Aportación del lenvatinib al tratamiento del carcinoma
hepatocelularDr. Javier Sastre
Servicio de Oncologia Médica
HC San Carlos
Lenvatinib
Tumour cell
VEGF
Lenvatinib
VEGF-receptor (1-3)
1. Stjepanovic N and Capdevila J. Biologics 2014;8:129–139.2. http://www.selleckchem.com/datasheet/E7080-DataSheet.html#s_ref (Accessed December 2017).
3. EMA Lenvatinib EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003727/WC500188676.pdf (Accessed February 2018).
PDGFPDFG-receptor
FGF receptor (1-4)
RETIC502,3:• VEGFR1 = 22 nM• VEGFR2 = 4.0 nM• VEGFR3 = 5.2 nM• Ret = 6.4 nM• PDGFR-α = 51 nM• PDGFR-β = 39 nM• FGFR1 = 61 nM• FGFR2 = 27 nM• FGFR3 = 52 nM• FGFR4 = 43 nM• KIT = 100 nM
• Lenvatinib (E7080) is an oral multiple receptor tyrosine kinase inhibitor targeting VEGFR-1-3, FGFR-1-4, RET, c-KIT, and PDGFR-beta1
• Lenvatinib potently inhibits FGFR-1, offering a potential opportunity to block one of the well known mechanisms of resistance to VEGF/VEGFRinhibitors1
c-KIT
Lenvatinib: Phase I MTD and Dose-finding Study
• 20 patients (9 in CP-A and 11 in CP-B) were enrolled
The MTD was 12 and 8 mg once daily (QD) in CP-A and CP-B, respectively
• DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia
• The most common grade 3/4 toxicities (any dose) included hypertension, hyperbilirubinemia, increased AST and proteinuria
• Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg QD was higher in patients with HCC compared with other solid tumours (phase I study)
• C24 h for 25 mg once daily lenvatinib was comparable with the 12mg CP-A group
Ikeda M et al. Clin Cancer Res. 2016;22: DOI: 10.1158/1078-0432.CCR-15-1354.
Lenvatinib Phase II Study: Design
• Aim: Assess the antitumor activity and safety of lenvatinib in patients with advanced HCC
Patients with advanced HCC (N=46) • ≥1 measurable target
lesion• 1–3 tumour lesions [>3
cm in diameter ([>5 cm diameter if only one lesion) or ≥ 4 lesions or portal vein invasion, extrahepatic invasion
• ECOG 0 or 1• Child-Pugh class A• Hepatectomy and local
therapy received for at least 6 and 4 weeks respectively
Lenvatinib12 mg PO QD, 28-day cycles
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Primary endpoint Time to progression (mRECIST)
Secondary endpointsObjective response rateType of progressive diseaseDisease control rateOverall survivalSafetyPharmacokinetic
Lenvatinib Phase II Study: Baseline Data
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Patient Characteristics (N = 46)
Median age, yrs (range) 66.5 (37-80)
Sex, n (%)FemaleMale
13 (28.3)33 (71.7)
Region, n (%)JapanSouth Korea
43 (93.5)3 (6.5)
Median weight, kg (range) 56.7 (42.8-85.5)
ECOG PS, n (%)01
38 (82.6)8 (17.4)
Child-Pugh class, n (%)AB
45 (97.8)1 (2.2)
BCLC staging, n (%)BC
19 (41.3)27 (58.7)
Portal vein invasion, n (%)YesNo
5 (10.8)41 (89.1)
Patient Characteristics (N = 46)
Extrahepatic metastases, n (%)YesNo
21 (45.7)25 (54.3)
Cause of HCC, n (%)Hepatitis BHepatitis CAlcoholNAFLDUnknown
15 (32.6)27 (58.7)
2 (4.3)1 (2.2)2 (4.3)
AFP value at baseline, n (%)<200 ng/ml≥200 ng/ml
27 (57.7)18 (39.1)
Prior surgery for HCC, n (%)NoYes
27 (58.7)19 (41.3)
Prior local therapy, n (%)NoYesRFAPEITACETAE
4 (8.7)42 (91.3)32 (69.6)12 (26.1)39 (84.8)
3 (6.5)
Prior chemotherapy, n (%)SorafenibOtherHepatic intra-arterial chemotherapy
6 (13.0)5 (10.9)5 (10.9)
Lenvatinib Phase II Study: Efficacy Data (Response Rate)
Parameter, n (%) Investigator assessment (mRECIST), n=46
IRRC assessment (mRECIST), n=46
IRRC assessment (RECIST 1.1), n=46
Best response
Complete response 0 0 0
Partial response 17 (37) 17 (37) 11 (24)
Stable disease 21 (46) 19 (41) 25 (54)
Progressive disease 5 (11) 6 (13) 6 (13)
Not evaluable 3 (7) 4 (9) 4 (9)
Objective response rate 17 (37) 17 (37) 11 (24)
Disease control rate 38 (83) 36 (78) 36 (78)
IRRC, independent radiologic review committee; mRECIST, modified response evaluation criteria in solid tumors.
