Retsevmo ® (selperkatinib)

För fullständig produktresumé för Retsevmo se FASS.

Denna information är endast avsedd för sjukvårdspersonal verksam i Sverige och som svar på din fråga. Informationen nedan är på engelska

Kan leverenzymerna ändras av Retsevmo® ▼ (selperkatinib)?

Ökningar av AST och/eller ALT observerades i LIBRETTO-001. Tillfälliga ökningar av totalt bilirubin och alkaliskt fosfatas sågs också.

Warnings and Precautions

Grade ≥3 increased ALT and grade ≥3 increased AST were reported in patients receiving selpercatinib.  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 Table 1.

Table 1. 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.

LIBRETTO-001 Clinical Trial

LIBRETTO-001 is a multicenter, open-label, phase 1/2 study of selpercatinib administered orally to patients with RET fusion-positive solid tumors, RET-mutant MTC, and other tumors with RET activation.1-4

Inclusion criteria included having adequate hepatic functioning defined as

  • ALT and AST ≤2.5 times the 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).5

In the phase 1/2 study, some but not all patients were previously treated with ICIs. Prior ICI therapy may be a contributing factor in these patients.5

ALT and AST Increases

Serious hepatic adverse reactions occurred in approximately 3% of patients treated with selpercatinib. In the overall population (N=746), increased AST occurred in 33% of patients, including grade 3 or 4 events in 9% of patients. Increased ALT occurred in 33% of patients, including grade 3 or 4 events in 10%.5

Table 2. Increases in ALT and AST by CTCAE Grade in the LIBRETTO-001 Population5

 

CTCAE Gradea
(N = 746)
b

Preferred Term, %

Any

1

2

3

4

ALT increased

33

17

6

9

1

AST increased

33

19

6

8

1

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

a Grade defined by CTCAE criteria.

b Data cut-off March 2020.

There were 9 ALT increased events and 9 AST increased events that were considered drug-related SAEs.5

Dose modifications in the LIBRETTO-001 Clinical Trial

Increased ALT/AST events were the most common reason for dose interruption and reduction as seen in Table 3.5

Table 3. Dosing Schedule Changes in the LIBRETTO-001 Clinical Trial Due to Increases in ALT or AST5

Dosing Schedule Change, n (%)a

ALT
Increased

AST
Increased

Interruption

42 (6)

37 (5)

Reduction

53 (7)

48 (6)

Discontinued

3 (<1)

2 (<1) 

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

a Data cut-off March 2020.

Other Hepatic Enzymes

Treatment-emergent elevations in alkaline phosphatase were reported in 91 patients (12%). Most treatment-emergent increases were 1 or 2 grades (n=81). There was one grade 4 event.5

Dose modifications due to increased blood alkaline phosphatase were 6 (1%) interruptions and 4 (1%) reductions. There were no discontinuations due to increased blood alkaline phosphatase.5

Treatment-emergent AEs of blood bilirubin and hyperbilirubinemia were observed in 91 patients (12%). Most elevations (n=80) were grades 1 and 2. One grade 4 blood bilirubin elevation was observed.5

Dose modifications due to increased blood bilirubin and hyperbilirubinemia were

  • interruption 12 (3%)

  • reduction 4 (1%), and

  • discontinuation (1 patient).5

Hy’s Law

None of the patients with increased hepatic enzymes met the Hy’s Law criteria for drug-induced hepatic injury.5

ALT/AST AE Criteria

Based on selpercatinib information available to date, increased ALT and AST were identified as adverse events of special interest.5

Increases in ALT and AST were locally graded by 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.6

Composite terms include MedDRA preferred terms for reporting AEs and were defined as

  • ALT increased

    • alanine aminotransferase increased

    • alanine aminotransferase abnormal, and

  • AST increased

    • aspartate aminotransferase increased

    • aspartate aminotransferase abnormal.5

References

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

2. Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). ClinicalTrials.gov identifier: NCT03157128. Updated July 2, 2020. Accessed January 25, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03157128

3. Wirth 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

4. Drilon 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

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

6. US 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.

Glossary

AE = adverse event

ALT = alanine aminotransferase 

AST = aspartate aminotransferase

CTCAE = Common Terminology Criteria for Adverse Events

ICI = immune checkpoint inhibitor

MedDRA = Medical Dictionary for Regulatory Activities

MTC = medullary thyroid cancer

RET = rearranged during transfection

SAE = serious adverse event

ULN = upper limit of normal

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.

Datum fӧr senaste ӧversyn 2021 M01 12


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