Retsevmo ® (selperkatinib)

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Är Retsevmo® ▼ (selperkatinib) säkert och effektivt vid sköldkörtelcancer?

I fas 2-studien LIBRETTO-001 visade selperkatinib varaktig antitumöraktivitet hos patienter med RET-förändrad sköldkörtelcancer.

LIBRETTO-001 Phase 1/2 Selpercatinib Use in RET-Altered Thyroid Cancer

The efficacy of selpercatinib was evaluated in a phase 1/2, multicenter, open-label, single-arm clinical trial in patients with advanced RET fusion-positive NSCLC, RET-mutant MTC and RET fusion-positive thyroid cancer: Study LIBRETTO-001 (NCT03157128).1-4

The phase 1 portion of the study established the MTD/RP2D of 160 mg twice daily.5,6

The phase 2 portion enrolled patients to 1 of 6 cohorts based on tumor type, RET alteration, and prior therapies.7

The primary endpoint of the phase 2 dose expansion portion of the study is ORR as determined by a blinded IRC according to RECIST v1.1. Key secondary endpoints of the phase 2 portion of the study are

  • DOR

  • CNS ORR

  • CNS DOR

  • PFS

  • OS

  • PK, and

  • safety.1-4

Treatment beyond progression was permitted with continued benefit.3,4

A data cutoff date of December 16, 2019 was used for the US registration while a data cutoff date of March 30, 2020 was used for EU registration.

As of December 16, 2019, a total of 702 patients were enrolled. A breakdown of the enrollment includes

  • NSCLC: 47.3%

  • MTC: 43.6%

  • thyroid cancers other than MTC: 5.4%, and 

  • other: 3.7%.8

As of March 30, 2020, a total of 746 patients were enrolled. A breakdown of the enrollment includes

  • NSCLC: 46.2%

  • MTC: 42.2%

  • thyroid cancers other than MTC: 5.6%, and 

  • other: 5.9%.8

For US registration, the patients evaluable for efficacy were the first

  • 105 patients enrolled with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy

  • 39 patients enrolled with RET fusion-positive NSCLC who were treatment-naïve

  • 55 patients enrolled with RET-mutant MTC who were previously treated with cabozantinib or vandetanib

  • 88 patients enrolled with RET-mutant MTC who were cabozantinib and vandetanib-naïve, and

  • 27 patients enrolled with RET fusion-positive thyroid cancer.3,4

For EU registration, previously treated patients with ≥6 months follow-up were considered efficacy eligible. This included

  • 218 patients with RET fusion-positive NSCLC

  • 143 patients with RET-mutant MTC, and

  • 22 patients with RET fusion-positive thyroid cancer.2

RET-Mutant MTC

Of the RET-mutant MTC patients who received prior cabozantinib and/or vandetanib, 143 were considered efficacy eligible (had ≥6 months follow-up). The PAS for selpercatinib registration in MTC, as defined with the health authority, consisted of the first 55 of the 143 consecutively enrolled patients.2,4

There were 88 RET-mutant MTC patients naïve to cabozantinib/vandetanib treatment also analyzed.4

Among the PAS, gender and age were similar among the treated and treatment-naïve groups. The majority of all patients (≥95%) had an ECOG PS of 0 or 1.2,4 Table 1 provides an overview of the MTC study population.

Table 1. RET-Mutant MTC Patient Characteristics4,8

Characteristic

PAS
(n=55)

Cabozantinib/Vandetanib-Naïve
(n=88)

Female/Male, %

35/65

34/66

Median age, years (range)

57 (17-84)

58 (15-82)

Race, %

White

89

85

Black

2

1

Asian

0

5

Other/Missing

9

9

Prior systemic regimens, median (range)

2 (1-8)

0 (0-2)

Prior cabozantinib and/or vandetanib, %

100

0

Cabozantinib only

24

0

Vandetanib only

33

0

Cabozantinib and vandetanib

44

0

Prior multikinase-inhibitor, %

100

8

Prior non-multikinase systemic therapy, %

31

10

Brain metastases, %

7

2

RET alteration, %

M918T

60

56

V804 M/L

9

7

Extracellular cysteine mutationa

13

23

Otherb

18

15

Abbreviations: MTC = medullary thyroid cancer; PAS = primary analysis set; RET = rearranged during transfection.

a Extracellular cysteine mutation was defined as a mutation that included at least one of the following cysteine residues: 609, 611, 618, 620,630, or 634.

b Other mutations included D631-liter633delinsE, E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del + D903_S904delinsEP, K666 N, T636-V637insCRT, and D378-G385delinsE.

