Retsevmo ® (selperkatinib)

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Vilka var de vanligaste RET-förändringarna i Retsevmo® ▼ (selperkatinib) studien?

De vanligaste RET-förändringarna i LIBRETTO-001 var KIF5B, CCDC6, NCOA4, M918T och extracellulär cystein.

LIBRETTO-001 Clinical Trial

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

Efficacy according to IRC assessment as of the December 16, 2019 data cutoff was as follows: 

  • In the PAS of 105 platinum-treated RET fusion-positive NSCLC patients, ORR was 64% and the median DOR was 17.5 months.1

  • In 39 treatment-naïve NSCLC patients, ORR was 85% and median DOR was not reached.1

  • The PAS of 55 prior cabozantinib and/or vandetanib patients with MTC, ORR was 69% and DOR was not reached.3

  • In the 88 RET-mutant MTC patients naïve to cabozantinib/vandetanib treatment, ORR was 73% and median DOR was 22 months.3

  • In the 19 previously treated RET fusion-positive thyroid patients, ORR was 79% and median DOR was 18.4 months. In the 8 treatment-naïve patients, ORR was 100% and DOR was not reached.3

As of data cutoff date of March 30, 2020, results based on IRC assessment for the patients who were considered efficacy eligible (previously treated patients with ≥6 months follow-up) were 

  • In the 218 RET fusion-positive NSCLC patients, ORR was 57% and median DOR was 17.5 months.2

  • In the 143 RET-mutant MTC patients, ORR was 69% and DOR was not reached.2

  • In the 22 RET fusion-positive thyroid patients, ORR was 77% and DOR was 18.4 months.2

RET Overview

RET can be altered by 2 primary mechanisms

  • chromosomal rearrangements that fuse the RET kinase domain with a partner protein dimerization domain producing hybrid proteins with ligand-independent activity,8-11 or

  • point mutations that directly or indirectly activate the RET kinase.12-14

Genetic alterations in the RET gene are implicated in the pathogenesis of several human cancers. For RET, fusions and mutations are the key alterations.13 The term RET-altered cancers encompasses RET-fusions and RET-mutations, as described in Table 1.

Table 1. RET-Altered Cancers15-17

 

RET-fusions

RET-mutations

Description

Genomic abnormalities that occur when the RET gene becomes fused with another unrelated gene.
The hybrid gene no longer functions normally, which can lead to an overproduction of abnormal RET proteins that are turned on all of the time, leading to uncontrolled cell growth.

Genomic abnormalities that occur when a small change in the RET gene alters the function of the protein, causing uncontrolled cell growth.

Most common alterations

  • KIF5B in lung cancer

  • CCDC6 and NCOA4 in thyroid cancer

RET M918T

Prevalence

  • 2% of NSCLC

  • 10-20% of papillary and other thyroid cancers

  • 1% of pancreatic cancer, salivary gland cancer, Spitz cancer, CRC, ovarian cancer, myeloproliferative disorder

Appears to be limited to MTC, with approximately

  • >60% in sporadic MTC, and

  • >90% in hereditary MTC.

Abbreviations: CCDC6 = coiled-coil domain containing 6; CRC = colorectal cancer; KIF5B = kinesin family member 5B; MTC = medullary thyroid cancer; NCOA4 = nuclear receptor coactivator 4; NSCLC = non-small cell lung cancer; RET = rearranged during transfection.

RET Alterations in LIBRETTO-001

In the LIBRETTO-001 population, the frequency of RET alterations was consistent with the most commonly occurring fusions and mutations in NSCLC and MTC (Table 2 and Table 3).5,6

Table 2. Frequency of RET-Fusions in the NSCLC Cohort of LIBRETTO-0015

RET Alteration, %

Previous Platinum-Based Therapy
(N=105)

Treatment-Naïve
(N=39)

KIF5B

56

67

CCDC6

23

21

NCOA4

2

0

RELCH

2

0

Othera

6

3

Unknownb

11

10

Abbreviations: CCDC6 = coiled-coil domain containing 6; KIF5B = Kinesin family member 5B; NCOA4 = nuclear receptor coactivator 4; NSCLC = non-small cell lung cancer; RELCH = RAB11 binding and LisH domain, coiled-coil and HEAT repeat containing; RET = rearranged during transfection.

a Other fusions identified in single tumors included CLIP1-RET, RBPMS-RET and DOCK1-RET, ARHGAP12-RET, CCDC88C-RET, TRIM24-RET, PRKAR1A-RET, and ERC1-RET.

b RET-fusion indicated by molecular analysis but fusion partner not identified.

