Är Retsevmo® ▼ (selperkatinib) säkert och effektivt i NSCLC?

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 n=105	Treatment-Naïve n=39
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 Results^2,3,8

Responseab	PAS3,c n=105	PAS8,d n=105	Previously Treated Efficacy Eligible2,8,de n=218	Treatment-Naïve3,c n=39
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

• 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

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.