1. SWOG S1406: Vemurafenib in Combination With Irinotecan and Cetuximab in BRAF V600E Metastatic CRC
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
CRC, colorectal cancer.
This activity is supported by educational grants by AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co, Inc..

2. SWOG S1406: Background
BRAF V600E: mutation leading to constitutive activation of BRAF kinase and MAPK pathway[1]
BRAF mutated in ~ 8% of mCRC cases
Associated with aggressive disease, poor prognosis, minimal benefit from standard chemotherapy[2]
Vemurafenib: kinase inhibitor selective for mutated BRAF protein[3]
Vemurafenib monotherapy associated with limited activity in mCRC
Phase I study suggested improved survival and response in combination with irinotecan + cetuximab in refractory mCRC with BRAF V600E[4]
Current study evaluated efficacy and safety of vemurafenib addition to irinotecan + cetuximab in pts with BRAF V600E mCRC[5]
mCRC, metastatic colorectal cancer
References:
Morris VK, et al. Clin Colorectal Cancer. 2014;13:
Pietrantonio F, et al. Eur J Cancer. 2015;51:
Kopetz S, et al. J Clin Oncol. 2015;33:
Hong DS, et al. Cancer Discov. 2016;6:
Kopetz S, et al. ASCO Abstract 3505.
Slide credit: clinicaloptions.com
References in slidenotes.

3. Until PD; crossover allowed to vemurafenib arm after PD
SWOG S1406: Study Design
Randomized, multicenter, open-label phase II trial
Stratified by prior irinotecan treatment (yes vs no)
Randomized 1:1
Vemurafenib 960 mg PO BID + Cetuximab 500 mg/m2 IV Q2W + Irinotecan 180 mg/m2 IV Q2W
(n = 49)
Pts with mCRC, extended RAS WT and BRAF V600E, previously treated with 1-2 systemic CT lines for metastatic or advanced unresectable disease, no prior panitumumab or cetuximab, no prior BRAF or MEK inhibitors, ECOG PS 0-1
(N = 106)*
Until PD
Until PD; crossover allowed to vemurafenib arm after PD
Cetuximab 500 mg/m2 IV Q2W + Irinotecan 180 mg/m2 IV Q2W
(n = 50)
*Only 99 pts eligible to receive treatment after randomization.
AE, adverse event; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PD, progressive disease; PS, performance status; WT, wild type
Primary endpoint: PFS
Secondary endpoints: OS, ORR, treatment-related AEs
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract ClinicalTrials.gov. NCT

4. SWOG S1406: Baseline Characteristics
Characteristic, n (%)
VIC (n = 49)
IC (n = 50)
Median age, yrs (range)
60 (34-83)
62 (31-83)
Female
21 (43)
37 (74)
Race
White
Black
Asian
43 (88)
1 (2)
4 (8)
49 (98)
0 (0)
Hispanic ethnicity
2 (4)
ECOG PS 1
25 (51)
27 (54)
Prior irinotecan
20 (41)
19 (38)
Prior regimens for mCRC 1 2
Failed adjuvant within 6 mos
27 (55)
19 (39)
3 (6)
26 (52)
17 (34)
7 (14)
ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PS, performance status, IC, irinotecan, cetuximab; m, median; VIC, vemurafenib, irinotecan, cetuximab.
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract 3505.

5. SWOG S1406: PFS (Primary Endpoint)
100
Events, n mPFS (95% CI)
VIC ( )
IC ( )
Median follow-up: 7.3 mos
Among 48% of pts who crossed over to VIC after PD on IC, mPFS was 5.8 mos
PFS significantly prolonged with vemurafenib in most subgroups
Significant benefit in pts with tumors on right vs left/rectum, no prior irinotecan, MSS, or mutated PIK3CA 80
HR: 0.48 (95% CI: ; P = .001) 60
PFS (%) 40
IC, irinotecan, cetuximab; m, median; MSS, microsatellite stable; PD, progressive disease; VIC, vemurafenib, irinotecan, cetuximab. 20 3 6 8 10 12 14
Mos
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract Reproduced with permission.

6. SWOG S1406: OS, Response
100
mOS, Mos
95% CI
VIC
9.6
( ) IC
5.9
( )
In crossover pts, mOS: 12.1 mos (95% CI: )
Distribution of responses significantly different with addition of vemurafenib vs IC alone (Chi-squared P = .001) 3 6 9 12 15 18 80 60
OS (%)
Endpoint, %
VIC (n = 44)*
IC (n = 47)*
Crossover (n = 24)†
PR‡ 16 4 17 SD 50 55
PD§ 18 66 NR
DCR 67 22 72 40
DCR, disease control rate; IC, irinotecan, cetuximab; m, median; NR, not reported; PD, progressive disease; SD, stable disease; VIC, vemurafenib, irinotecan, cetuximab. 20
HR: 0.73 (95% CI: ; P = .19)
*Measurable disease in 93 pts overall. †Excludes 6 pts (2 pts without PD before crossover, 4 pts without measurable disease). ‡Includes confirmed and unconfirmed. §Includes symptomatic deterioration.
Mos
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract Reproduced with permission.

7. SWOG S1406: Safety
AE-related discontinuations more common with vemurafenib combination (16%) vs cetuximab + irinotecan alone (6%)
Median duration of treatment imbalanced between arms
88 days for VIC
47 days for IC
Grade 3/4 AE, n (%)
VIC (n = 46)
IC (n = 46)
Anemia
6 (13)
0 (0)
Dehydration
5 (11)
3 (7)
Diarrhea
11 (24)
Febrile neutropenia
2 (4)
Fatigue
7 (15)
Neutropenia
15 (33)
Rash
Hypomagnesemia
Nausea
9 (20)
1 (2)
Arthralgia
AE, adverse event; IC, irinotecan, cetuximab; VIC, vemurafenib, irinotecan, cetuximab.
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract 3505.

8. SWOG S1406: Investigator Conclusions
Addition of vemurafenib to cetuximab + irinotecan associated with significantly prolonged PFS in mCRC pts with BRAF V600E
mPFS: 4.3 vs 2.0 mos, respectively (HR: 0.48; P = .001)
PFS benefit observed across most subgroups
Addition of vemurafenib associated with benefit in pts crossing over after PD on IC alone
mPFS: 5.8 mos; mOS: 12.1 mos
mOS numerically higher with VIC (9.6 mos) vs IC alone (5.9 mos), but did not reach statistical significance (HR: 0.73; P = .19)
Analysis limited by 48% crossover to VIC after PD on IC alone
Investigators concluded that VIC is a new treatment for BRAF V600E mCRC
IC, irinotecan, cetuximab; m, median; mCRC, metastatic colorectal cancer; PD, progressive disease; VIC, vemurafenib, irinotecan, cetuximab.
Slide credit: clinicaloptions.com
Kopetz S, et al. ASCO Abstract 3505.

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