Efficacy Results

Table 2 presents a summary of efficacy results.

Table 2. RET-Mutant MTC Efficacy Results2,4,8

Responseab

PAS4,c
(n=55)

PAS8,d
(n=55)

Previously Treated
Efficacy Eligible2,8,ed
(n=143)

Cabozantinib/
Vandetanib-Naïve4,c
(n=88)

Confirmed ORR, % (95% CI)

69 (55-81)

69 (55-81)

69 (61-77)

73 (62-82)

Complete response, n (%)

5 (9)

6 (11)

6 (4)

10 (11)

Partial response, n (%)

33 (60)

32 (58)

93 (65)

54 (61)

Stable disease, n (%)

14 (25)

14 (26)

35 (25)

20 (23)

Progressive disease, n (%)

1 (2)

1 (2)

2 (1)

2 (2)

Not evaluable, n (%)

2 (4)f

2 (4)

7 (5)

2 (2)

Duration of response

Median, months (95% CI)

NE (19-NE)

NE (19-NE)

NE (19-NE)

22g (NE-NE)

Censored, n (%)

32 (84)

29 (76)

81 (82)

60 (94)

Median follow-up, months

14

17

10

8

Progression-free survival

Median, months (95% CI)

NE (24-NE)

NE (24-NE)

NE (20-NE)

24g (NE-NE)

Censored, n (%)

42 (76)

39 (71)

107 (75)

80 (91)

Median follow-up, months

17

20

14

11

1-year PFS rate, % (95% CI)

82 (69-90)

82 (69-90)

77 (68-84)

92 (82-97)

Abbreviations: MTC = medullary thyroid cancer; NE = not estimable; ORR = objective response rate; PAS = primary analysis set; PFS = progression-free survival; RET = rearranged during transfection.

a Efficacy based on independent review.

b Total % may be different than the sum of the individual due to rounding.

c Data cutoff date of December 16, 2019.

d Data cutoff date of March 30, 2020.

e Eligible patients include all patients in the analysis set who had the opportunity to be followed for at least 6 months from the first dose of selpercatinib.

f Includes 1 patient who died prior to their first response assessment.

g Unstable median, based on fewer than 10% of total number of events.

Overall response rate was similar regardless of prior therapy and DOR was not reached in all subgroups. The ORR for the RET-mutant population included 5 patients with a RET V804M/L gatekeeper mutation with 3 responses.4

Biochemical response rates for calcitonin and CEA were evaluated. The median time to calcitonin response was 0.5 months (range 0.4-1.9) and to CEA response 1.8 months (range, 0.4-18.8).4 Table 3 provides a breakdown of overall response.

Table 3. RET-Mutant MTC Biochemical Response in PAS4,6

Response, n (%)ab

Calcitonin
(n=54)

CEA
(n=53)

ORR, % (95% CI)

91 (80-97)

66 (52-79)

Complete response

14 (26)

8 (15)

Partial response

35 (65)

27 (51)

Stable disease

0 (0)

9 (17)

Progressive disease

1 (2)

7 (13)

Not evaluable

4 (7)

2 (4)

Abbreviations: CEA = carcinoembryonic antigen; CR = complete response; MTC = medullary thyroid cancer; ORR = objective response rate; PAS = primary analysis set; PD = progressive disease; PR = partial response; RET = rearranged during transfection; SD = stable disease.

a Data cutoff date of December 16, 2019.

b Biochemical response rate refers to a change from baseline in serum tumor markers maintained for ≥4 weeks. Rate values are: CR = normalization; PR = ≥50% reduction; SD = between -50% to +50%; PD = ≥50% increase.

