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).

What is the incidence of hypersensitivity using Retsevmo® ▼ (selpercatinib)?

Grades 1-3 hypersensitivity events were reported in 5.9% of patients in the LIBRETTO-001 trial. No life threatening, debilitating, or fatal events were reported.

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Warnings and Precautions

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed in patients with non-small cell lung cancer (NSCLC) previously treated with anti programmed death-1 (PD‑1)/programmed death-ligand 1 (PDL‑1) immunotherapy.1

Signs and symptoms of hypersensitivity included

  • fever
  • rash, and
  • arthralgias or myalgias with concurrent decreased platelets or elevated aminotransferases.1

Suspend selpercatinib if hypersensitivity occurs. Begin steroid treatment, continuing until patient reaches target dose and then tapered.1

Based on the grade of hypersensitivity reactions, selpercatinib may require dose modification.1

Permanently discontinue selpercatinib for recurrent hypersensitivity.1

Dosing Modifications

Management of some adverse reactions may require dose interruption and/or dose reduction. Selpercatinib dose modifications are summarized in Dosing Modifications for All Grades Hypersensitivity and Recommended Dose Modifications for Selpercatinib for Adverse Reactions Based on Body Weight.

Dosing Modifications for All Grades Hypersensitivity1

All Grades

  • Suspend dose until toxicity resolves and begin corticosteroids at a dose of 1 mg/kg  Resume selpercatinib at 40 mg twice daily while continuing steroid treatment. Discontinue selpercatinib for recurrent hypersensitivity.
  • If after at least 7 days, selpercatinib is tolerated without recurrent hypersensitivity, incrementally increase the selpercatinib dose by 1 dose level each week, until the dose taken prior to the onset of hypersensitivity is reached. Taper steroid dose after selpercatinib has been tolerated for at least 7 days at the final dose.
Recommended Dose Modifications for Selpercatinib for Adverse Reactions Based on Body Weight1

Dose Reduction

Patients Weighing Less Than 50 kg

Patients Weighing 50 kg or Greater

First

80 mg orally twice daily

120 mg orally twice daily

Second

40 mg orally twice daily

80 mg orally twice daily

Third

40 mg orally once daily

Not Applicable

Management of hypersensitivity reaction recurrence based on severity is outlined in Management of Hypersensitivity Reaction Recurrence.

Management of Hypersensitivity Reaction Recurrence2,3

Severity

Dose Modification

Severe

Hold selpercatinib and repeat management as outlined in Dosing Modifications for All Grades Hypersensitivity table above. Target dose should be adjusted to one dose level below that at which recurrence occurred.

  • If a clinically significant recurrence of drug hypersensitivity occurs at the initial re-exposure dose, selpercatinib should be discontinued.
  • If no clinically significant recurrence after a minimum of 7 days on re-exposure dose, then selpercatinib may be escalated sequentially.
  • Once patient has tolerated treatment for a minimum of 7 days at the final dose, steroids may be tapered slowly.

Mild (eg, isolated rash, myalgia, or low-grade fever)

Cautiously continue selpercatinib with supportive therapy such as topical creams or ibuprofen.

Incidence of Hypersensitivity in LIBRETTO-001

Hypersensitivity in the Overall Population

As of June 2021 cutoff date (N=796), 47 patients (5.9%) experienced any-grade hypersensitivity, which included 9 grade 1 events, 23 grade 2 events, and15 grade 3 events.  There were no life-threatening/debilitating or fatal events reported.4

Hypersensitivity/drug hypersensitivity was considered serious and selpercatinib-related in 16 patients (8 patients with prior immune checkpoint inhibitor (ICI) history, and 4 patients in the ICI-naïve cohort).2

There were 2 events of grade 1 (n=1) and grade 3 (n=1) anaphylactic reactions. The events were deemed not related to selpercatinib.4