Table 3.  Frequency of RET Alterations in the Thyroid Cancer Cohort of LIBRETTO-0016

RET Alteration, %

Medullary Thyroid Cancer

RET Fusion-Positive TC
(N=19)

Previous Vande and/or Cabo Therapy (n=55)

Treatment-Naïve (n=88)

M918T

60

56

0

CCDC6

0

0

47

NCOA4

0

0

32

Extracellular Cysteinea

13

23

0

V804M/L

9

7

0

Otherbc

18

15

21

Abbreviations: cabo = cabozantinib; CCDC6 = cluster of differentiation 69; NCOA4 = nuclear receptor coactivator 4; RET = rearranged during transfection; TC = thyroid cancer; vande = vandetanib.

a Extracellular cysteine mutation defined as mutation including at least 1 of the following cysteine residues: 609, 611, 618, 620, 630, and 634.

b For treatment-naive medullary thyroid cancer and RET fusion-positive thyroid cancer, other includes: D631-L633delinsE, E632-L633del, A883F, D631-L633delinsV, L790F, D898-E901del, D898_E901del + D903_S904delinsEP, K666N, T636-V637insCRT, D378-G385delinsE.

c For RET fusion-positive thyroid cancer, fusions identified in single tumors included CCDC186-RET, ERC1-RET, KTN1-RET, and RUFY3-RET. 

Efficacy by Alteration Type

The primary endpoint of the phase 2 dose expansion portion of the study is ORR as determined by a blinded IRC according to RECIST v1.1.1-4

Table 4. Objective Response Rate by Tumor Type as Assessed by BIRC5,6

Response

RET Fusion-Positive NSCLC

RET Mutant-MTC

RET Fusion-Positive TC

Previously Treated (n=105)a

Treatment-Naïve (n=39)

Previously Treated (n =55)b

Treatment-Naïve (n=88)

(N=19)

ORR, % (95% CI)

64 (54-73)

85 (70-94)

69 (55-81)

73 (62-82)

79 (54-94)

Abbreviations: BIRC = blinded independent review committee; MTC = medullary thyroid cancer; NSCLC = non-small cell lung cancer; ORR = objective response rate; RET = rearranged during transfection; TC = thyroid cancer.

a Previously treated with platinum-based therapy.

b Previous vandetanib and/or cabozantinib therapy.

Objective response rate and DOR by RET fusion partner, as assessed by IRC is presented in Table 5.


Table 5. Efficacy by Fusion Partners in NSCLC as Assessed by IRC18

 

Objective Response Rate

Duration of Response (Months)

 

Patients (n)

  Responders n (%)a

   95% CI

Median

 Range

RET FUSION Partners

105

 67 (63.8)

 53.85,  72.96

17.51

1.87+, 26.22+

  KIF5B

59

 34 (57.6)

 44.07,  70.39

NR

1.87+, 23.95+

  CCDC6

24

 19 (79.2)

 57.85,  92.87

14.65

1.87+, 17.84+

  NCOA4

2

  1 (PR, NE)

NA

NR

13.86+

  OTHER

8

  4 (50.0)

 15.70,  84.30

10.17

5.55, 14.59+

    KIAA1468

2

  0 (SD, SD)

NA

NA

NA

    ARHGAP12

1

  1 (PR)

NA

NR

14.59+

    CCDC88C

1

  0 (SD)

NA

NA

NA

    CLIP1

1

  1 (PR)

NA

 5.55

5.55

    PRKAR1A

1

  1 (PR)

NA

12.02

12.02

    RBPM AND DOCK1

1

  1 (PR)

NA

 8.31

8.31

    TRIM24

1

  0 (SD)

NA

NA

NA

  UNKNOWN

12

  9 (75.0)

 42.81,  94.51

12.12

3.68, 26.22+

    RET REARRANGEMENT

    BY FISH

9

  6 (66.7)

 29.93,  92.51

 9.48

3.68, 26.22+

    UNKNOWN

3

  3 (100.0)

 29.24, 100.00

NR

9.23+, 14.75+

+ Indicates censored.