RET Fusion-Positive Thyroid Cancer

Of the RET fusion-positive thyroid patients who were RAI-refractory (if RAI was an appropriate treatment option), 22 were considered efficacy eligible (had ≥6 months follow-up). As defined with the health authority, the PAS was based on the first 19 of the 22 consecutively enrolled patients.2

Eight RET fusion-positive thyroid cancer patients who were systemic therapy naïve were also analyzed.8

Patient characteristics for the PAS and systemic therapy naïve are described in Table 4. The majority of all patients (89%) had an ECOG PS of 0 or 1. All patients had metastatic disease with primary tumor histologies including 

  • papillary thyroid cancer 21 (78%) 

  • poorly differentiated thyroid cancer 3 (11%)

  • anaplastic thyroid cancer 2 (7%), and

  • Hurthle cell thyroid cancer 1 (4%).2,8

Table 4. RET Fusion-Positive Thyroid Cancer Patient Characteristics4,8

Characteristic

Previously Treated
(n=19)

Systemic Therapy-Naïve
(n=8)

Female/Male, %

53/47

37.5/62.5

Median age, years (range)

54

57

Race, %

White

74

75

Black

5

0

Asian

11

0

Other/Missing

11

25

Histologic type of thyroid cancer, %

Papillary

68

100

Poorly differentiated

16

0

Hurthle cell

5

0

Anaplastic

11

0

Prior systemic regimens, median (range)

4 (1-7)

2 (1-4)

Prior multikinase inhibitor, %

79

0

Cabozantinib

5

0

Vandetanib

5

0

Sorafenib

37

0

Lenvatinib

42

0

Other MKIs

26

0

Radioactive Iodine, %

84

100

Measurable disease, %

95

100

RET alteration, %

CCDC6

47

63

NCOA4

32

38

Other RET fusiona 

21

0

Abbreviations: CCDC6 = coiled-coil domain containing 6; MKI: multikinase inhibitor; NCOA4 = nuclear receptor coactivator 4; RET = rearranged during transfection.

a Fusions that were identified in single tumors included CCDC186, ERC1, KTN1, and RUFY3.

Efficacy Results

Table 5 presents efficacy results.

Table 5. RET Fusion-Positive Thyroid Efficacy Results2,4,8

Responsea

Previously
Treated PAS4,b
n=19

Previously
Treated PAS8,c
n=19

Previously Treated
Efficacy Eligible2,8,c
n=22

Systemic
Therapy-Naïve8,b
n=8

Confirmed ORR (95% CI), %

79 (54-94)

79 (54-94)

77 (55-92)

100 (63-100)

Complete response, n (%)

1 (5)

2 (11)

2 (9)

1 (13)

Partial response, n (%)

14 (74)

13 (68)

15 (68)

7 (88)

Stable disease, n (%)

4 (21)

4 (21)

5 (23)

0 (0)

Progressive disease, n (%)

0 (0)

0 (0)

0 (0)

0 (0)

Not evaluable, n (%)

0 (0)

0 (0)

0 (0)

0 (0)

Duration of response

Median, months (95% CI)

18 (8-NE)

18 (8-NE)

18 (10-NE)

NE (NE-NE)

Censored, n (%)

9 (60)

7 (47)

9 (53)

8 (100)

Median follow-up, months

18

20

20

9

Progression-free survival

Median, months (95% CI)

20 (9-NE) 

20 (9-NE)

20 (11-NE)

NE (NE-NE)

Censored, n (%)

11 (58)

9 (47)

12 (55)

8 (100)

Median follow-up, months

14

22

17

11

1-year PFS rate, % (95% CI)

64 (37-82)

68 (42-84)

69 (43-85)

100 (NE-NE)

Abbreviations: NE = not estimable; ORR = objective response rate; PAS = primary analysis set; PFS = progression-free survival; RET = rearranged during transfection.

a  Total % may be different than the sum of the individual due to rounding.

b Data cutoff date of December 16, 2019.

c Data cutoff date of March 30, 2020.

Safety Results

The safety analysis is based on all patients who received at least 1 dose of selpercatinib as of the cutoff date of March 30, 2020 (N=746).8

Table 6 summarizes treatment-emergent adverse reactions occurring in the safety population.