Hypersensitivity is a composite term that includes hypersensitivity and drug hypersensitivity. In LIBRETTO-001, drug hypersensitivity was defined as, “a constellation of symptoms and findings characterized by a maculopapular rash, often preceded by fever with associated  arthralgias or myalgias, followed by at least one or more of the following signs and symptoms: more commonly, thrombocytopenia and/or increased aspartate aminotransferase/alanine aminotransferase levels, and less commonly, decreased blood pressure, tachycardia, and/or increased creatinine level.2

Time to Onset of Hypersensitivity

As part of a post hoc safety analysis of LIBRETTO-001 data cutoff date of December 16, 2019 (N=702), time to onset of selected treatment-emergent adverse events was evaluated. The median time for onset of hypersensitivity was 1.7 weeks, with a range of 0.9 to 77 weeks.5

In a data cutoff of June 2021, the median time for onset of hypersensitivity was 1.9 weeks, with a range of 0.7 to 112.1 weeks.4

Mechanism of Action of Hypersensitivity Reactions

The exact mechanism of action of these hypersensitivity reactions on selpercatinib are not known, they were deemed to be immune-mediated responses based on the timing of onset and constellation of symptoms and findings.2

Although the initial hypersensitivity events had features similar to a type IV immune-mediated hypersensitivity reaction such as drug reaction with eosinophilia and systemic symptoms (DRESS), they did not fully meet the definition. The hypersensitivity reactions experienced while on selpercatinib treatment  had a shorter median time to onset and resolution compared with DRESS, as well as a shorter median time to resolution.2 

Additionally, some of the clinical and laboratory manifestation of the reaction from the initial cases were noted to be consistent with cytokine-mediated reactions observed in patients receiving targeted therapies after ICI.2

Impact of Prior Immuno-Oncology Therapy on Hypersensitivity Reactions With Selpercatinib

An association of hypersensitivity with precedent immuno-oncology (IO) therapy has been observed previously with pneumonitis and liver function tests, adverse events, and with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase  (ALK) inhibitors in EGFR-mutated and ALK-fusion non-small cell lung cancer (NSCLC), respectively.6,7 A similar safety finding has also been observed with a less selective, investigational rearranged during transfection (RET) inhibitor, RXDX-105.8

Patients who had received other treatments, including ICI prior to the trial enrollment were included in the trial. While patients pretreated with ICI therapy may be at increased risk of hypersensitivity reactions with selpercatinib, the overall safety and tolerability in this patient population was not impacted and most patients were able to remain on therapy.2

In a custom safety clustering analysis of the overall safety data as of December 2019 (N=329), hypersensitivity reactions were identified in 30 patients utilizing defined criteria. Twenty-four patients experienced a selpercatinib-related hypersensitivity reaction, with 22 of them being in the NSCLC cohort. Of the 22 patients, 17 had a history of prior ICI therapy. Therapies received by the overall group of patients with prior ICI therapy (N=152) included

  • atezolizumab
  • avelumab
  • cemiplimab
  • durvalumab
  • nivolumab
  • pembrolizumab, and
  • spartalizumab.2

    Adverse events that occurred in greater than or equal to 20% of patients were comparable in the prior ICI therapy group compared to the overall safety population, with the exception of any grade thrombocytopenia which occurred more in the prior ICI therapy group (24% vs 17%).2

    As of the data cutoff date of March 2020, 24.7% (184/746) of patients treated with selpercatinib had previously received antiprogrammed death-1 (PD‑1)/programmed death-ligand 1 (PD‑L1) immunotherapy. Hypersensitivity occurred in a total of 5.2% (39/746) of patients receiving selpercatinib, including grade 3 hypersensitivity in 1.7% (13/746) of patients.1

    Of the 39 patients with hypersensitivity, 64.1% (25/39) had NSCLC and had received prior anti–PD‑1/PD‑L1 immunotherapy.1

    Patients in the prior ICI therapy group tended to have more hypersensitivity reactions when compared to patients who did not have prior therapy and to the overall safety population and the NSCLC cohort (Hypersensitivity Reactions by Treatment History Compared to the LIBRETTO-001 Overall Safety Population and NSCLC Cohort).2,4


