Retsevmo ® (selperkatinib)

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Hur vanliga är överkänslighetsreaktioner med Retsevmo® ▼ (selperatinib)?

läkemedelsöverkänslighet samt överkänslighet av svårighetsgrader 1-3 rapporterades i LIBRETTO-001-studien med Retsevmo (selperkatinib).

Warnings and Precautions

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed in patients with NSCLC previously treated with anti PD‑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 Table 1 and Table 2.

Table 1. 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.

Table 2. 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 Table 3.

Table 3. Management of Hypersensitivity Reaction Recurrence2

Severity

Dose Modification

Severe

Hold selpercatinib and repeat management as outlined in Dose Adjustment for Drug 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 (e.g. isolated rash, myalgia, or low-grade fever)

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

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 MTC, and other tumors with RET activation.3-5

Patients who had received other treatments, including ICIs prior to the trial enrollment were included in the trial.5 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

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. 2

Clinical Trial Experience

Hypersensitivity/drug hypersensitivity occurred in 5.2% of patients receiving selpercatinib, including a grade 3 event in 1.7%. The median time to onset was 1.9 weeks (range: 0.9 weeks to 77 weeks).1

Signs and symptoms of hypersensitivity reactions typically included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.1 Less common reactions include decreased blood pressure, tachycardia, and/or creatinine increase.2

There were no grade 4 or 5 hypersensitivity/drug hypersensitivity events. Table 4 provides the occurrence of drug related hypersensitivity events by severity in the overall population.

Table 4. Selpercatinib-Related Hypersensitivity TEAEs in the LIBRETTO-001 Population by Severity6

Preferred term, n (%)ab

Grade 1

Grade 2

Grade 3

Total

Drug hypersensitivity

0

10 (1)

9 (1)

19 (3)

Hypersensitivity

3 (<1)

7 (1)

3 (<1)

13 (2)

Abbreviation: TEAE = treatment-emergent adverse event.

a Severity as defined by Common Terminology Criteria for Adverse Events.

b Data cut-off March 2020.

Hypersensitivity/drug hypersensitivity was considered serious and selpercatinib-related in 14 patients.6

There were 2 events of grade 1 (n=1) and grade 3 (n=1) anaphylactic reactions. The events were deemed not related to selpercatinib.6

Immuno-Oncology History

An association of hypersensitivity with precedent IO therapy has been observed previously with pneumonitis and LFT AEs, and with EGFR and ALK inhibitors in EGFR-mutated and ALK-fusion NSCLC, respectively.7,8 A similar safety finding has also been observed with a less selective, investigational RET inhibitor, RXDX-105.9

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 those patients, 17 had a history of prior IO therapy including

  • pembrolizumab

  • nivolumab

  • bevacizumab, and

  • bevacizumab/nivolumab combination.2,6

Adverse events that occurred in ≥25% 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 data cut-off 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

Grade 3 hypersensitivity occurred in 3.8% (7/184) of the patients previously treated with anti‑PD‑1/PD‑L1 immunotherapy.1

The median time to onset was 1.9 weeks (range: 0.9 week to 77 weeks): 1.7 weeks in patients with previous anti‑PD‑1/PD‑L1 immunotherapy and 8.9 weeks in patients who were immunotherapy naïve.1

As seen in Table 5, 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.6

Table 5. Hypersensitivity Reactions by Treatment History Compared to the LIBRETTO-001 Overall Safety Population6 

TEAE of hypersensitivity, n (%)ab

Prior ICI Therapy
(n=184)

No Prior ICI Therapy
(n=562)

Overall Safety Population
(n=746)

Any grade

25 (14)

14 (3)

39 (5)

Grade 1

2 (1)

5 1)

7 (1)

Grade 2

16 (9)

3 (1)

19 (3)

Grade 3

7(4)

6 (1)

13 (2)

Serious TEAE

10 (5)

4 (1)

14 (2)

Related to selpercatinib

Any grade

23 (13)

8 (1)

31 (4)

Serious TEAE

10 (5)

4 (1)

14 (2)

Dose modification

Interruption

4 (2)

2 (<1)

6 (1)

Reduction

20 (11)

6 (1)

26 (4)

Discontinuation

2 (1)

1 (<1)

3 (<1)

Time to first onset

Median (range), weeks

2 (1-16)

9 (1-77)

2 (1-77)

Outcome of last episode

Recovered/resolved

23 (13)

 11 (2)

34 (5)

Not recovered/not resolved

2 (1)

3 (1)

5 (1)

Abbreviations: ICI = immune checkpoint inhibitor; TEAE = treatment-emergent adverse event.

a Data cutoff date March 2020. Hypersensitivity reactions are presented regardless of causality unless otherwise specified.

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

Tumor response was evaluated by prior ICI treatment history in the PAS (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 (Table 6).2

Table 6. 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), months

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 = month; NE = not evaluable; ORR = objective response rate.

References

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

2. McCoach C, Daniel S. W. Tan DSW, Besse B, et al. Hypersensitivity reactions to selpercatinib in patients with RET fusion-positive non-small-cell lung cancer (NSCLC). 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

3. 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

4. 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

5. 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

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

7. Lin 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

8. Oshima 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

9. Drilon 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

Glossary

AE = adverse event

ALK = anaplastic lymphoma kinase 

EGFR = epidermal growth factor receptor

ICI = immune checkpoint inhibitor

IO = immuno-oncology

LFT = liver function test

MTC = medullary thyroid cancer

NSCLC = non-small cell lung cancer

PAS = primary analysis set

PD-1 = programmed death-1

PD-L1 = programmed death-ligand 1

RET = rearranged during transfection

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 January 14, 2021


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