First line treatment for metastatic colorectal cancer Chih-Yi Chen 2017.03.29~30

Outline Introduction Chemotherapy First-Line target therapies Treatment comparative Conclusion

Introduction Colorectal cancer is the third most common cancer worldwide. Approximately 25% of patients with colorectal cancer present with overt metastatic disease, and metastatic disease develops in 40 to 50% of newly diagnosed patients.

Introduction Stage IV colon cancer is divided into stage IVA and stage IVB. Stage IVA: Cancer may have spread through the colon wall and may have spread to nearby organs or lymph nodes. Cancer has spread to one organ that is not near the colon, such as the liver, lung, or ovary, or to a distant lymph node. Stage IVB: Cancer may have spread through the colon wall and may have spread to nearby organs or lymph nodes. Cancer has spread to more than one organ that is not near the colon or into the lining of the abdominal wall.

Introduction Unresectable metastatic colorectal cancer is generally not curable with current technology. Management centers around palliation and control of symptoms, control of tumor growth, and attempts to lengthen progression-free and overall survival. DeVita Jr. MD, Vincent T. 「DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology

Chemotherapy

Historical development Oxaliplatin (2004) 5-FU+ Leucovorin (1991) Irinotecan (2000) 5-FU (1962) Capecitabine (2001) The regulatory approvals described in this timeline refer to those made by the FDA in the USA. Although not shown in the timeline, 5-FU was first approved by the FDA in 1962. Abbreviations: 5-FU, 5-fluorouracil; ALL, acute lymphoblastic leukaemia; CRC, colorectal cancer; dUTPase, deoxyuridine triphosphate nucleotidohydrolyase; NSCLC, non-small-cell lung cancer; PK/PD, pharmacokinetic/pharmacodynamics; TFT, trifluorothymidine; TS, thymidylate synthase. Nature Reviews Clinical Oncology 11, 282–298 (2014) doi:10.1038/nrclinonc.2014.51

Median overall survival of selected regimens Median overall survival of selected regimens. Abbreviations: 5-FU/LV, 5-fluorouracil/leucovorin; FOL-FIRI, irinotecan/5-fluorouracil/leucovorin; FOLFOX, oxaliplatin/5-fluorouracil/leucovorin; IFL, irinotecan/bolus 5-fluorouracil/leucovorin; OS, overall survival. Richard M. Goldberg The Oncologist 2006;11:981-987 ©2006 by AlphaMed Press

progression or unacceptable toxicity GERCOR Study Patients No prior mCRC treatment Adjuvant chemotherapy allowed if >6 mo before inclusion 226 patients FOLFIRI FOLFOX6 FOLFIRI FOLFOX6 Treat to progression Primary outcome: second PFS progression or unacceptable toxicity Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229.

Efficacy Time to second progression Overall survival 21.5 14.2 20.6 10.9 Both sequences achieved a prolonged survival and similar efficacy. Mucositis, nausea/vomiting, and alopecia were more frequent with FOLFIRI, and neutropenia and neurosensory toxicity were more frequent with FOLFOX6.

No prior mCRC treatment Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With FOLFIRI As First-Line Treatment for Metastatic Colorectal Cancer Patients No prior mCRC treatment Previous fluoropyrimidine-based adjuvant chemotherapy allowed if >6 mo before inclusion 244 patients FOLFIRI FOLFOXIRI Treat to progression Data have suggested that exposure to all the three main active cytotoxic agents obtains the best outcome in unresectable patients, but that only 50% to 80% of patients can be exposed to all three drugs in a sequential strategy with doublets. Primary end point: response rate Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25:1670.

Objective Responses

Survival progression-free survival overall survival 9.8 22.6 6.9 16.7 The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics.

Target therapies

Target therapies development 2004 bevacizumab cetuximab 2006 panitumumab 2012 ziv-aflibercept regorafenib 2015 ramucirumab

First-Line Treatment: Anti- VEGF Therapy

Tumor angiogenesis Angiogenesis is a necessary part of the process in the progression of cancer from small, localized neoplasms to larger, growing, and potentially metastatic tumors. To grow beyond 1 to 2 mm in diameter, a tumor needs an independent blood supply, which is acquired by the expression of growth factors that recruit new vasculature from existing blood vessels. This process continues even as the tumor matures. Thus, upregulation of angiogenesis is a key step in sustained tumor growth and may also be critical for tumor metastasis.1-4 Biooncology.com. (2017). Tumor Angiogenesis and the VEGF pathway | BioOncology. [online] Available at: https://www.biooncology.com/pathways/vegf/vegf-tumor-angiogenesis.html [Accessed 20 Mar. 2017].

