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..

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;13:164-171. Pietrantonio F, et al. Eur J Cancer. 2015;51:587-594. Kopetz S, et al. J Clin Oncol. 2015;33:4032-4038. Hong DS, et al. Cancer Discov. 2016;6:1352-1365. Kopetz S, et al. ASCO 2017. Abstract 3505. Slide credit: clinicaloptions.com References in slidenotes.

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 2017. Abstract 3505. ClinicalTrials.gov. NCT02164916.

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 2017. Abstract 3505.

SWOG S1406: PFS (Primary Endpoint) 100 Events, n mPFS (95% CI) VIC 40 4.3 (3.6-5.7) IC 48 2.0 (1.8-2.1) 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: 0.31-0.75; 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 2017. Abstract 3505. Reproduced with permission.

SWOG S1406: OS, Response 100 mOS, Mos 95% CI VIC 9.6 (7.5-13.1) IC 5.9 (3.0-9.9) In crossover pts, mOS: 12.1 mos (95% CI: 4.5-12.5) 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: 0.45-1.17; 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 2017. Abstract 3505. Reproduced with permission.

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 2017. Abstract 3505.

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 2017. Abstract 3505.

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