1. REFLECT: Phase III Noninferiority Study of the Multikinase Inhibitor Lenvatinib vs Sorafenib as First-line Therapy in Unresectable Hepatocellular Carcinoma
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. First-line Lenvatinib vs Sorafenib in Pts With Unresectable HCC: Background
Sorafenib is the only FDA-approved systemic agent for unresectable HCC, a leading cause of cancer death in need of new therapies[1,2]
In a phase III trial, sorafenib extended survival in pts with advanced HCC[3]
Sunitinib, brivanib, linifanib, and erlotinib + sorafenib each failed to demonstrate noninferior or superior OS vs sorafenib in pts with advanced HCC in phase III trials[4-7]
Lenvatinib: multikinase inhibitor of VEGF1-3, FGF1-4, PDGFRα, RET, and KIT[8]
In a phase II study, showed activity in pts with advanced HCC
Current phase III REFLECT study compared lenvatinib vs sorafenib in pts with unresectable HCC[9]
HCC, hepatocellular carcinoma.
References:
1. Ferlay J, et al. Int J Cancer. 2015;136:E359-E386.
2. Sorafenib [package insert]
3. Llovet JM, et al. N Engl J Med. 2008;359:
4. Cheng AL, et al. J Clin Oncol. 2013;31:
5. Johnson PJ, et al. J Clin Oncol. 2013;31:
6. Cainap C, et al. J Clin Oncol. 2015;33:
7. Zhu AX, et al. J Clin Oncol. 2015;33:
8. Ikeda K, et al. J Gastroenterol. 2017;52:
9. Cheng AL, et al. ASCO Abstract 4001.
Slide credit: clinicaloptions.com
References in slidenotes.

3. 8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD
REFLECT: Study Design
Multicenter, randomized, open-label phase III noninferiority study
Stratified by region (Asia-Pacific vs Western), MVI and/or EHS (yes vs no), ECOG PS (0 vs 1), and BW (< vs ≥ 60 kg)
Lenvatinib
8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD
(n = 478)
Pts with unresectable HCC, no prior systemic therapy, ≥ 1 measurable target lesion, BCLC stage B/C, Child-Pugh A, ECOG PS 0/1, and adequate organ function
(N = 954)
Sorafenib
400 mg BID
(n = 476)
BCLC, Barcelona Clinic Liver Cancer; BW, body weight; CBR, clinical benefit rate; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; MVI, macroscopic portal vein invasion; PK, pharmacokinetic; PS, performance status; QoL, quality of life; TTP, time to progression.
Primary endpoint: OS
Noninferiority margin 1.08; criteria met if upper limit of 2-sided 95% CI for HR < 1.08
Secondary endpoints: PFS, TTP, ORR, QoL, lenvatinib PK
Other endpoints: DCR, CBR, exploratory biomarker analysis
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.

4. REFLECT: Baseline Characteristics
Lenvatinib
(n = 478)
Sorafenib
(n = 476)
Mean age, yrs
61.3
61.2
Male, n (%)
405 (85)
401 (84)
Region, n (%)
Western
Asia-Pacific
157 (33)
321 (67)
319 (67)
Body weight, n (%)
< 60 kg
≥ 60 kg
153 (32)
325 (68)
146 (31)
330 (69)
ECOG PS, n (%) 1
304 (64)
174 (36)
301 (63)
175 (37)
MVI and/or EHS diagnosis, n (%)
329 (69)
336 (71)
BL AFP level, n (%)
< 200 ng/mL
≥ 200 ng/mL
255 (53)
222 (46)
286 (60)
187 (39)
Median BL AFP level, ng/mL
133.1
71.2
Characteristic, n (%)
Lenvatinib
(n = 478)
Sorafenib
(n = 476)
Child-Pugh class A B
475 (99)
3 (1)
471 (99)
5 (1)
BCLC stage
B (intermediate)
C (advanced)
104 (22)
374 (78)
92 (19)
384 (81)
Involved disease sites per pt 1 2
≥ 3
207 (43)
167 (35)
103 (22)
207 (44)
183 (38)
86 (18)
Etiology of chronic liver disease
HBV
HCV
Alcohol
Other
Unknown
251 (53)
91 (19)
36 (8)
38 (8)
62 (13)
228 (48)
126 (27)
21 (4)
32 (7)
69 (15)
Concomitant HBV/HCV therapy
163 (34)
149 (31)
AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BL, baseline; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HBV, hepatitis B virus; HCV, hepatitis C virus; MVI, macroscopic portal vein invasion; PS, performance status.
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.

5. REFLECT: OS (Primary Endpoint)
1.0
Median, mos (95% CI)
Lenvatinib: 13.6 (12.1−14.9)
Sorafenib: 12.3 (10.4−13.9)
0.9
0.8
0.7
0.6
HR: 0.92 (95% CI: )
Probability of OS
0.5
0.4
0.3
0.2
0.1 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n
478
476
436
440
374
348
297
282
253
230
207
192
178
156
140
116
102 83 67 57 40 33 21 16 8 2 4
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract Reproduced with permission.