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Lenvatinib Phase II Study: Efficacy Data (TTP and OS)
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Median TTP was 7.4 months Median OS was 18.7 months
0
Est
imate
d p
robabilit
y (
%)
0
20
40
60
80
100
0
Est
imate
d p
robabilit
y (
%)
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 2 4 6 8 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 4410
Survival time (months)TTP (months)
46 35 31 20 15 10 9 5 2 1 0 46 45 45 40 39 31 27 27 24 21 17 14 13 13 11 10 10 9 5 4 3 03300000000IRR
No. at Risk
12 mg
Lenvatinib
No. at Risk
IRR Assessment
Censored Observations
12 mg Lenvatinib
Censored Observations
Lenvatinib Phase II Study: Efficacy Data (Best Overall Response)
60
40
20
0
-20
-40
-60
-80
-100
80
Ch
ange
fro
m b
asel
ine
(%)
Best overall response
PR (n=17)
SD (n=19)
PD (n=6)
NE (n=3)
*
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Lenvatinib Phase II Study: Safety (1)Adverse event, n (%) All grades, n=46 Grade 3, n=46 Grade 4 (n = 46)
Hypertension 35 (76.1) 25 (54.3) 0
PPE syndrome 30 (65.2) 4 (8.7) 0
Decreased appetite 28 (60.9) 1 (2.2) 0
Proteinuria 28 (60.9) 9 (19.6) 0
Fatigue 25 (54.3) 0 0
Diarrhoea 20 (43.5) 6 (13.0) 0
Constipation 19 (41.3) 0 0
Nausea 17 (37.0) 1 (2.2) 0
Dysphonia 17 (37.0) 0 0
Thromobcytopenia 16 (34.8) 9 (19.6) 1 (2.2)
Peripheral oedema 16 (34.8) 0 0
Decreased weight 14 (30.4) 2 (4.3) 0
Neutropenia 13 (28.3) 2 (4.3) 0
Nasopharyngitis 13 (28.3) 0 0
Rash 13 (28.3) 0 0
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Lenvatinib Phase II Study: Safety (2)
Adverse event, n (%) All grades, n=46 Grade 3, n=46 Grade 4 (n = 46)
Increased blood thyroid-stimulating hormone level
12 (26.1) 0 0
Back pain 11 (23.9) 0 0
Stomatitis 11 (23.9) 0 0
Vomiting 11 (23.9) 1 (2.2) 0
Pyrexia 10 (21.7) 0 0
Hypothyroidism 10 (21.7) 0 0
Insomnia 10 (21.7) 0 0
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
Lenvatinib Phase II Study: Conclusions
• Median TTP was 7.4 months [95 % CI 5.5–9.4]
• 37 % of patients had partial response and 41 % had stable disease (DCR: 78 %)
• Median OS was 18.7 months (95 % CI 12.7–25.1)
• The most common AEs were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %)
• Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively
Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC; however early dose modification was necessary in
patients with lower body weight
Ikeda K et al. J Gastroenterol. 2017; 52:512–19.
12
• Median TTP was 7.4 months [95 % CI 5.5–9.4]
• 37 % of patients had partial response and 41 % had stable disease (DCR: 78 %)
• Median OS was 18.7 months (95 % CI 12.7–25.1)
• The most common AEs were hypertension (76 %), palmar-plantar erythrodysesthesiasyndrome (65 %), decreased appetite (61 %), and proteinuria (61 %)
• Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively
Lenvatinib Phase II Study: Conclusions
Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC; however early dose modification was necessary in
patients with lower body weightIkeda K et al. J Gastroenterol. 2017; 52:512–19.
