Disclosure: Dirk Arnold

1. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV + CT: Results of a randomised phase III intergroup study – TML (ML18147) D Arnold1, T Andre2, J Bennouna3, J Sastre4, P Österlund5, R Greil6E Van Cutsem7, R von Moos8, I Reyes-Rivera9, B Bendahmane10, S Kubicka11 on behalf of the AIO, GERCOR, FFCD, UNICANCER GI, TTD, GEMCAD and AGMT groups 1Hamburg, Germany; 2Paris, France; 3Nantes, France; 4Madrid, Spain5Helsinki, Finland; 6Salzburg, Austria; 7Leuven, Belgium; 8Chur, Switzerland 9South San Francisco, USA; 10Basel, Switzerland; 11Reutlingen, Germany

2. Disclosure: Dirk Arnold • Consultant / advisory board: F. Hoffmann-La Roche, Merck Serono, Amgen • Honoraria: F. Hoffmann-La Roche, Merck Serono, Amgen • Research funding: F. Hoffmann-La Roche

3. Background • Bevacizumab (BEV) in combination with fluoropyrimidine-based chemotherapy (CT) is a standard of care for mCRC in first-line and (BEV-naive) second-line settings • VEGF is an early and persistent promoter of tumour angiogenesis.1 Sustained VEGF inhibition achieves and maintains tumour regression in preclinical studies2,3 • In non-randomised observational studies (BRiTE, ARIES) in patients with mCRC, continuing anti-angiogenic therapy with BEV + CT beyond first progressive disease (PD) correlates with prolonged survival vs no continuation of BEV4,5 1. Ferrara et al. Nature Med 2003;9:669–76 2. Klement et al. J Clin Invest 2000;105:R15–24 3. Klement et al. Clin Cancer Res 2002;8:221–232 4. Grothey et al. J Clin Oncol 2008;26:5326–34 5. Cohn et al. J Clin Oncol 2010;28(15s):Abstr 3596

4. Aims and objectives • The efficacy and safety of BEV continued after first PD has not been investigated in a randomised clinical trial • TML (ML18147) is the first randomised phase III study to evaluate BEV continued with standard second-line CT in patients with mCRC who progressed after BEV plus standard first-line CT

5. Study design and patient characteristics

6. ML18147 study design (phase III) Standard second-line CT (oxaliplatin or irinotecan-based) until PD BEV + standard first-line CT (either oxaliplatin oririnotecan-based)(n=820) PD Randomise 1:1 BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD CT switch: Oxaliplatin →Irinotecan Irinotecan→ Oxaliplatin Study conducted in 220 centres in Europe and Saudi Arabia

7. Statistical considerations • Study initiated as AIO KRK 0504 then transferred to Roche (after enrolment of 261 patients) • Primary endpoint changed from PFS to OS • Sample size increased from 572 to 810 patients • Designed to detect 30% (HR 0.77) improvement in median OS(90% power, 2-sided 5%) • 613 events required for analysis • OS curves estimated using Kaplan–Meier method, differences assessed using unstratified log-rank tests • Unstratified Cox regression model used to estimate HR for OS • Stratified log-rank tests and Cox regression analyses used as supportive analyses

8. Main eligibility criteria Inclusion • Patients ≥18 years with histologically confirmed diagnosis of mCRC • Eastern Cooperative Oncology Group (ECOG) PS 0–2 • PD (≥1 measurable lesion according to RECIST v1 assessed by investigator, documented by CT or MRI), ≤4 weeks prior to start of study treatment • Previously treated with BEV plus standard first-line CT, not candidates for primary metastasectomy Exclusion • Diagnosis of PD >3 months after last BEV administration • First-line patients with PFS in first-line of <3 months • Patients receiving <3 consecutive months of BEV in first-line

9. Demographic and baseline characteristics: Randomised patients Patients were accrued between February 2006 and June 2010

10. Demographic and baseline characteristics: Randomised patients (cont’d) aPatient population refers to sequential enrolment of patients in original AIO study and subsequent enrolment in ML18147 when study was transferred to Roche