6. REFLECT: PFS by mRECIST
1.0
Median, mos (95% CI)
Lenvatinib: 7.4 (6.9−8.8)
Sorafenib: 3.7 (3.6−4.6)
0.9
0.8
0.7
0.6
HR: 0.66 (95% CI: )
Log-rank test: P <
Probability of PFS
0.5
0.4
0.3
0.2
0.1 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n
478
476
345
262
223
140
172 94
106 56 69 41 44 33 28 22 14 9 4 2 2
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract Reproduced with permission.

7. REFLECT: Other Efficacy Outcomes
Outcome,* Mos (95% CI)
Lenvatinib
(n = 478)
Sorafenib
(n = 476)
OR (95% CI)
P Value
ORR, % (95% CI)
CR, n (%)
PR, n (%)
SD, n (%)
Durable SD, n (%)
PD, n (%)
Unknown/NE, n (%)
24.1 ( )
6 (1.3)
109 (22.8)
246 (51.5)
167 (34.9)
71 (14.9)
46 (9.6)
9.2 ( )
2 (0.4)
42 (8.8)
244 (51.3)
139 (29.2)
147 (30.9)
41 (8.6)
3.13 ( )
<
DCR, % (95% CI)
75.5 ( )
60.5 ( )
Median TTP
8.9 ( )
3.7 ( )
0.63 ( )
DCR, disease control rate; mRECIST, modified Response Evaluation Criteria In Solid Tumors; NE, not estimable; PD, progressive disease; SD, stable disease; TTP, time to progression.
*Tumor assessments according to mRECIST by investigator.
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.

8. REFLECT: Safety and QoL
Health-related QoL
Baseline QoL scores similar between arms, both decreasing after treatment
Role functioning, pain, diarrhea, nutrition, and body image QoL scores decreased earlier with sorafenib vs lenvatinib (nominal P < .05)
TEAEs, n (%)
Lenvatinib
(n = 476)
Sorafenib
(n = 475)
Any
Tx related
470 (99)
447 (94)
472 (99)
452 (95)
Grade ≥ 3
357 (75)
270 (57)
316 (67)
231 (49)
Serious
205 (43)
84 (18)
144 (30)
48 (10)
Tx related causing dose modification
Reduction
Reduction/interruption
Discontinuation
176 (37)
252 (53)
42 (9)
181 (38)
236 (50)
34 (7)
QoL, quality of life; TEAE, treatment-emergent adverse event; Tx, treatment.
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.

9. REFLECT: Most Common TEAEs
TEAEs Occurring in
≥ 15% of Pts, n (%)
Lenvatinib
(n = 476)
Sorafenib
(n = 475)
Any
Grade 3/4
Hypertension
201 (42)
111 (23)
144 (30)
68 (14)
Diarrhea
184 (39)
20 (4)
220 (46)
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)
Hand-foot syndrome
128 (27)
249 (52)
54 (11)
Proteinuria
117 (25)
27 (6)
8 (2)
Dysphonia
113 (24)
1 (< 1)
57 (12)
Nausea
93 (20)
4 (1)
TEAEs Occurring in ≥ 15% of Pts, n (%)
Lenvatinib
(n = 476)
Sorafenib
(n = 475)
Any
Grade 3/4
Decreased platelet count
87 (18)
26 (6)
58 (12)
16 (3)
Abdominal pain
81 (17)
8 (2)
13 (3)
Hypothyroidism
78 (16)
Vomiting
77 (16)
6 (1)
36 (8)
5 (1)
Constipation
76 (16)
3 (1)
52 (11)
Elevated AST
65 (14)
24 (5)
80 (17)
38 (8)
Rash
46 (10)
2 (< 1)
Alopecia
14 (3)
119 (25)
AST, aspartate aminotransferase; NA, not applicable; TEAE, treatment-emergent adverse event.
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.

10. Conclusions
In pts with unresectable HCC and no prior systemic therapy for HCC, lenvatinib demonstrated noninferior OS vs sorafenib
Median OS: 13.6 (95% CI: ) vs 12.3 mos (95% CI: ); HR: (95% CI: )
Lenvatinib significantly increased PFS, TTP, and ORR vs sorafenib
Safety profiles for both agents appeared consistent with those previously reported in HCC
Most common all-grade TEAEs in lenvatinib arm: hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), fatigue (30%), hand-foot syndrome (27%)
Investigators conclude that lenvatinib may be potential treatment option for advanced HCC
HCC, hepatocellular carcinoma; TEAE, treatment-emergent adverse event; TTP, time to progression.
Slide credit: clinicaloptions.com
Cheng AL, et al. ASCO Abstract 4001.
Slide credit: clinicaloptions.com

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