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Design
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Patients with advanced HCC (N=954) • No prior systemic therapy• ≥1 measurable target lesion• BCLC stage B or C• ECOG 0 or 1• Child-Pugh class A• Adequate organ function
Lenvatinib (n=478)8 mg (bodyweight <60 kg) or 12 mg
(bodyweight ≥60 kg) PO QD
Primary endpoint Overall survival
Secondary endpointsProgression-free survivalTime to progressionObjective response rateQuality of lifePharmacokinetics
Sorafenib (n= 476)400 mg PO BID
1:1
Stratified by geography (Asia vs Western); macrovascular invasion and/or extrahepatic
disease; ECOG PS (0 vs 1); Bodyweight (<60 kg vs ≥60 kg)
Aim: To assess the efficacy of lenvatinib vs sorafenib in the first-line treatment of patients with unresectable HCC
Open-label, phase 3, multicentre, non-inferiority trial
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Baseline Data (1)
Patient Characteristics, n (%) Lenvatinib (n = 478) Sorafenib (n = 476) Total (n = 954)
Median age, years (range) 63.0 (20-88) 62.0 (22-88) 62.0 (20-88)
Sex MaleFemale
405 (85)73 (15)
401 (84)75 (16)
806 (84)148 (16)
Region WesternAsia-Pacific
157 (33)321 (67)
157 (33)319 (67)
314 (33)640 (67)
Race WhiteAsianOther
135 (28)334 (70)
9 (2)
141 (30)326 (68)
9 (2)
276 (29)660 (69)
18 (2)
Body weight <60 kg≥60 kg
153 (32)325 (68)
146 (31)330 (69)
299 (31)655 (69)
ECOG PS 01
304 (64)174 (36)
301 (63)175 (37)
605 (63)349 (37)
Child-Pugh class AB
475 (99)3 (1)
471 (99)5 (1)
946 (99)8 (1)
Macrovascular invasion (MI) Yes No
109 (23)369 (77)
90 (19)386 (81)
199 (21)755 (79)
Extrahepatic spread (EHS) Yes No
291 (61)187 (39)
295 (62)181 (38)
586 (61)368 (39)
MI, EHS or both Yes No
329 (69) 149 (31)
336 (71) 140 (29)
665 (70)289 (30)
Underlying cirrhosis (masked, independent review)
YesNo
356 (74)122 (26)
364 (76)112 (24)
720 (75)234 (25)
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Baseline Data (2)
Patient Characteristics, n (%) Lenvatinib (n = 478) Sorafenib (n = 476) Total (n = 954)
BCLC staging BC
104 (22)374 (78)
92 (19)384 (81)
196 (21)758 (79)
Involved disease sites LiverLung
441 (92)163 (34)
430 (90)144 (30)
871 (91)307 (32)
Involved disease sites per patient
12≥3
207 (43)167 (35)103 (22)
207 (43)183 (38)86 (18)
414 (43)350 (37)189 (20)
Aetiology of chronic liver disease
Hepatitis BHepatitis CAlcoholOtherUnknown
251 (53)91 (19)36 (8)38 (8)
62 (13)
228 (48)126 (26)
21 (4)32 (7)
69 (14)
479 (50)217 (23)
57 (6)70 (7)
131 (14)
Baseline AFP concentration (ng/ml)
Patients, n (%)Mean (SD)Median (IQR)
471 (99)17507.5 (105137.4)133.1 (8.0-3730.6)
463 (97)16678.5 (94789.5)71.2 (5.2-1081.8)
934 (98)17096.5 (100088.8)
89.0 (6.3-2120.2)
Baseline AFP concentration group, ng/ml
<200≥200Missing
255 (53)222 (46)
1 (<1)
286 (60)187 (39)
3 (1)
541 (57)409 (43)
4 (<1)
Concomitant systemic antiviral therapy for hepatitis B or C, n (%)
163 (34) 149 (31) 312 (33)
Previous therapy Previous anticancer proceduresRadiotherapy
327 (68)
49 (10)
344 (72)
60 (13)
671 (70)
109 (11)
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Efficacy (Primary Endpoint OS)
0 3 6 9 12 15 18 2421 3630 42