The VEGF signaling pathway 1. Upstream activators stimulate the production of VEGF. 2. VEGF binds to receptors on endothelial cells. 3. Angiogenesis is mediated primarily through the interaction of VEGF-A with VEGFR-2. 4. Other variants of the VEGF ligand and receptor play a secondary role in this process. VEGF ligands mediate their angiogenic effects by binding to specific VEGF receptors, leading to subsequent signal transduction. VEGF = vascular endothelial growth factor

Treat to progression or for 96 weeks Patients No prior mCRC treatment Adjuvant 5-FU containing chemotherapy allowed if >12 mo between tx and relapse Primary outcome: overall survival N=813 IFL + placebo 1:1 Randomization IFL + bevacizumab Irinotecan 125 mg/m2 Once weekly for 4 wk; cycle repeated every 6 wk Fluorouracil 500 mg/m2 Leucovorin 20 mg/m2 Bevacizumab 5 mg/kg Every 2 wk Treat to progression or for 96 weeks Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004

Efficacy The addition of bevacizumab to bolus IFL conferred a clinically meaningful and statistically significant improvement in overall survival, progression-free survival, and response rate. Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.

Bevacizumab + XELOX or FOLFOX-4 Treat to progression or for 48 weeks Patients Unresectable mCRC No prior systemic therapy for MCRC or previous treatment with oxaliplatin or bevacizumab were allowed. Primary end point was progression-free survival (PFS). N= 1401 Placebo + XELOX or FOLFOX-4 1:1:1:1 Randomization Bevacizumab or placebo (bevacizumab vehicle) was administered as a 30- to 90-minute intravenous infusion before oxaliplatin at a dose of 7.5 mg/kg on day 1 of a 3-week cycle when given with XELOX or 5 mg/kg on day 1 of a 2-week cycle when given with FOLFOX-4. XELOX consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1,000 mg/m2 twice daily on days 1 through 14 (28 doses) of a 21-day cycle. Bevacizumab + XELOX or FOLFOX-4 Treat to progression or for 48 weeks Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as rst-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013-2019.

Survival Overall Survival Progression-free Survival Overall Survival The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with mCRC.

Median time to event (months) Overall survival Treatment subgroup comparison No. of events Median time to event (months) Hazard ratio (97.5% CI) FOLFOX4/FOLFOX4-placebo/ FOLFOX4-bevacizumab 847 19.5 0.95 (0.85 –1.06) XELOX/XELOX-placebo/ XELOX-bevacizumab 820 19.8 FOLFOX4/FOLFOX4-placebo 573 18.9 0.95 (0.83 –1.09) XELOX/XELOX-placebo 546 19.0 274 21.0 0.95 (0.78 –1.15) 21.6 FOLFOX4 284 17.7 0.87 (0.72 –1.05) XELOX 266 18.8 updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer. Cassidy, J., Clarke, S., Díaz-Rubio, E., Scheithauer, W., Figer, A., Wong, R., Koski, S., Rittweger, K., Gilberg, F. and Saltz, L. (2011). XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. British Journal of Cancer, 105(1), pp.58-64.

TRIBE Study Treat to progression Patients Unresectable mCRC No prior mCRC treatment Adjuvant oxaliplatin-containing chemotherapy allowed if >12 mo. between tx and relapse Primary endpoint was progression-free survival N=508 FOLFIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) 1:1 Randomization FOLFOXIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) bevacizumab (intravenous dose of 5 mg/kg) plus either FOLFIRI, consisting of a 180 mg/m2 intravenous infusion of irinotecan for 60 min followed by a 200 mg/m2 intravenous infusion of leucovorin for 120 min, a 400 mg/m2 intravenous bolus of fluorouracil, and a 2400 mg/m2 continuous infusion of fluorouracil for 46 h FOLFOXIRI, consisting of a 165 mg/m2 intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m2 intravenous infusion of oxaliplatin given concurrently with leucovorin at a dose of 200 mg/m2 for 120 min, followed by a 3200 mg/m2 continuous infusion of fluorouracil for 48 h. Treatment cycles were repeated every 14 days for up to 12 cycles Treat to progression Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as rst-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 2015;16:1306-1315.

