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Retsevmo ® ▼ (selpercatinib)

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How to manage hypersensitivity with Retsevmo® (selpercatinib)

Hypersensitivity occurred in 6% of patients who received selpercatinib in LIBRETTO-001. Suspend selpercatinib until hypersensitivity resolves and begin steroid treatment.

UK_cFAQ_SEL413_HYPERSENSITIVITY
UK_cFAQ_SEL413_HYPERSENSITIVITYen-GB

Hypersensitivity information from the Retsevmo Summary of Product Characteristics

Hypersensitivity is a common, serious side effect of selpercatinib, which requires immediate suspension of selpercatinib and initiation of corticosteroid treatment. Section 4.2 of the summary of product characteristics (SmPC) provides full information on management.1

Section 4.8 of the SmPC provides further details regarding the frequency and the time to onset.1

For complete information, please consult the Retsevmo Summary of Product Characteristics, particularly:

  • Section 4.2: Posology and method of administration 
  • Section 4.4 Special warnings and precautions for use
  • Section 4.8: Undesirable effects1

Below is additional data from clinical trials, including information on incidence, severity, management, and mechanism of action of hypersensitivity reactions. A full description of the clinical studies referenced is available in Section 5.1 of the SmPC.1

Content overview

Incidence of hypersensitivity with selpercatinib

   Impact of prior immuno-oncology therapy on hypersensitivity reactions with selpercatinib

   Patients who crossed over from immune checkpoint inhibitor treatment to selpercatinib in LIBRETTO-431

Patients with prior immune checkpoint inhibitor treatment in LIBRETTO-001

   Anaphylactic reactions in selpercatinib-treated patients

Selpercatinib dosing modifications in clinical studies due to hypersensitivity

Mechanism of action of hypersensitivity reactions

Overview of clinical trials with selpercatinib

References

Incidence of hypersensitivity with selpercatinib

Hypersensitivity is a composite term that includes hypersensitivity and drug hypersensitivity.2

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 levels.3

Hypersensitivity occurred in 6% of patients receiving selpercatinib in LIBRETTO-001, including grade 3 hypersensitivity in 1.9%. The median time to onset was typically between days 7-21 of therapy.2

LIBRETTO-001 was a single arm phase 1/2 study that included patients with prior treatments as well as those who were treatment naïve.3,4

LIBRETTO-431 was a randomized phase 3 study in patients with treatment naïve NSCLC.  The control arm was a regimen of a platinum agent plus pemetrexed with or without pembrolizumab., Patients on the control arm were given the option to crossover to selpercatinib if disease progression had occurred. A total of 36 patients who had received pembrolizumab (approximately 60%) crossed over to receive selpercatinib.5

Across LIBRETTO-001 and LIBRETTO-431, 17% of selpercatinib-treated patients with a history of immune checkpoint inhibitor (ICI) therapy experienced hypersensitivity. Hypersensitivity in Selpercatinib-Treated Patients With a History of Prior Immune Checkpoint Inhibitor Therapy presents an overview of hypersensitivity reactions in patients who received selpercatinib in LIBRETTO-001 or in the intent-to-treat pembrolizumab group.2

Hypersensitivity in Selpercatinib-Treated Patients With a History of Prior Immune Checkpoint Inhibitor Therapy2

Hypersensitivity severity, n (%)a

LIBRETTO-001b
(N=169)

LIBRETTO-431cd
(N=36)

Overall incidencee

All grades

26 (15)

8 (22)

Grade ≥3

7 (4)

5 (14)

aHypersensitivity is a composite term that includes hypersensitivity and drug hypersensitivity.

bJune 2023 data cutoff.

cMay 2023 data cutoff.

dThirty-six patients in the intent-to-treat pembrolizumab group crossed over to selpercatinib therapy.

eNo grade 4 or 5 events of hypersensitivity reported.

Impact of prior immuno-oncology therapy on hypersensitivity reactions with selpercatinib

In LIBRETTO-001, patients pretreated with an ICI 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 crossed over from immune checkpoint inhibitor treatment to selpercatinib in LIBRETTO-431

In LIBRETTO-431, patients randomized to the control group were given the option to crossover to selpercatinib after disease progression. As a result, 42 patients from the control group (approximately 60%) crossed over to receive selpercatinib as their second line of treatment.  Eighty percent of the control arm received pembrolizumab.5 

Hypersensitivity Reactions in LIBRETTO-431 provides an overview of hypersensitivity reactions and severity in patients who crossed over to selpercatinib in LIBRETTO-431.