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
Pro
bab
ility
Time (months)
27 3933
Number at riskLenvatinib 478 436 374 297 253 207 178 140 102 67 40 21 8 2 0
Sorafenib 476 440 348 282 230 192 156 116 83 57 33 16 8 4 0
Median (month) (95% CI)
Lenvatinib 13.6 (12.1–14.9)
Sorafenib 12.3 (10.4–13.9)
HR (95% CI): 0.92 (0.79–1.06)
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Efficacy(OS Sub-group Analysis)
Characteristic SubgroupEvents/Patients HR (95% CI)
Lenvatinib vs Sorafenib
Median (months)
Lenvatinib Sorafenib Lenvatinib Sorafenib
Overall 351/478 350/476 0.92 (0.79-1.06) 13.6 12.3
Age< 65 y≥ 65y
203/270148/208
204/283146/193
0.94 (0.77-1.15)0.84 (0.66-1.07)
12.414.6
11.413.4
SexMaleFemale
293/40558/73
293/40157/75
0.91 (0.77-1.07)0.84 (0.56-1.26)
13.415.3
12.411.4
RegionAsia-PacificWestern
243/321108/157
248/319102/157
0.86 (0.72-1.02)1.08 (0.82-1.42)
13.513.6
11.014.2
ECOG-PSPS = 0PS = 1
221/304130/174
223/301127/175
0.88 (0.73-1.06)0.97 (0.76-1.25)
14.610.7
12.810.3
Body weight< 60 kg≥ 60 kg
110/153241/325
113/146237/330
0.85 (0.65-1.11)0.95 (0.79-1.14)
13.413.7
10.312.5
MVI, EHS or bothYesNo
250/329101/149
259/33691/140
0.87 (0.73-1.04)1.05 (0.79-1.40)
11.518.0
9.818.0
AFP at baseline< 200 ng/mL≥ 200 ng/mL
167/255183/222
193/286154/187
0.91 (0.74-1.12)0.78 (0.63-0.98)
19.510.4
16.38.2
EtiologyHBVHCV
196/25975/103
186/24497/135
0.83 (0.68-1.02)0.91 (0.66-1.26)
13.415.3
10.214.1
BCLC stagingStage BStage C
71/104280/374
65/92285/384
0.91 (0.65-1.28)0.92 (0.77-1.08)
18.511.8
17.310.3
Posttreatmentanticancer therapy
YesNo
143/206208/272
175/243175/233
0.84 (0.67-1.06)0.91 (0.74-1.11)
19.510.5
17.07.9
Favors Lenvatinib Favors Sorafenib0.5 21
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Efficacy (Secondary Endpoint PFS by mRECIST)
0 3 6 9 12 15 18 2421 3630 42
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
Pro
bab
ility
Time (months)
27 3933
Number at riskLenvatinib 478 345 223 172 106 69 44 28 14 9 4 2 0 0
Sorafenib 476 262 140 94 56 41 33 22 14 9 4 2 2 0
Median (month) (95% CI)
Lenvatinib 7.4 (6.9–8.8)
Sorafenib 3.7 (3.6–4.6)
HR (95% CI): 0.66 (0.57–0.77)Log-rank Test: p-value: <0.0001
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Efficacy (PFS Sub-group Analysis)
Characteristic SubgroupEvents/Patients HR (95% CI)
Lenvatinib vs Sorafenib
Median (months)
Lenvatinib Sorafenib Lenvatinib Sorafenib
Overall 349/478 367/476 0.66 (0.57-0.77) 7.4 3.7
Age< 65 y≥ 65y
201/270148/208
223/283144/193
0.67 (0.55-0.82)0.61 (0.48-0.78)
7.37.4
3.65.4
SexMaleFemale
293/40551/73
308/40159/75
0.66 (0.56-0.77)0.75 (0.49-1.13)
7.47.4
3.74.6
RegionAsia-PacificWestern
249/321100/157
264/319103/157
0.61 (0.51-0.73)0.81 (0.61-1.08)
7.37.4
3.65.5
ECOG-PSPS = 0PS = 1
220/304129/174
233/301134/175
0.63 (0.52-0.76)0.70 (0.55-0.90)
7.47.3
3.73.7
Body weight< 60 kg≥ 60 kg
111/153238/325
121/146246/330
0.61 (0.46-0.79)0.69 (0.58-0.83)
7.47.4
3.63.7
MVI, EHS or bothYesNo
246/329103/149
265/336102/140
0.64 (0.54-0.77)0.73 (0.55-0.97)
7.39.2
3.65.6
AFP at baseline< 200 ng/mL≥ 200 ng/mL
186/255163/222
209/286157/187
0.68 (0.55-0.83)0.59 (0.47-0.75)
9.05.5
5.42.4
EtiologyHBVHCV
205/25970/103