Abbreviations: ARHGAP12 = Rho GTPase-activating protein 12; CCDC6 = coiled-coil domain containing 6; CCDC88C = coiled-coil domain containing 88C; CLIP1=CAP-GLY domain containing linker protein 1; CR = complete response; DOCK1 = Dedicator Of Cytokinesis 1; FISH = fluorescence in situ hybridization; IRC = independent review committee; KIF5B = Kinesin family member 5B; NA = not applicable; NCOA4 = nuclear receptor coactivator 4; NE = not evaluable; NR = not reached; NSCLC = non-small cell lung cancer; PD = progressive disease; PRKAR1A = Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha; RBPM = RNA Binding Protein With Multiple Splicing-Like Pseudogene, including: function, proteins, disorders; RELCH = RAB11 binding and LisH domain, coiled-coil and HEAT repeat containing; RET = rearranged during transfection; TRIM24 = Tripartite Motif Containing 24.

a Percentage is calculated based on the number of patients n as the denominator.

Efficacy by mutation type in the MTC population is presented in Table 6.

Table 6.  Efficacy by Mutation Type in the MTC Population as Assessed by IRC18

 

Objective Response Rate

Duration of Response (months)

RET Mutation Type

Patients (n)

 Responders n (%)

    95% CI

 Median

    Range

M918T

 33

 21 (63,6)

 45.12,  79.60

19.12

2.79+, 23.13+

Extracellular Cysteine Mutation

  7

  5 (71.4)

 29.04,  96.33

  NR

2.76+, 18.14+

V804M/L

  5

  3 (60.0)

 14.66,  94.73

  NR

14.75+, 22.87+

 Other

 10

  9 (90.0)

 55.50,  99.75

  NR

3.48+, 23.95+

+ Indicates censored.

Abbreviations: NR = not reached; RET = rearranged during transfection.

Safety in LIBRETTO-001 Clinical Trial

In the overall safety population (N=746), 690 patients (93%) experienced a drug-related TEAE, including 293 (93%) in the RET-mutant MTC and 322 (93%) in the RET fusion-positive NSCLC cohorts (Table 7).18

Table 7. Selpercatinib-Related TEAEs in ≥15% of Overall Safety Populationa18

Preferred Term, n (%)

RET-Mutant MTC
(n=315)

RET Fusion-Positive NSCLC
(n=345)

Overall Safety Population
(N=746)

Dry mouth

104 (33)

137 (40)

265 (36)

ALT increased

71 (23)

107 (31)

197 (26)

AST increased

71 (23)

109 (32)

196 (26)

Hypertension

90 (29)

80 (23)

190 (26)

Diarrhea

55 (18)

90 (26)

163 (22)

Fatigue

76 (24)

48 (14)

144 (19)

Peripheral edema

47 (15)

54 (16)

108 (15)

ECG QT prolonged

47 (15)

46 (13)

103 (14)

Constipation

59 (19)

30 (9)

97 (13)

Rash

28 (9)

52 (15)

87 (12)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram;  MTC = medullary thyroid cancer; NSCLC = non-small cell lung cancer; RET = rearranged during transfection; TEAE = treatment-emergent adverse event.

a Data cut-off 30Mar2020.

Selpercatinib-related grade 3/4 TEAEs occurred in 239 patients (32%) in the overall safety population. By tumor type, 31% of MTC and 35% of NSCLC patients experienced related grades 3 and 4 events. There were no drug related grade 5 TEAEs reported.18

Table 8 lists the drug-related grades 3 and 4 TEAEs that occurred in ≥1% of the overall safety population.