Hypersensitivity Reactions in LIBRETTO-4312

Hypersensitivity, n (%)

Selpercatinib Population
(N=158)

Selpercatinib Crossover Population
(N=42)

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Composite term

Hypersensitivitya

3 (2)

1 (<1)

8 (19)

5 (12)

Preferred terms

Hypersensitivity

3 (2)

1 (<1)

7 (17)

4 (10)

Drug hypersensitivity

0

0

1 (2)

1 (2)

aComposite term that includes hypersensitivity and drug hypersensitivity.

Two patients in the crossover population (5%) discontinued selpercatinib due to hypersensitivity.2

Patients with prior immune checkpoint inhibitor treatment in LIBRETTO-001

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.3

    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%).3

    As of the data cutoff date of March 2020, 24.7% (184/746) of patients treated with selpercatinib had previously received anti PD‑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).2,3


    Hypersensitivity Reactions by Treatment History Compared to the LIBRETTO-001 Overall Safety Population and NSCLC Cohort2,3

    TEAE of Hypersensitivity
    n (%)ab

    Prior ICI Therapy

    No Prior ICI Therapy

    Overall Safety Population2c
    (n=796)

    NSCLC
    Cohort2c
    (n=356)

    Safety
    Population2c
    (n=184)

    NSCLC
    Cohort3d
    (n=152)

    Safety Population2c
    (n=562)

    NSCLC
    Cohort3d
    (n=177)

    Severityefg

    Any grade

    25 (14)

    17 (11)

    14 (3)

    5 (3)

    47 (6)

    34 (10)

    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)

    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.

    Anaphylactic reactions in selpercatinib-treated patients

    In LIBRETTO-001, there were 2 events of grade 1 (n=1) and grade 3 (n=1) anaphylactic reactions reported. The events were not considered serious or related to selpercatinib.2

    In LIBRETTO-431, there was one event of grade ≥3 anaphylactic shock reported. It was not considered serious or related to selpercatinib.2

    Selpercatinib dosing modifications in clinical studies due to hypersensitivity

    Selpercatinib Dosing Modifications Due to Hypersensitivity provides dose modifications due to hypersensitivity to in selpercatinib-treated patients.

    Selpercatinib Dosing Modifications Due to Hypersensitivity2

    Dosing Adjustment, %

    LIBRETTO-001
    (N=837)a

    LIBRETTO-431
    (N=256)b

    Interruption

    4

    <1

    Reduction

    4

    1

    Discontinuation

    <1

    0

    aData cut-off January 2023.

    bAs of May 2023 data cutoff, LIBRETTO-431 had 158 patients in the selpecatinib group, and 98 patients in the control group.

    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.3

    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.3

    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.3

    Overview of clinical trials with selpercatinib

    LIBRETTO-001 is a phase 1/2, multicenter, open-label, single-arm clinical trial (NCT03157128) evaluating efficacy and safety of selpercatinib in patients with advanced rearranged during transfection (RET) fusion-positive solid tumors and RET-mutant medullary thyroid cancer.1,4,6,7

    LIBRETTO-431 is a global, open-label, randomized, phase 3 trial comparing selpercatinib to platinum-based chemotherapy and pemetrexed with or without pembrolizumab as initial treatment in patients with locally advanced or metastatic RET fusion-positive nonsquamous NSCLC (NCT04194944).5,8

    References

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

    2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    3McCoach 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. J Thorac Oncol. 2022;17(6):768-778. https://doi.org/10.1016/j.jtho.2022.02.004

    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

    5Zhou C, Solomon BJ, Loong K, et al; LIBRETTO-431 Trial Investigators. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion–positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. https://www.nejm.org/doi/10.1056/NEJMoa2309457

    6Wirth 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

    7A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). ClinicalTrials.gov identifier: NCT03157128. Updated January 20, 2025. Accessed February 5, 2025. https://www.clinicaltrials.gov/ct2/show/NCT03157128

    8Loong HH, Goto K, Solomon BJ, et al. Randomized phase III study of first-line selpercatinib versus pembrolizumab and chemotherapy in RET fusion-positive NSCLC. Abstract presented at: 48th Annual Meeting of the European Society for Medical Oncology (ESMO); October 21 2023; Madrid Spain. Accessed October 21, 2023. https://cslide.ctimeetingtech.com/esmo2023/attendee/confcal/presentation/list?q=Herbert+Loong&r=st~3

    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: 07 November 2023

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