    Hypersensitivity Reactions by Treatment History Compared to the LIBRETTO-001 Overall Safety Population and NSCLC Cohort2,4

    TEAE of Hypersensitivity
    n (%)ab

    Prior ICI Therapy

    No Prior ICI Therapy

    Overall Safety Population4c
    (n=796)

    NSCLC
    Cohort4c
    (n=356)

    Safety
    Population4c
    (n=184)

    NSCLC
    Cohort2d
    (n=152)

    Safety Population4c
    (n=562)

    NSCLC
    Cohort2d
    (n=177)

    Severityefg

    Any grade

    25 (14)

    17 (11)

    14 (3)

    5 (3)

    47 (6)

    34 (10)

    Grade 1

    2 (1)

    1 (1)

    5 (1)

    0

    9 (1)

    4 (1)

    Grade 2

    16 (9)

    11 (7)

    3 (1)

    1 (1)

    23 (3)

    18 (5)

    Grade 3

    7(4)

    5 (3)

    6 (1)

    4 (2)

    15 (2)

    12 (3)

    Serious

    10 (5)

    8 (5)

    4 (1)

    4 (2)

    16 (2)

    14 (4)

    Related to selpercatinib

    Any grade

    23 (13)

    17 (11)

    8 (1)

    5 (3)

    35 (4)

    30 (9)

    Serious

    10 (5)

    8 (5)

    4 (1)

    4 (2)

    16 (2)

    14 (4)

    Dose modificationh

    Interruption

    4 (2)

    4 (3)

    2 (<1)

    2 (1)

    32 (4)

    27 (8)

    Reduction

    20 (11)

    14 (9)

    6 (1)

    4 (2)

    31 (4)

    27 (8)

    Discontinuation

    2 (1)

    2 (1)

    1 (<1)

    1 (1)

    3 (<1)

    2 (1)

    Time to first onset

    Median (range), weeks

    2 (1-16)

    2 (1-3)

    9 (1-77)

    1 (1-5)

    2 (1-112)

    2 (1-22)

    Outcome of last episode

    Recovered/resolved

    23 (13)

    16 (11)

     11 (2)

    4 (2)

    40 (5)

    31 (9)

    Not recovered/not resolved

    2 (1)

    0

    3 (1)

    1 (1)

    7 (1)

    3 (1)

    Abbreviations: ICI = immune checkpoint inhibitor; MedDRA = Medical Dictionary for Regulatory Activities; NSCLC = non-small cell lung cancer; TEAE = treatment-emergent adverse event.

    aThis analysis is based on consolidated preferred MedDRA terms of “hypersensitivity” and “drug hypersensitivity.”

    bPatients with multiple severity ratings for one or more hypersensitivity events were counted once under the maximum severity.

    cData cutoff date June 2021.

    dData cutoff date December 2019.

    eResults are presented regardless of reported causality unless otherwise specified.

    fCommon Terminology Criteria for Adverse Events (v4.03).

    gA grade 1 or 2 event considered by the investigator to be medically important was reported as a serious event.

    hFor each hypersensitivity event resulting in dose modification, a patient was counted once under the most significant action taken (discontinuation, reduction, or interruption, respectively) if more than one action occurred. A patient who experienced multiple events could be counted under more than one action.