11. Second-line chemotherapy during study: Randomised patients 1. Douillard et al. Lancet 2000;355:1041–7

12. Primary endpoint:overall survival

13. OS: ITT population 1.0 CT (n=410) BEV + CT (n=409) 0.8 Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) 0.6 Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) 0.4 OS estimate 0.2 0 9.8 mo 11.2 mo 0 6 12 18 24 30 36 42 48 Time (months) No. at risk CT 410 293 162 51 24 7 3 2 0 BEV + CT 409 328 188 64 29 13 4 1 0 Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0) aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

14. Subsequent anti-cancer therapies: Safety population EGFR: epidermal growth factor receptor

15. Subgroup analysis of OS: ITT population HR 0 1 2 aPatient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when study was transferred to Roche. All patients listed under AIO were included in primary analysis

16. Secondary endpoints: PFS and best overall response

17. PFS: ITT population 1.0 CT (n=410) BEV + CT (n=409) 0.8 Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test) 0.6 Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test) 0.4 PFS estimate 0.2 0 4.1 mo 5.7 mo 0 6 12 18 24 30 36 42 Time (months) No. at risk CT 410 119 20 6 4 0 0 0 BEV + CT 409 189 45 12 5 2 2 0 aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

18. Best overall response: Measurable disease population aPatients with a best overall response of confirmed complete or partial responsebThis analysis was not prespecified cIncludes ‘not-evaluable’ or ‘no tumour assessment’ following baseline visit

19. Safety

20. Treatment duration: Safety population CT (n=409) BEV + CT (n=401) 0 Duration from randomisation (ie first study drug) until discontinuation of all study drugs was 3.2 months for CT and 4.2 months for BEV + CT

21. Overview of adverse events: Safety population aPD leading to death captured for some patients as grade 5 AE; these events were excluded from this summary AE: adverse event

22. Grade 3–5 adverse events (incidence ≥2%) in any arm: Safety population

23. Adverse events of special interest to BEV: Safety population ATE: arterial thromboembolic events; GI: gastrointestinal; RPLS: reverse posterior leukoencephalopathy syndrome; VTE: venous thromboembolic events

24. Summary and Conclusions

25. Summary • BEV + standard second-line CT, crossed over from BEV + standard first-line CT, significantly prolongs OS and PFS • OS • Median: BEV + CT 11.2 months, CT 9.8 months • HR: 0.81 (95% CI: 0.69–0.94), p=0.0062a • PFS • Median: BEV + CT 5.7 months, CT 4.1 months • HR: 0.68 (95% CI: 0.59–0.78), p≤0.0001a • Findings from subgroup analyses for OS generally consistent with overall population • Treatment effect according to gender appeared to be different; however, treatment-gender interaction test was not statistically significant • Differences in best overall response rate not statistically significant; low response rate in both treatment groups • AEs not increased when continuing BEV beyond PD; AE profile consistent with previous findings aUnstratified log-rank test

26. Conclusions • First randomised clinical trial that prospectively investigated the impact of continued VEGF inhibition with BEV beyond first progression • Study confirms that continuing BEV beyond first progression while modifying CT is beneficial for patients with mCRC and leads to a significant improvement in OS and PFS • This provides a new second-line treatment option for patients who have been treated with BEV + standard CT in first line while maintaining an acceptable safety profile • Findings indicate a potential new model for treatment approaches through multiple lines and this is currently being investigated in other tumour types

27. Acknowledgements • Patients and their families • Investigators, study coordinators and nurses • ML18147 study team at Roche