Efficacy overall survival 29.8 25.8 FOLFOXIRI plus bevacizumab as a valuable option for the first-line treatment of patients with metastatic colorectal cancer.

Indication approved by FDA in USA Bevacizumab Trade name Avastin (100 mg/4 mL/vial) Indication approved by FDA in USA Metastatic colorectal cancer, with intravenous 5-fluorouracil–based chemotherapy for first-or second-line treatment. Metastatic colorectal cancer, with fluoropyrimidine-irinotecan-or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin containing regimen. Indications approved by MOHW 轉移性大腸直腸癌(mCRC)： Avastin (bevacizumab)與含有irinotecan/5-fluorouracil/leucovorin或5-fluorouracil/leucovorin的化學療法合併使用，可以作為轉移性大腸或直腸癌患者的第一線治療。 Avastin與含有5-fluorouracil/leucovorin/oxaliplatin的化學療法合併使用，可以作為先前接受過以fluoropyrimidine為基礎的化學療法無效且未曾接受過Avastin治療的轉移性大腸或直腸癌患者的治療。 Avastin (bevacizumab)與含有fluoropyrimidine-oxaliplatin-為基礎的化學療法合併使用，可以做為第一線已接受過以Avastin併用fluoropyrimidine-irinotecan-為基礎的化療後惡化之轉移性大腸或直腸癌患者的第二線治療。 Reimbursement rate 9055元/vial Reimbursement regulation 9.37.Bevacizumab (如Avastin)：（100/6/1、101/05/1、106/4/1) 1.轉移性大腸或直腸癌： (1)Bevacizumab 與含有irinotecan/ 5-fluorouracil/ leucovorin或5-fluorouracil/ leucovorin的化學療法合併使用，作為轉移性大腸或直腸癌患者的第一線治療。 (2)使用總療程以36週為上限(106/4/1)。 (3)須經事前審查核准後使用，每次申請事前審查之療程以18週為限，再次申請必須提出客觀證據（如：影像學）證實無惡化，才可繼續使用。(106/4/1)

First-Line Treatment: Anti- EGFR Therapy

Agents targeting the EGFR Particularly in view of their expense and toxicity, the identification of patients who are most likely to respond to the anti-EGFR monoclonal antibodies cetuximab or panitumumab is an important clinical question. Tumor overexpression of several genes involved in the EGFR signaling pathway and downstream events might identify patients who are most likely to respond to anti-EGFR agents.

Agents targeting the EGFR It is now well established that activating mutations in KRAS, which result in constitutive activation of the RAS-RAF-ERK pathway, result in resistance to anti-EGFR therapy.

cetuximab plus FOLFIRI The CRYSTAL  study Patients Unresectable mCRC No prior mCRC treatment Adjuvant chemotherapy allowed if >6 mo between tx and relapse Primary end point was progression-free survival time N=1198 cetuximab plus FOLFIRI 1:1 Randomization FOLFIRI On day 1 of each 14-day period during the study, patients in the FOLFIRI group received a 30- to 90-minute infusion of irinotecan at a dose of 180 mg per square meter of body-surface area; an in- fusion, for 120 minutes, of racemic leucovorin or l-leucovorin at a dose of 400 or 200 mg, respec- tively, per square meter of body-surface area; fluo- rouracil in a bolus of 400 mg per square meter of body-surface area and then continuous infusion for 46 hours of 2400 mg per square meter of body- surface area. During the study, patients in the cetuximab– FOLFIRI group received cetuximab in an initial 120-minute infusion on day 1 of 400 mg per square meter of body-surface area, followed by 60- minute infusions of cetuximab at a dose of 250 mg per square meter of body-surface area, once week- ly Treat to progression Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 april 2, 2009

Progression-free survival HR: 0.68 (95% CI, 0.50 to 0.94) P=0.02 9.9 8.7 HR: 0.85 (95% CI, 0.72 to 0.99; P=0.048) 8.9 8.0 0.85 (95% CI, 0.72 to 0.99; P=0.048

Overall Survival HR: 0.93 (95% CI, 0.81 to 1.07; P=0.31 0.84 (95% CI, 0.64 to 1.11) 24.9 21.0 19.9 18.6 This trial provides confirmation that, cetuximab plus FOLFIRI reduces the risk of progression of metastatic colorectal cancer when used as the first-line treatment and that this benefit is seen mainly in patients with wild-type–KRAS tumors. The incidence rates of grade 3 or 4 diarrhea, skin reactions, and infusion-related reactions were significantly higher with cetuximab plus FOLFIRI.

