Related to Treatment

Hepatic Enzyme, %a

Any Grade

Grade ≥3

Any Grade

Grade ≥3

ALT increasedb

36

11

29

9

AST increasedc

37

9

29

6

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

aJune 2021 data cutoff.

bComposite term includes preferred terms ALT abnormal and ALT increased.

cComposite term includes preferred terms AST abnormal and AST increased.

Twelve 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 .3

Time to Onset of Increased Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001

As of June 2021 data cutoff (N=796), time to onset of increased ALT was a median of 5.8 weeks (range 0.1 to 131.7 weeks). The time to onset of increased AST was a median of 6.0 weeks (range 0.1 to 174.7 weeks).3

Dosage Modifications for Increased Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001

Dosing Schedule Changes  Due to Increased Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001 (N=796)3

Dosing Schedule Change, %a

ALT
Increased

AST
Increased

Interruption

12

11

Reduction

8

7

Discontinued

1

1

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

aJune 2021 data cutoff.

Additional Hepatic Enzyme Abnormalities in LIBRETTO-001

The incidence and severity of additional hepatic enzyme abnormalities in LIBRETTO-001 are summarized in Additional Hepatic Enzyme Abnormalities That Occurred in ≥10% of the LIBRETTO-001 Population (N=796).

Additional Hepatic Enzyme Abnormalities That Occurred in ≥10% of the LIBRETTO-001 Population (N=796)3

 

Any Causality

Related to Treatment

Preferred Term, %a

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Blood ALP increased

15

2

8

1

Blood bilirubin increased

12

1

8

<1

Hypoalbuminemia

12

1

3

0

Ascites

11

1

7

1

Abbreviations: ALP = alkaline phosphatase.

aJune 2021 data cutoff.

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.3

Dosage Modifications for Other Hepatic Abnormalities in LIBRETTO-001

Dosing Schedule Modifications Due to Changes in Hepatic Enzymes Other Than Alanine Aminotransferase and Aspartate Aminotransferase in LIBRETTO-001 (N=796)3

Dosing Schedule Change, (%)a

Blood ALP increased

Blood Bilirubin Increased

Hypoalbuminemia

Ascites

Interruption

2

2

<1

2

Reduction

1

1

0

1

Discontinued

0

<1

0

<1

Abbreviations: ALP = alkaline phosphatase.

aJune 2021 data cutoff.

LIBRETTO-001 Clinical Trial and Hepatic Function

The efficacy of selpercatinib was evaluated in a phase 1/2, multicenter, open-label, single-arm clinical trial in patients with advanced rearranged during transfection (RET) fusion-positive non-small cell lung cancer, RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer, and RET fusion-positive tumors other than lung or thyroid: Study LIBRETTO-001 (NCT03157128).1,4-6

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).3

In the phase 1/2 study, some but not all patients were previously treated with immune checkpoint inhibitor (ICIs). Prior ICI therapy may be a contributing factor in these patients.3

Alanine Aminotransferase and Aspartate Aminotransferase Adverse Event Criteria

Based on selpercatinib information available to date, increased ALT and AST were identified as adverse events of special interest.3

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.7

References

1Retsevmo [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Drilon A, Subbiah V, Gautschi O, et al. Durability of efficacy and safety with selpercatinib in patients with RET fusion+ non-small-cell lung cancer: LIBRETTO-001. Poster presented at European Lung Cancer Congress (ELCC Virtual) 2022; March 30-April 2, 2022.

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. https://dx.doi.org/10.1056/NEJMoa2005653

5Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. https://dx.doi.org/10.1056/NEJMoa2005651

6Phase 1/2 study of LOXO-292 in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). ClinicalTrials.gov identifier: NCT03157128. Updated May 23, 2022. Accessed May 25, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03157128

7US 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.

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: 08 April 2022


Contact Lilly

Call or Email us

If you want to ask a Medical Information question or you want to report an adverse event or product complaint you can call us or email us at ukmedinfo@lilly.com

Available Mon - Fri, 10am - 4pm, excluding Bank Holidays

Or you can

Chat with Us

Click to Chat is Offline

If you have a question, you can chat online with a Lilly Medical Information professional.

Submit a request