Table 8. Selpercatinib-Related Grade 3/4 TEAEs in ≥1% of the Overall Safety Populationa18

Preferred Term, n (%)

Overall Safety Population (N=746)

Hypertension

93 (13)

ALT increased

60 (8)

AST increased

47 (6)

ECG QT prolonged

21 (3)

Thrombocytopenia

14 (2)

Diarrhea

12 (2)

Neutropenia

11 (2)

Lymphopenia

9  (1)

Drug hypersensitivity

9 (1)

Fatigue

8 (1)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; TEAE = treatment-emergent adverse event.

a Data cut-off 30Mar2020.

Serious Adverse Events

In the overall safety population (N=746), drug-related SAEs occurred in 8% of patients. By tumor type, 6% of MTC patients and 11% of NSCLC patients experienced related SAEs. Selpercatinib-related SAEs experienced in ≥1% of the overall safety population were

  • drug hypersensitivity 

  • ALT increased

  • AST increased

  • hypertension, and

  • hypersensitivity.18

Overall, reported on-study TEAEs with fatal outcomes or those occurring within 28 days of last study drug dose occurred in 103 patients, with 25 of the deaths attributed to an AE. None of the TEAEs with fatal outcomes were considered to be related to selpercatinib by the investigator.18

Dosage Modification

Dosing modifications due to TEAEs are presented in Table 9.

Table 9. Selpercatinib Dosage Modifications Due to Adverse Reactions in the LIBRETTO-001 Overall Populationa18

Dose Modification, n (%)

Any AR

Interruption

334 (45)

Reduction

251 (34)

Discontinuation

45 (6)

AR = adverse reaction.

a Data cut-off 30Mar2020.

Discontinuation rate due to an AE considered to be related to selpercatinib was 2%. Related discontinuation events, that occurred in 3 patients each (0.4%) were ALT increased and sepsis.

Related discontinuation events that occurred in 2 patients each (0.3%) were

  • AST increased

  • cardiac failure

  • drug hypersensitivity

  • fatigue

  • pericardial effusion

  • pneumonia, and

  • thrombocytopenia.18

References

1. 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

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

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. 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

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. Romei C, Ciampi R, Elisei, R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016;12(4):192-202. https://doi.org/10.1038/nrendo.2016.11

9. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375-377. https://doi.org/10.1038/nm.2644

10. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378-381. https://doi.org/10.1038/nm.2658

11. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18(3):382-384. https://doi.org/10.1038/nm.2673

12. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-856. https://doi.org/10.1093/hmg/2.7.851

13. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-460. http://dx.doi.org/10.1038/363458a0

14. Hofstra RM, Landsvater I, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376. https://doi.org/10.1038/367375a0

15. Drilon A, Hu ZI, Lai GG, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. https://doi.org/10.1038/nrclinonc.2017.175

16. Pietrantonio F, Di Nicolantonio F, Schrock AB, et al. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann Oncol. 2018;29(6):1394-1401. https://dx.doi.org/10.1093/annonc/mdy090

17. Su X, He C, Ma J, et al. RET/PTC rearrangements are associated with elevated postoperative TSH levels and multifocal lesions in papillary thyroid cancer without concomitant thyroid benign disease. PLoS One. 2016;11(11):e0165596. https://dx.doi.org/10.1371/journal.pone.0165596

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

Glossary

AE = adverse event

ALT = alanine aminotransferase 

AST = aspartate aminotransferase

DOR = duration of response

IRC = independent review committee

MTC = medullary thyroid cancer

MTD = maximum tolerated dose

NSCLC = non-small cell lung cancer

ORR = objective response rate

PAS = primary analysis set

RECIST = Response Evaluation Criteria in Solid Tumors

RET = rearranged during transfection

RP2D = recommended phase 2 dose

SAE = serious adverse event

TEAE = treatment-emergent adverse event

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 M02 01


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