199/244103/135
0.62 (0.50-0.75)0.78 (0.56-1.09)
7.37.4
3.65.3
BCLC stagingStage BStage C
72/104277/374
66/92301/384
0.70 (0.50-0.99)0.63 (0.53-0.75)
9.17.3
5.53.7
Posttreatmentanticancer therapy
YesNo
177/206172/272
204/243163/233
0.58 (0.47-0.72)0.70 (0.56-0.87)
7.28.0
3.63.7
Alcohol 19/33 18/23 0.27 (0.11–0.66) 8.8 3.9
Favors Lenvatinib Favors Sorafenib0.5 21
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
0.1
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Efficacy (Secondary Endpoint TTP)
0 3 6 9 12 15 18 2421 3630 42
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
Cu
mu
lati
ve p
rogr
essi
on
rat
e
Time (months)
27 3933
Number at riskLenvatinib 478 341 218 170 106 69 43 28 14 9 4 2 0 0
Sorafenib 476 258 139 94 55 41 33 22 14 9 4 2 2 0
Median (month) (95% CI)
Lenvatinib 8.9 (7.4–9.2)
Sorafenib 3.7 (3.6–5.4)
HR (95% CI): 0.63 (0.53–0.73)Log-rank Test: P-value: <0.00001
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Maximum Change in Tumour Size (investigator assessed per mRECIST)
Lenvatinib (n = 478) Sorafenib (n = 476) Effect size p value
Median OS, months95% CI
13.6 12.1-14.9
12.3 10.4-13.9
HR 0.92 (0.79–1.06) -
Median PFS, months95% CI
7.4 6.9-8.8
3.7 3.6-4.6
HR 0.66 (0.57–0.77) <0.0001
Median TTP, months95% CI
8.9 7.4-9.2
3.7 3.6-5.4
HR 0.63 (0.53–0.73) <0.0001
ORR, n (%)95% CI
115 (24.1)20.2–27.9
44 (9.2)6.6–11.8
OR 3.13 (2.15–4.56) <0.0001
CR 6 (1) 2 (<1) - -
PR 109 (23) 42 (9) - -
SD 246 (51) 244 (51) - -
Durable SD 167 (35) 139 (29) - -
PD 71 (15) 147 (31) - -
Unknown/NE 46 (10) 41 (9) - -
DCR, n (%)95% CI
361 (75.5)71.7–79.4
288 (60.5)56.1–64.9
- -
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Maximum Change in Tumour Size (masked, independent review per mRECIST)
Lenvatinib (n = 478) Sorafenib (n = 476) Effect size p value
Median PFS, months95% CI
7.35.6–7.5
3.63.6–3.7
HR 0.64 (0.55–0.75) <0.0001
Median TTP, months95% CI
7.47.2-9.1
3.7 3.6-3.9
HR 0.60 (0.51–0.71) <0.0001
ORR, n (%)95% CI
194 (40.6)36.2–45.0
59 (12.4)9.4–15.4
OR 5.01 (3.59–7.01) <0.0001
CR 10 (2) 4 (1) - -
PR 184 (38) 55 (12) - -
SD 159 (33) 219 (46) - -
Durable SD 84 (18) 90 (19) - -
PD 79 (17) 152 (32) - -
Unknown/NE 46 (10) 46 (10) - -
DCR, n (%)95% CI
353 (73.8)69.9–77.8
278 (58.4)54.0–62.8
- -
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Safety (treatment-emergent AEs)
Overview of TEAEs, n(%) Lenvatinib (n = 476) Sorafenib (n = 475)
Treatment-emergent adverse events (TEAEs)
Any TEAETreatment-related TEAE
470 (99)447 (94)
472 (99)452 (95)
Any TEAE ≥ grade 3Treatment-related TEAE ≥ grade 3
357 (75)270 (57)
316 (67)231 (49)
Any serious AETreatment-related serious TEAE
205 (43)84 (18)
144 (30)48 (10)
Dose modifications
Drug interruption due to related TEAEs 190 (40) 153 (32)
Dose reduction due to related TEAEs 176 (37) 181 (38)
Drug discontinuations due to related TEAEs 42 (9) 34 (7)
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
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Lenvatinib Phase III Non-inferiority Study: Safety (most frequent TEAEs)
AE ≥15% of patients, n (%) Lenvatinib (n=476) Sorafenib (n = 475)
Any grade Grade 3/4 Any grade Grade 3/4