28. ML18147 study investigators Austria: Andel J, Balcke P, Benedicic B, Eisterer W, Fridrick M, Greil R, Jagdt B, Keil F, Kretschmer A, Krippl P, Oexle H, Pecherstorfer M, Samonigg H, Schmid M, Thaler J, Tinchon C, Weiss H; Belgium: Arts J, De Man M, Demolin G, Janssens J, Polus M, Van Cutsem E. Czech Republic:Benczikova B, Melichar B, Prausova J, Vitek P. Denmark: Andersen FZ, Jensen BB, Keldsen N, Østerlind K, Vistisen K. Estonia: Elme A, Magi A, Ojamaa K. Finland: Osterlund P, Ristamäki R, Salminen T. France: André T, Ben Abdelghani M, Bennouna J, Borg C, Bouche O, Bouhier-Leporrier K, Breysacher G, Chone L, Clavero Fabri M-C,Deplanque G, Desseigne F, Dourthe L-M, Ezenfis J, Faroux R, François E, Garnier C, Gaspard M-H, Hebbar M, Illory JF, Kaminsky M-C, Lecomte T, Legoux J-L, Levache B, Lobry C, Lotz J-P, Mabro M, Manet-Lacombe S, Manfredi S, Matysiak Budnik T, Miglianico L, Mineur L, Moullet I, Naman H, Nouyrigat P, Oziel-Taieb S, Perrier H, Pezet D, Philip J, Pottier V, Porneuf M, Ramdani M, Re D, Rinaldi Y, Spaeth D, Taieb J, Terrebonne E, Texereau P, Thirot Bidault A, Tournigand C, Tubiana-Mathieu N, Vantelon J-M, Viret F, Ychou M. Germany: Arnold D, Bangerter M, Bertram ME, Bohnsteen B, Brinkmann L, Caca K, Constantin C,Cordes H-J, Dietrich G, Eggert J, Engel E, Fahlke J, Fensterer H, Florschütz A, Folprecht G, Forstbauer H, Freier W, Freund M, Frickhofen N, Gäbele E, Geißler M, Gieseler F, Göhler T, Graeven U, Groschek M, Grundeis M, Hacker U, Hagen V, Hebart HF, Hegewisch-Becker S, Heike M, Herrmann T, Hildebrandt B, Höffkes H-G, Hübner G, Hübner J, Kettner E, Kneba M, Kohnke JW, Kojouharoff G, König C, Kretzschmar A, Kröning H, Kubicka S, Kürner K, Lammert F, Lerchenmüller C, Lück A, Meiler J, Mergenthaler H-G, Müller L, Müller-Naendrup C, Nusch A, Papke J, Porschen R, Rädle J, Reddemann C, Ridwelski K, Riera-Knorrenschild J, Rudi J, Schlichting C, Schmalenberger A, Schimanski C-C, Schlegel F, Schmidt P, Schmiegel W, Schmitz S, Schulze-Bergkamen H, Schwaner I, Schwarzer A, Schwerdtfeger M, Selbach J, Sieber M, Siebler J, Staib P, Stauch M, Steffens C-C, Stübs P, Tischendorf J, Trarbach T, Tummes D, Valdix A-R, Vogel A, Von Wichert GPL, Walther M, Welslau W, Wilhelm G, Wobster H, Wolf T, Zeigenhagen N, Zomorodbaksch B. Netherlands: Batman E, Bloemendal HJ, Kehrer DFS. Norway: Guren T, Indrebø G, Kersten C, Soerbye H. Portugal: Fragoso M, Fragoso R, Mellidez JC, Sa A. Saudi Arabia: Aljobran A, Darwish T. Spain: Alonso-Orduna V, Aparicio J, Aranda E, Bosch C, Galan-Brotons A, Busquier Hernandez I, Camara JC, Campos Cervera JM, Carlos Garcia Giron C, Del Prado PM, Donnay O, Escudero P, Falco E, Gallego Plazas J, Garcia Alfonso P, Gonzalez Flores E, Gravalos C, Guardeno R, Juárez A, Lopez Ladron A, Losa Gaspa F, MªVicent Vergé J, Marcuello Gaspar E, Massuti Sureda B, Molina J, Montero IC, Muñoa AL, Naranjo MB, Oruezabal Moreno MJ, Pachón Olmos V, Pericay C, Reina Zoilo JJ, Rivera F, Ruiz Casado A, Safont MJ, Salud Salvia A, Sastre Valera J, Tobena M, Toral JC, Valenti V, Valladares Ayerbes M, Vera R, Vieitez de Prado JM. Sweden: Berglund A, Fernebro E. Switzerland: Hess-Umbricht V, Pless M, Popescu R, Von Moos R, Winterhalder R