The OPUS study Treat to progression Patients No prior mCRC treatment adjuvant C/T was allowed Primary end point was response N= 337, 179 → WT KRAS cetuximab + FOLFOX4 1:1 Randomization FOLFOX4 FOLFOX-4 (oxaliplatin 85 mg/m2; folinic acid 200 mg/m2, followed by 5-FU, as a 400 mg/m2 intravenous bolus then a 600 mg/m2 infusion over 22 h, days 1 and 2 of a 14-day cycle) with or without cetuximab (initial dose 400 mg/m2 and 250 mg/m2/week thereafter) Treat to progression Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22:1535-1546..

Response KRAS-wt KRAS/BRAF-wt MT KRAS 34 0.0027 57 36 0.0029 60 53 0.029 7.2 0.0064 8.3 0.0083 8.6 0.0153 5.5 FOLFOX + C PFS FOLFOX RR

Overall survival The addition of cetuximab to FOLFOX-4 as first-line therapy for mCRC improved clinical outcome compared with FOLFOX-4 alone in patients whose tumors were wild type for KRAS and confirmed KRAS tumor mutation status as a clinically useful predictive factor for the efficacy of cetuximab plus FOLFOX-4 in relation to response and PFS.

Indication approved by FDA in USA Cetuximab Trade name Erbitux (100 mg/20 mL/vial) Indication approved by FDA in USA K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by FDA-approved tests in combination with FOLFIRI for first-line treatment, in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. Limitation of Use: Erbitux is not indicated for treatment of Ras-mutant colorectal cancer. Indications approved by MOHW Erbitux適用於治療具表皮生長因子受體表現型(EGFR expressing)，RAS原生型(wild-type)之轉移性直腸結腸癌患者 • 與FOLFIRI (Folinic acid/ 5-FU/ Irinotecan)合併使用之第一線治療。 • 與FOLFOX合併使用之第一線治療。 Reimbursement rate 5998元/vial Reimbursement regulation 9.27.Cetuximab（如Erbitux）：(104/11/1、106/1/1) 1.直腸結腸癌治療部分： (1)與FOLFIRI或FOLFOX合併使用於治療具表皮生長因子受體表現型(EGFR expressing)，RAS原生型之轉移性直腸結腸癌病患之第一線治療。(104/11/1、106/1/1) I.本藥品需經事前審查核准後使用，每次申請事前審查之療程以18週為限，再次申請必須提出客觀證據（如：影像學）證實無惡化，才可繼續使用。 II.使用總療程以36週為上限。 III.本藥品不得與bevacizumab併用。 (2)與irinotecan合併使用，治療已接受過含5-fluorouracil (5-FU)、irinotecan及oxaliplatin二線以上之細胞毒性治療失敗、具有表皮生長因子受體(EGFR)表現型且K-ras基因沒有突變的轉移性直腸結腸癌的病患。(98/8/1) I.本藥需經事前審查核准後使用，每次申請事前審查之療程以9週為限，再次申請必須提出客觀證據（如：影像學）證實無惡化，才可繼續使用。 II.使用總療程以18週為上限。

The PRIME Study Treat to progression Patients No prior mCRC treatment Fluorouracil- based adjuvant C/T allowed if >6 mo between tx and relapse. However, prior oxaliplatin wasn’t allowed. Primary end point was progression-free survival time N=1183, 656 → WT KRAS 440 →MT KRAS Panitumumab + FOLFOX4 1:1 Randomization FOLFOX4 Panitumumab was administered intravenously (IV) over 1 hour at 6 mg/kg every 2 weeks on day 1 before FOLFOX4 chemotherapy. If tolerated, subsequent infusions could be administered over 30 minutes. FOLFOX4 was administered every 2 weeks as oxaliplatin 85 mg/m2 IV infusion on day 1 and leucovorin 200 mg/m2 (or equivalent) IV infusion followed by fluorouracil 400 mg/m2 IV bolus and 600 mg/m2 22-hour continuous infusion on days 1 and 2. Treatment was administered until progression or unacceptable toxicity Treat to progression Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional uorouracil, leucovorin, and oxaliplatin versus alone as first line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME 7 study. J Clin Oncol 2010;28:4697-4705.