Hypertension 201 (42) 111 (23) 144 (30) 68 (14)
Diarrhoea 184 (39) 20 (4) 220 (46) 20 (4)
Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1)
Decreased weight 147 (31) 36 (8) 106 (22) 14 (3)
Fatigue 141 (30) 18 (4) 119 (25) 17 (4)
Palmar-plantar erythordysesthesia 128 (27) 14 (3) 249 (52) 54 (11)
Proteinuria 117 (25) 27 (6) 54 (11) 8 (2)
Dysphonia 113 (24) 1 (<1) 57 (12) 0
Nausea 93 (20) 4 (1) 68 (14) 4 (1)
Decreased platelet count 87 (18) 26 (5) 58 (12) 16 (3)
Abdominal pain 81 (17) 8 (2) 87 (18) 13 (3)
Hypothyroidism 78 (16) 0 8 (2) 0
Vomiting 77 (16) 6 (1) 36 (8) 5 (1)
Constipation 76 (16) 3 (1) 52 (11) 0
Elevated AST 65 (14) 24 (5) 80 (17) 38 (8)
Rash 46 (10) 0 76 (16) 2 (<1)
Alopecia 14 (3) 0 119 (25) 0
Increased bilirubin 71 (15) 31 (7) 63 (13) 23 (5)
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
25
Lenvatinib Phase III Non-inferiority Study: Health-related quality of life
Baseline scores on the EORTC QLQ-C30 and HCC-specific QLQ-HCC18 questionnaires were similar between the lenvatinib- and sorafenib-treated patients• Following treatment, scores declined in both treatment groups
Compared with lenvatinib-treated patients, it was observed that those treated with sorafenib experienced (nominal p<0.05):
• Earlier worsening of role functioning, pain, and diarrhoea scores from QLQ-C30
• Earlier deterioration of nutrition and body image from QLQ-HCC18
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
26
• Lenvatinib demonstrated non-inferiority versus sorafenib in OS in patients with unresectable HCC (13.6 months vs 12.3 months, for lenvatinib and sorafenib respectively)
• Lenvatinib treatment resulted in statistically significant improvements in PFS, TTP, ORR vs sorafenib
• The safety profiles of lenvatinib was consistent with the known safety profiles of this TKI in HCC
• No new safety signals were reported for either agent
Lenvatinib Phase III Non-inferiority Study: Conclusions
Lenvatinib may be a potential first-line systemic treatment option in patients with advanced, unresectable HCC
Kudo M et al. Lancet. 2018 Feb 9. pii: S0140-6736(18)30207-1. [Epub ahead of print].
Training HCC – Module 4 Internal Ipsen
Phase Ib Lenvatinib + Pembrolizumab
Ikeda et al. @ASCO 2018
A Phase 1b Trial of Lenvatinib (LEN) Plus Pembrolizumab
in Patients With Unresectable HCC
ORR: 42%
Lenvatinib combination ongoing phase III trials: Trial design
AdvancedHCC & VHB infection
1:1
Nivolumab 480 mg every 4w
+
Lenvatinib 12 mg/day
(8mg in < 60Kg)
Lenvatinib 12 mg/day
(8mg in < 60Kg)
Treatment until disease
Progression or unaceptable
toxicity
Primary objective:Overall survival
Secondary objectives:PFSResponse rateToxicity and Quality of Live
216 ptes
ClinicalTrials.gov Identifier: NCT04044651
Lenvatinib combination ongoing phase III trials: Trial design
AdvancedHCC 1:1
Pembrolizumab 200 mg every 3w
+
Lenvatinib 12 mg/day
(8mg in < 60Kg)
Lenvatinib 12 mg/day
(8mg in < 60Kg)
Treatment until disease
Progression or unaceptable
toxicity
Primary objective:Overall survivalPFS
Secondary objectives:Response rateToxicity and Quality of LivePharmacokinetic assessment
750 ptes
ClinicalTrials.gov Identifier: NCT03713593