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Retsevmo ® (selperkatinib)
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LIBRETTO-001 Phase 1/2 Selpercatinib Use in NSCLC
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
Patient Characteristics
Of the RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy in LIBRETTO-001, 218 were considered efficacy eligible (had ≥6 months follow-up). The PAS, as defined with the health authority, consisted of the first 105 of the 218 consecutively enrolled patients.2,3
There were 39 patients with treatment-naïve RET fusion-positive NSCLC also analyzed.3
Table 1 describes patient characteristics. Median age was 61 years in the treated and treatment-naïve groups. The majority of all patients (≥99%) had an ECOG PS of 0 or 1. Of the 144 total PAS patients, the most common known RET fusion partners were KIF5B (59%), CCDC6 (22%), and NCOA4 (1.4%).3
In the 105 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy, RET-fusions were detected in patients using
NGS (85 patients in tumor and 9 in blood or plasma)
FISH (9), or
PCR assay (2).3
Table 1. RET Fusion-Positive NSCLC Patient Characteristics3
Characteristica |
NSCLC
PAS |
Treatment-Naïve |
Female/Male, % |
59/41 |
56/44 |
Median age, years (range) |
61 (23-81) |
61 (23-86) |
Race, % |
||
White |
52 |
72 |
Asian |
38 |
18 |
Black |
5 |
8 |
Other/Missing |
5 |
3 |
Smoking status, % |
||
Never smoked |
71 |
74 |
Former smoker |
28 |
23 |
Current smoker |
1 |
3 |
NSCLC histological subtype, % |
||
Adenocarcinoma |
86 |
87 |
Large cell neuroendocrine carcinoma |
2 |
0 |
Squamous cell carcinoma |
1 |
0 |
Not otherwise specified |
11 |
13 |
Prior systemic regimens, median (range) |
3 (1-15) |
0 |
Prior platinum-based chemotherapy, % |
100 |
0 |
Prior PD-1/PD-L1 inhibitor, % |
55 |
0 |
Prior multikinase inhibitorb, % |
48 |
0 |
Brain metastases, % |
36 |
18 |
Measurable disease, % |
99 |
100 |
RET fusion, % |
||
KIF5B |
56 |
67 |
CCDC6 |
23 |
21 |
NCOA4 |
2 |
0 |
RELCH |
2 |
0 |
Other |
6 |
3 |
Not determinedc |
11 |
10 |
Abbreviations: CCDC6 = coiled-coil domain containing 6; KIF5B = kinesin family member 5B; MKI = multitargeted kinase inhibitor; NCOA4 = nuclear receptor coactivator 4; NSCLC = non-small cell lung cancer; PAS = primary analysis set; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; RELCH = RAB11 Binding And LisH Domain, Coiled-Coil And HEAT Repeat Containing; RET = rearranged during transfection.
a Total % may be different than the sum of the individual components due to rounding.
b MKIs administered included cabozantinib (16 patients), vandetanib (8), lenvatinib (7), and others (36). Patients may have received more than 1 MKI.
c RET fusion was indicated by molecular analysis, but the fusion partner was not identified.
Efficacy Results
A summary of efficacy results is summarized in Table 2.
Table 2. RET Fusion-Positive NSCLC Efficacy Results2,3,8
Responseab |
PAS3,c |
PAS8,d |
Treatment-Naïve3,c |
|
Confirmed ORR, % (95% CI) |
64 (54-73) |
67 (54-73) |
57 (50-64) |
85 (70-94) |
Complete response, n (%) |
2 (2) |
3 (3) |
9 (4) |
0 (0) |
Partial response, n (%) |
65 (62) |
64 (61) |
115 (53) |
33 (85) |
Stable disease, n (%) |
30 (29) |
30 (29) |
81 (37) |
4 (10) |
Progressive disease, n (%) |
4 (4) |
4 (4) |
5 (2) |
1 (3) |
Not evaluable, n (%) |
4 (4) |
4 (4) |
8 (4) |
1 (3) |
Duration of response |
||||
Median, months (95% CI) |
18 (12-NE) |
18 (12-NE) |
18 (13-NE) |
NE (12-NE) |
Censored, n (%) |
44 (66) |
39 (58) |
86 (69) |
26 (79) |
Median follow-up, months |
12 |
16 |
12 |
7 |
Progression-free survival |
||||
Median, months (95% CI) |
17 (14-NE) |
19 (14-NE) |
19 (17-NE) |
NE (14-NE) |
Censored, n (%) |
61 (58) |
55 (52) |
144 (66) |
30 (77) |
Median follow-up, months |
14 |
17 |
19 |
9 |
1-year PFS rate, % (95% CI) |
66 (55-74) |
66 (56-74) |
70 (62-76) |
75 (56-87) |
Abbreviations: NE = not estimable; NSCLC = non-small cell lung cancer; 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 with prior platinum treatment in the analysis set who had the opportunity to be followed for at least 6 months from the first dose of selpercatinib.
In the PAS, the median time to response was 1.8 months. Response was similar regardless of fusion partner or the type or number of prior therapies, including anti-PD-1/PD-L1 agents and off-label MKIs.3,5
CNS Activity
In the RET fusion-positive NSCLC population, 96 patients had brain metastases at baseline. Of those 96 patients, 23 had measurable CNS metastases as assessed by an IRC. The ORR in the evaluable patients was 87% (20/23; 95% CI 66-97). The DOR was 9 months (range: 2.8-23.9+).2
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 3 summarizes treatment-emergent adverse reactions occurring in the safety population.
Table 3. 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
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
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
CCDC6 = coiled-coil domain containing 6
CNS = central nervous system
DOR = duration of response
ECOG = Eastern Cooperative Oncology Group
IRC = independent review committee
KIF5B = kinesin family member 5B
MKI = multikinase inhibitor
MTC = medullary thyroid cancer
MTD = maximum tolerated dose
NCOA4 = nuclear receptor coactivator 4
NSCLC = non-small cell lung cancer
ORR = overall response rate
OS = overall survival
PAS = primary analysis set
PD-1 = programmed death-1
PD-L1 = programmed death-ligand 1
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.
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