Table 6.  Adverse Reactions in Patients Who Received Selpercatinib in LIBRETTO-0012

Adverse Reaction, %

Grades 1-4

Grades 3-4

Investigationsa

AST increased

55

9

ALT increased

49.5

10.6

Lymphocyte count decreased

46.2

16.1

Creatinine increased

39.1

1.2

Platelets decreased

34.5

3

Magnesium decreased

25.6

0.5

Gastrointestinal

Dry mouthb

40.3

0

Diarrheab

39

3.5c

Constipation

27.1

0.5c

Abdominal painb

25.5

1.9c

Nausea

23.5

0.7c

Vomiting

16.2

0.9c

General

Edemab

38.7

0.5c

Fatigueb

38.2

2.3c

Pyrexia

14.3

0.1c

Vascular

Hypertensionb

37.4

19.4

Skin and subcutaneous tissue

Rashb

28.7

0.7c

Nervous system

Headacheb

24

1.5c

Dizzinessb

14.6

0.1c

Cardiac

ECG QT prolongedb

18.1

4.0

Blood and lymphatic

Hemorrhage

16.6

2.4

Metabolism and nutrition

Decreased appetite

14.1

0.1c

Immune system

Hypersensitivityd

5.2

1.7c

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

a Based on laboratory assessments. Only patients with baseline and at least one post-baseline result are included.

b Consolidated terms.

c Only includes a grade 3 adverse reaction.

d Hypersensitivity reactions were characterized by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient's first cycle of treatment (typically between days 7-21).

A total of 35% of patients experienced a treatment-emergent SAE.8 The most common serious ADRs were ALT increased (1.6%), AST increased (1.6%), and hypertension (0.9%).2

Fatal adverse reactions occurred in 3% of patients. Fatal adverse reactions which occurred in >1 patient included

  • sepsis (n=3)

  • cardiac arrest (n=3)

  • cardio-respiratory arrest (n=2)

  • pneumonia (n=2), and

  • respiratory failure (n=2).8

Permanent discontinuation of selpercatinib for TEAEs, regardless of attribution, occurred in 45 (6%) patients. Sixteen of the 45 patients (2%) discontinued selpercatinib because of a treatment-related AE. The ADRs resulting in permanent discontinuation (2 or more patients) included

  • hypersensitivity (0.4%)

  • increased ALT (0.4%)

  • increased AST (0.3%), and

  • thrombocytopenia (0.3%).2,8

Dosage interruptions due to an adverse reaction occurred in 45% of patients who received selpercatinib. Adverse reactions requiring dosage interruption in ≥2% of patients who received selpercatinib included

  • ALT increased

  • AST increased

  • hypertension

  • diarrhea

  • pyrexia

  • QT prolongation

  • pneumonia

  • abdominal pain

  • fatigue, and

  • blood bilirubin increased.8

Dose reductions due to an adverse reaction occurred in 34% of patients who received selpercatinib. Adverse reactions requiring dosage reductions in >2% of patients who received selpercatinib included

  • ALT increased

  • AST increased

  • fatigue

  • QT prolongation

  • fatigue

  • drug hypersensitivity

  • diarrhea, and

  • thrombocytopenia.8

References

1. 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 11, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03157128

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

3. 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

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. Goto K, Oxnard GR, Tan DSW, et al. Selpercatinib (LOXO-292) in patients with RET fusion-positive non-small cell lung cancer (NSCLC). Poster presented at: 56th Annual Meeting of the American Society of Clinical Oncology (ASCO Virtual); May 29-31, 2020. Accessed May 22, 2020. https://meetinglibrary.asco.org/record/188463/abstract

6. Shah MH, Sherman EJ, Robinson B, et al. Selpercatinib (LOXO-292) in patients with RET-altered thyroid cancer. Poster presented at: 56th Annual Meeting of the American Society of Clinical Oncology (ASCO Virtual); May 29-31, 2020. Accessed May 22, 2020. https://meetinglibrary.asco.org/record/187939/abstract

7. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET fusion-positive lung cancers. Talk presented at: 20th Annual World Conference on Lung Cancer (WCLC); September 7-10, 2019; Barcelona, Spain. https://library.iaslc.org/virtual-library-search?product_id=15

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

Glossary

ALT = alanine aminotransferase 

AST = aspartate aminotransferase

CEA = carcinoembryonic antigen 

CNS = central nervous system

DOR = duration of response

ECOG = Eastern Cooperative Oncology Group

IRC = independent review committee

MTC = medullary thyroid cancer

MTD = maximum tolerated dose

NSCLC = non-small cell lung cancer

ORR = overall response rate

OS = overall survival

PAS = primary analysis set

PFS = progression-free survival

PK = pharmacokinetic(s)

PS = performance status

RAI = radioactive iodine

RECIST = Response Evaluation Criteria in Solid Tumors

RET = rearranged during transfection

RP2D = recommended phase 2 dose

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 13


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