    Tumor Response by Treatment History

    Tumor response was evaluated by prior ICI treatment history in the primary analysis set (N=105) patients who had previously received platinum-based therapy or were treatment naïve. Regardless of prior ICI treatment, patients pre-treated with platinum-based therapy had similar responses to selpercatinib (Response by Platinum-Based Therapy With or Without ICI Compared to Treatment Naïve Patients).3

    Response by Platinum-Based Therapy With or Without ICI Compared to Treatment Naïve Patients2

    Response

    Pretreated with  Platinum Chemotherapy

    Treatment Naïve
    (n=39)

    Prior ICI
    (n=58)

    No  Prior ICI
    (n=47)

    ORR by IRC, % (95% CI)

    66 (51.9–77.5)

    62 (46.4–75.5)

    85 (69.5–94.1)

    DOR, median (95% CI), mo

    NE (12.0–NE)

    17.5 (10.3–NE)

    NE (12.0–NE)

    Duration of follow-up, median, mo

    11.9

    12.7

    7.4

    Abbreviations: DOR = duration of response; ICI = immune checkpoint inhibitor; IRC = independent review committee; mo = months; NE = not evaluable; ORR = objective response rate.

    Of the 22 patients with NSCLC who experienced a selpercatinib-related drug hypersensitivity reaction, 11 had  been evaluated by an independent review committee using RECIST 1.1 by the data cutoff date. Of these patients,

    • 5 patients with prior ICI treatment had a confirmed partial response
    • 4 patients had stable disease, and
    • 2 patients had progressive disease.2

    At the time of data cutoff, 5 patients with confirmed partial response were still receiving selpercatinib treatment at reduced doses of 40 mg twice daily (n=2), 80 mg twice daily (n=1), 120 mg twice daily (n=2).2

    LIBRETTO-001 Clinical Trial Overview

    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 medullary thyroid cancer, and other tumors with RET activation.9-11

    Patients who had received other treatments, including ICI prior to the trial enrollment were included in the trial.11 While patients pretreated with ICI therapy may be at increased risk of hypersensitivity reactions with selpercatinib, the overall safety and tolerability in this patient population was not impacted and most patients were able to remain on therapy.3

    Patients who experienced drug hypersensitivity with selpercatinib also responded to treatment despite undergoing holds and dose reductions. In some of these cases, treatment continued at doses lower than the recommended dose of 160 mg twice daily.3

    References

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

    2McCoach CE, Rolfo C, Drilon A, et al. Hypersensitivity reactions to selpercatinib treatment with or without prior immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer in LIBRETTO-001. JTO 2022. https://doi.org/10.1016/j.jtho.2022.02.004

    3McCoach C, Tan DSW, Besse B, et al. Hypersensitivity reactions (HR) to selpercatinib in RET fusion+ non-small-cell lung cancer (NSCLC) patients (pts) following immune checkpoint inhibition (CPI). Poster presented at: Annual Meeting of the European Society for Medical Oncology (ESMO Virtual); September 19-21, 2020. Accessed September 17, 2020. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/hypersensitivity-reactions-hr-to-selpercatinib-in-ret-fusion-non-small-cell-lung-cancer-nsclc-patients-pts-following-immune-checkpoint-inhib

    4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    5Bauer TM, Besse B, Loong HHF, et al. Safety of selpercatinib for RET-altered advanced solid tumors: a post hoc analysis of LIBRETTO-001. Poster presented at: American Association for Cancer Research (AACR/Virtual); April 10-15, 2021. Accessed April 22, 2021. https://assets.ctfassets.net/mpejy6umgthp/2UXgfmZkQecRWJdCbhCpzm/1c617b0391d07ba4a9c37106d8622b75/AACR2021_DV816_Bauer_JZJA.pdf

    6Lin JJ, Chen E, Yeap BY, et al. Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non–small cell lung cancer. J Thorac Oncol. 2019;14(1):135-140. https://doi.org/10.1016/j.jtho.2018.09.001

    7Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol. 2018;4(8):1112-1115. https://dx.doi.org/10.1001/jamaoncol.2017.4526

    8Drilon A, Fu S, Patel MR, et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov. 2019;9(3):384-395. https://dx.doi.org/10.1158/2159-8290.CD-18-0839

    9A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001) (LIBRETTO-001). ClinicalTrials.gov identifier: NCT03157128. Updated May 23, 2022. Accessed June 1, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03157128

    10Wirth 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

    11Drilon 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

    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: 01 June 2022


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