Progression-free survival wild-type (WT) KRAS mutant (MT) KRAS 8.8 7.3 9.6 8.0

Overall survival wild-type (WT) KRAS mutant (MT) KRAS 19.3 15.5 23.9 19.7 In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS. In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm. Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy.

Vectibix (100 mg/5 mL/vial) Indication approved by FDA in USA Panitumumab Trade name Vectibix (100 mg/5 mL/vial) Indication approved by FDA in USA Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: In combination with FOLFOX for first-line treatment. As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown. Indications approved by MOHW 治療RAS基因正常之轉移性大腸直腸癌(mCRC)成人病患： １、與FOLFOX 併用作為第一線療法。 ２、在接受含有Fluoropyrimidine、Oxaliplatin與Irinotecan之化學療法失敗後，作為單一療法使用。 Reimbursement rate 13222元/vial Reimbursement regulation 9.53. Panitumumab (如Vectibix)：(105/4/1) 1.與FOLFOX(folinic acid/5-fluorouracil/oxaliplatin)合併使用於治療K-RAS基因及N-RAS基因沒有突變之轉移性直腸結腸癌病患之第一線治療。 2.本藥品需經事前審查核准後使用，每次申請事前審查之療程以12週為限，再次申請必須提出客觀證據（如：影像學）證實無惡化，才可繼續使用。 3.使用總療程以24週為上限。 4.Vectibix+FOLFOX與Erbitux+FOLFIRI二者僅能擇一使用。唯有在無法忍受化療（其副作用）時方可互換。

First line anti-EGFR or anti-VEGF?

FIRE-3 Study Treat to progression Patients No prior mCRC treatment adjuvant C/T allowed if >6 mo between tx and trial enrolment. N=592 KRAS exon 2 wild-type Primary end point was the proportion of patients who had an objective response FOLFIRI + cetuximab 1:1 Randomization FOLFIRI + bevacizumab Treat to progression Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open-label, phase 3 trial. Lancet Oncol 2014.

Best overall response 62 58 p=0·32 RAS WT 65 60 p=0·14 RAS MT 38 58

Survival 33.1 25.6 10.2 10.4 p=0.54 p=0.011 p=0.017 28.7 25.0 10.0 10.3 p=0.55 Both targeted agents seemed to be equally effective in terms of progression-free survival when combined first-line with FOLFIRI. However, overall survival was significantly longer in the FOLFIRI plus cetuximab group.

PEAK Phase II Study Treat to progression Patients No prior mCRC treatment adjuvant C/T allowed if >52 weeks before random assignment. N=285 KRAS exon 2 wild-type The primary end point was progression-free survival panitumumab + mFOLFOX6 1:1 Randomization bevacizumab + mFOLFOX6 mFOLFOX6 with either panitumumab 6 mg/kg once every 2 weeks or bevacizumab 5 mg/kg once every 2 weeks Treat to progression Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32:2240.

Progression-free survival extended WT RAS 9.5 13.0 p=0.029 wild-type (WT) KRAS exon 2 10.1 10.9 p=0.353 wild-type (WT) KRAS exon 2 10.1 10.9 p=0.353

Overall survival extended WT RAS 28.9 41.3 p=0.058 wild-type (WT) KRAS exon 2 24.3 34.2 p=0.009 Improved OS benefit with first-line use of anti-EGFR therapy in patients with WT KRAS exon2 mCRC. Patients who are WT by extended RAS analysis seem more likely to benefit from anti-EGFR therapy.

Regimens OS(month) PFS(month) IFL + Bevacizumab: IFL 20.3 : 15.6 10.6 : 6.2 XELOX or FOLFOX-4 + Bevacizumab: XELOX or FOLFOX-4 21.3 : 19.9 9.4 : 8.0 FOLFOXIRI + Bevacizumab ： FOLFIRI + Bevacizumab 29.8 : 25.8 12.3 : 9.7 FOLFIRI + Cetuximab: FOLFIRI (WT KRAS) 24.9:21 9.9 : 8.7 FOLFOX4 + Panitumumab : FOLFOX4 (WT KRAS) 23.9 : 19.7 9.6 : 8.0 FOLFIRI + Bevacizumab (WT KRAS) 33.1 : 25.6 10.4 : 10.2 mFOLFOX6 + Panitumumab : mFOLFOX6 + Bevacizumab (WT KRAS) 41.3 : 28.9 13.0 : 9.5

Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Eligibility Criteria Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Overall Survival <br /> Presented By Alan Venook at 2014 ASCO Annual Meeting

Presented By Alan Venook at 2014 ASCO Annual Meeting CALGB/SWOG 80405: Progression-Free Survival<br />(Investigator Determined) Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Overall Survival<br />FOLFOX Treated Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Overall Survival<br />FOLFIRI Treated Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Conclusions Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB 80405: Side of primary tumor Methods Population KRAS wt pts in main analysis Pre-amendment KRAS mut pts Data extraction Study chart, other supporting information if available Side of 1° determination Definitive information: Colonoscopy, surgical or imaging report Presented by:

80405: Side of Primary Tumors TRANSVERSE N = 66 RIGHT N = 293 (27%) LEFT N = 732 (68%) COULD NOT DETERMINE N = 46  Right-sided tumors are associated with a clinical presentation of iron deficiency anemia from occult blood loss and molecular features include defective mismatch repair genes, as well as mutations in theKRAS and BRAF oncogenes and in microRNA-31. Left-sided tumors are associated with CIN, p53, NRAS, microRNA-146a, microRNA-147b, and microRNA-1288, and typically present with hematochezia and change in bowel habits. Presented by:

80405: Overall Survival by Sidedness Median HR (95% CI) (95% CI) 33.3 Side N (Events) p Left 732 (550) (31.4-35.7) 19.4 1.55 (1.32-1.82) < 0.0001 Right 293 (242) (16.7-23.6) Left Right Presented by:

80405: OS by Sidedness (Bevacizumab) Median Side N (Events) HR(95% CI) p (95% CI) 31.4 (28.3-33.6) Left 356 (280) 1.32 (1.05-1.65) 0.01 24.2 (17.9-30.3) Right 150 (121) Right Left Presented by:

80405: OS by Sidedness (Cetuximab) Median (95% CI) HR (95% CI) Side N (Events) p 36.0 Left 376 (270) 1.87 (1.48-2.32) (32.6-40.3) 16.7 <0.0001 Right 143 (121) (13.1-19.4) Left Right Presented by:

80405: Sidedness is Prognostic Overall Survival (OS) KRAS wt N = 1025 Right 1° Median OS (mos) Left 1° Median OS (mos) Hazard Ratio 95% CI (adjusted*) P (adjusted*) All pts 19.4 33.3 1.55 (1.32,1.82) P < 0.0001 Cet 16.7 36.0 1.87 (1.48, 2.32) Bev 24.2 31.4 1.32 (1.05, 1.65) P = 0.01 19.3 MONTHS IS A BIG DIFFERENCE !! *Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases Presented by:

80405: Overall Survival by Sidedness and Biologic 31.4 (28.3-33.6) 36.0 (32.6-40.3) 24.2 (17.9-30.3) 16.7 (13.1-19.4) Presented by:

Summary of Primary Tumor Sidedness in mCRC Patients with R-sided primaries had much worse outcomes than pts with L-sided primaries, independent of biologic arm (prognostic) 1st line cetuximab and bevacizumab have different treatment effects in sidedness subgroups Sidedness is likely a surrogate for tumor biology Future trials to stratify patients by primary sidedness Remember: this is a retrospective ad hoc analysis; these results will factor in when making tx decisions but this is not the whole story

Conclusion For metastatic colorectal cancer: FOLFOX and FOLFIRI have similar first-line efficacy, and the decision to use one or the other should mainly be based on the expected toxicity profile of both regimens. A triplet regimen(FOLFOXIRI) could be considered an option for first-line therapy in selected patients for whom a more aggressive initial approach is chosen as long as they are able to tolerate intensive therapy. (eg, younger age, high tumor load or highly symptomatic disease, conversion therapy for initially resectable but potentially resectable liver metastases, RAS or BRAF mutation),

Conclusion For patients with MT KRAS tumors, first line : FOLFIRI ± bevacizumab (健保) FOLFOX or XELOX ± bevacizumab FOLFOXIRI ± bevacizumab For patients with WT KRAS tumors, first line : Left-side: cetuximab-containing regimens Right-side: bevacizumab-containing regimens FOLFOX + panitumumab

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Q&A Name: For patients with MT KRAS tumors, first line : For patients with WT KRAS tumors, first line : Left-side: Right-side: