State of the Art Colorectal Cancer (CRC) Marc Peeters, MD, PhD Antwerp University Hospital Edegem, Belgium

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1 State of the Art Colorectal Cancer (CRC) Marc Peeters, MD, PhD Antwerp University Hospital Edegem, Belgium

2 Objectives 02 Review current approaches for the management of CRC Discuss current challenges/unmet needs in the treatment of mcrc

3 CRC Is A Global Health Burden 03 Global: 1.4 million new CRC cases and 0.7 million deaths in 2012 Source: GLOBOCAN Global Cancer Facts & Figures 3 rd Edition.

4 Incidence of CRC in the Americas Male (M) Female (F) 04 Combined (M+F) Top 10 countries with highest incidence (Est. no. x1000): * U.S Brazil 33.9 Canada 23.8 Argentina 13.5 Mexico 8.7 Columbia 5.7 Cuba 3.9 Chile 3.6 Peru 3.1 Venezuela 2.9 * Per 100,000, age standardized to the World Standard Population; Source: GLOBOCAN 2012 Global Cancer Facts & Figures 3 rd Edition.

5 CRC: Stages at Diagnosis and 5-Year Survival 05 SEER, Surveillance, Epidemiology, and End Results Program, NIH/NCI. Accessed August 26, 2015.

6 Treatments of Early Stage Colon and Rectal Cancer

7 1. Labianca et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24;Suppl 6:vi64-vi72; 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V ; 3. Glimelius et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol. 2013;24;Suppl 6:vi81-vi88; 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Rectal Cancer V Treatment for Stage 0, I, II and III Colon and Rectal Cancer (NCCN & EMSO Treatment Guidelines) Colon 1,2 Rectal 3,4 07 Stage 0 Stage I Local excision, simple polypectomy, or segmentary en-bloc resection Wide surgical resection and anastomosis Local excision by Total Mesorectal Excision (TME) Stage II Surgery without adjuvant chemotherapy Tri-modal Therapy: Chemo-radiation Stage III High risk features Surgery with Adjuvant FOLFOX or CapeOX, FLOX, Capecitabine Or 5-FU/Leucovorin Rectal surgery Adjuvant chemotherapy

8 Benson et al. J Clin Oncol. 2004;22:3408. Adjuvant Chemotherapy in Stage II Colon Cancer Meta-analysis of 3732 patients from 12 trials

9 Adjuvant Chemotherapy in Stage III Colon Cancer MOSAIC trial 1 Similar results were seen in other randomised adjuvant trials with other regimens 2,3 1. André et al. J Clin Oncol 2009; 27:3109; 2. Yothers et al. J Clin Oncol. 2011; 29:3768; 3. Haller et al. J Clin Oncol. 2011;29:1465.

10 Trimodality Therapy in the Treatment of Stage II/III Rectal Cancer 010 It is effective, but is quite intensive and difficult to complete 1 EORTC % did not initiate post-operative chemotherapy Only 43% received the planned dose Significant delay ( 18 weeks) from diagnosis until first dose of systemic adjuvant chemotherapy, which may increase systemic recurrence risk due to 3 : Delay in starting chemotherapy (FOLFOX) Omission of chemotherapy (FOLFOX) Intolerance or dose reduction Are all 3 modalities needed? 3 1. Waiser. ASCO Bosset et al. N Engl J Med 2006;355: Schrag. ASCO 2015.

11 Current Approaches to Improve the Management of Patients With Stage II/III Rectal Cancer 011 Total neoadjuvant treatment (both radiation and chemotherapy before surgery) may help address the undertreatment issue 1 Multiple phase 2 trials show favourable results 1 High rates of clinical response and downstaging; pcr of 15-33%; no excess surgical complication rates Ongoing Phase 3 trial (RAPIDO, NCT ) 2 CAPOX and XRT (5.5 weeks) TME Optional chemo vs XRT (1 week) XELOX (x6) TME Trials testing selective use of one modality (radiation, surgery, chemotherapy) 1. Schrag. ASCO Available at: NCT ?term=RAPIDO&rank=1. Accessed September 1, 2015.

12 Treatment of Metastatic CRC

13 Management of Resectable Metastatic CRC

14 Treatment of Resectable Synchronous Metastatic Colon Cancer (NCCN) 014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V

15 Treatment of Resectable Synchronous Metastatic Rectal Cancer (NCCN) 015 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Rectal Cancer V

16 Treatment for Resectable Metachronous Metastatic Colon or Rectal Cancer: NCCN Guidelines 016 Neoadjuvant Chemotherapy: FOLFOX or CapeOx (preferred) FLOX Capecitabine Or 5-FU/Leucovorin Surgery Adjuvant Chemotherapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Rectal Cancer V

17 Treatment of Unresectable Metastatic CRC

18 Approved Targeted Agents for the Treatment of Unresectable Metastatic CRC 018 Bevacizumab ziv-aflibercept VEGFA VEGFB PIGF VEFGA VEGFC VEGFD VEGFC VEGFD PDGF FGF Cetuximab Panitumumab *Ramucirumab VEGFR-1 VEGFR-3 VEGFR-2 PDGFR-α PDGFR-β FGFR-1 FGFR-3 FGFR-2 EGFR Regorafenib Migration Proliferation Survival Permeability Angiogenesis *Approval by FDA was granted in April 2015; approval by EMA is pending. Modified from Clarke & Hurwitz. J Gastrointest Oncol. 2013;4:253.

19 First-line Treatment of mcrc

20 NCCN Guidelines: Recommendations for the First-line Treatment of Metastatic CRC NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V

21 ESMO Guidelines for the First-line Treatment of Metastatic CRC * * * *2 nd -line treatment of patients refractory to an irinotecan-based chemotherapy regimen must consist of an oxaliplatin-containing combination (FOLFOX or CAPOX); and for patients refractory to FOLFOX or CAPOX, an irinotecan-based regimen is proposed as 2 nd -line treatment. Van Cutsem et al. Ann Oncol. 2014;25(suppl 3):iii1-iii9.

22 Summary of Pivotal Trials of Anti-VEGF and Anti-EGFR Agents in the 1 st -line Treatment of mcrc 022 Trial Agent Treatment Control OS PFS (mos) HR P (mos) HR P AVF2017/A 1 Bevaciz. Bevaciz. + IFL IFL 20.3 vs < vs <0.001 CRYSTAL 2,3 Cetux. Cetux. + FOLFIRI FOLFIRI 28.4 vs 20.2* (RAS WT) vs <0.001 PRIME 4,5 Panitum. Panitum. + FOLFOX4 FOLFOX vs 20.2* (RAS WT) vs <0.004 Bold indicates primary endpoint of the clinical trial Bevaciz, Bevacizumab; Cetux., Cetuximab, Panitum., Panitumumab; IFL, fluorouracil, irinotecan, leucovorin; CT; chemotherapy; WT, Wild type; OS, overall survival; mos, months; HR, hazard ratio; P, P-value. 1. Hurwitz et al. N Engl J Med. 2004;350:2335; 2. Van Cutsem et al. N Engl J Med. 2009;360:1408; 3. Van Cutsem et al. J Clin Oncol. 2015;33:692; 4. Douillard et al. J Clin Oncol. 2010;28:4697; 5. Douillard et al. N Engl J Med. 2013;369:1023.

23 Second-line Treatment of mcrc

24 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V NCCN Guidelines: Recommendations for the Second-line Treatment of Metastatic CRC 024

25 Summary of Pivotal Trials of Antiangiogenic and Anti-EGFR Agents in the 2 nd -line Treatment of mcrc 025 Trial Agent Treatment Control ML18147/A 1 Bevaciz. Bevaciz. + Switch CT Switch CT OS PFS (mos) HR P (mos) HR P 11.2 vs vs < VELOUR 2 ziv-aflib. Ziv-Aflib. + FOLFIRI FOLFIRI 13.5 vs vs RAISE 3 Ramucir. Ramucir. + FOLFIRI FOLFIRI 13.3 vs vs ,5 Panitum. Panitum. + FOLFIRI FOLFIRI 14.5 vs vs Bold, indicates primary endpoint of the clinical trial Bevaciz, Bevacizumab; Panitum., Panitumumab; ziv-aflib., ziv-aflibercept; Ramucir., Ramucirumab, Regoraf., Regorafenib; IFL, fluorouracil, irinotecan, leucovorin; CT; chemotherapy; BSC, best supportive care; OS, overall survival; mos, months; HR, hazard ratio; P, P-value. 1. Bennouna et al. Lancet Oncol. 2013;14:29; 2. Van Cutsem et al. J Clin Oncol. 2012;30: ; 3. Tabernero et al. Lancet Oncol. 2015;16:499; 4. Peeters et al. J Clin Oncol. 2010;28:4706; 5. Peeters et al. Ann Oncol. 2014;25:107.

26 Current Management of 3 rd -line mcrc

27 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V NCCN Guidelines: Recommendations for the 3rd-line Treatment of Metastatic CRC 027

28 Summary of Pivotal Trials of Targeted Agent in the 3rd-line Treatment of mcrc Trial Agent Treatment Control OS PFS CORRECT 1 Regoraf.* Regorafenib + BSC BSC 6.4 vs vs <0.001 NCIC CO.17 2* Cetux. Cetux. BSC 9.5 vs 4.8 (RAS WT) 0.55 < vs <0.001 Amado et al. 3 Panitum. Panitum. + BSC BSC 8.1 vs 7.6 (RAS WT) vs <0.001 *In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy. 1. Grothey et al. Lancet Oncol. 2013;381:303; 2. Karapetis et al. N Engl J Med. 2008;359:1757; 3. Amado et al. J Clin Oncol. 2008;26:1626.

29 Key Issues in the Treatment of mcrc

30 Anti-EGFR vs Anti-VEGF in the First-line Treatment of mcrc

31 Anti-EGFR vs Anti-VEGF in the First-line Treatment of mcrc Phase 3 trials Trial Regimen Primary endpoint Secondary endpoints PEAK trial 1 KRAS-wt: N=285 RAS-wt: N=170 FIRE-3 trial 2,3 KRAS-wt: N=592 RAS-wt: N=400 FOLFOX + panitum vs FOLFOX + bev FOLFIRI + cetux vs FOLFIRI + bev KRAS-wt: PFS: 10.9 (panitum) vs 10.1 mos (bev) (HR, 087; P=0.353) RAS-wt: PFS: 13 (panitum) vs 9.5 mos (bev) (HR, 0.65; P=0.029) KRAS-wt: ORR (independent): 66.5% (cetux) vs 55.6% (OR, 1.18; P=0.18) RAS-wt: ORR (independent): 72% (cetux) vs 56% (OR, 2; P=0.003) *No significant difference in median PFS between the arms. KRAS-wt: OS: 34.2 (panitum) vs 24.3 mos (bev) (HR, 0.62, P=0.009) RAS-wt: OS: 41.3 (panitum) vs 28.9 mos (bev) (HR, 0.63; P=0.058) KRAS-wt:* OS: 28.7 (cetux) vs 25 mos (bev) (HR, 0.77; P=0.017) RAS-wt:* OS: 33.1 (cetux) vs 25 mos (bev) (HR, 0.7; P=0.0059) Post-PD treatment Anti-EGFR : Bev arm: 38% Panitum arm: 21% Cetuximab-arm: 78% received 2 nd -line treatment Bev-arm: 76% received 2 nd -line treatment 1.Schwartzberg et al. J Clin Oncol.2014;32:2240; 2.Heinemann V et al. Lancet. Oncol. 2014;15:1065; 3. Stintzing S et al. Ann Oncol.2014;25:abstr LBA11.

32 Anti-EGFR vs Anti-VEGF in the First-line Treatment of mcrc (cont d) Trial Regimen Primary endpoint Secondary endpoints Post-PD treatment CALGB 80405) 1-3 KRAS-wt: N=1,137 RAS-wt: N=526 FOLFOX or FOLFIRI + cetux vs FOLFOX or FOLFIRI + bev KRAS-wt: OS: 29.9 (cetux) vs 29 mos (bev) (HR, 92; P=0.30) RAS-wt: OS: 30.8 (cetux) vs 30.3 mos (bev) (HR, 0.9; P=0.40) KRAS-wt: PFS: 10.4 (cetux) vs 10.8 mos (bev) (HR, 1.04, P=0.55) RAS-wt: PFS: 10.9 (cetux) vs 11.4 mos (bev) (HR, 1.1; P=0.31) Phase 3 trial Details not provided 1.Venook et al. J Clin Oncol. 2014;32(suppl 5s; abstr LBA3). 2. Lenz et al. Ann Oncol. 2014;25(abstr 5010). 3. Venook et al. Ann Oncol. 2014;25:(abstr LBA10).

33 Issues Associated With Anti-EGFR Therapies in the Treatment of mcrc

34 The Majority of mcrc Patients Are Not Suitable for EGFR-targeted Therapies 034 RAS (KRASNRAS)- and BRAF-mutations predict lack of response to anti-egfr therapy 1-3 Frequency of KRAS, RAS and BRAF mutations in mcrc The majority of mcrc patients ( 56%) harbour mutant KRAS/NRAS or BRAF 1-3 Only 44% of these patients are RAS and BRAF wild type and suitable for anti-egfr-containing therapy However, even RAS- and BRAF-wt status in CRC does not ensure responsiveness to anti-egfr agents, suggesting additional determinants of sensitivity 3 1. NCCN Clinical Guidelines. V3.2015; 2. Cancer Genome Atlas Network. Nature. 2012;487:330; 3. Fakih. J Clin Oncol. 2015;33; ; 4. Bettegowda et al. Sci Transl Med. 2014;6:224ra24

35 Development of Treatment-related Resistance Is a Major Issue in Patients With KRAS- and or BRAF- WT mcrc Emergence of RAS and BRAF mutations during anti-egfr treatment as mechanism of resistance 1-4 Majority of patients with RAS and BRAF WT disease will test positive for one or more KRAS, NRAS, or BRAF mutations in the cdna or on repeat tumour biopsy before or at the time of anti-egfr resistance 2 RAS mutations seen in up to 60% of tumour samples biopsied at the time of resistance to anti-egfr therapy 3,4 In a study of 24 objective responders to anti-egfr therapy who subsequently progressed, 23 developed a detectable mutation involving the MAPK pathway. The majority of these were RAS- or BRAFactivating mutations 2 1. Fakih. J Clin Oncol. 2015;33; ; 2. Bettegowda et al. Sci Transl Med. 2014;6:224ra24; 3. Misale et al. Nature. 2012;486:532; 4. Diaz et al. Nature. 2012;486:

36 Current Approaches to Overcome Resistance to EGFR-targeted Agents in mcrc 036 Inhibition of RAS signalling pathway in patients with BRAF V600 mutations Anti-EGFR Dabrafenib + trametinib 1 ORR: 7% mpfs: 3.5 months Panitumumab + dabrafenib 2 ORR: 10% mpfs: 10.1 months Panitumumab + dabrafenib + trametinib 2 ORR: 26% mpfs: 9.0 months Remains an active area of research and clinical development 1. Corcoran et al. J Clin Oncol. 2014;32(suppl;abstr 3517). 2. Atreya et al. J Clin Oncol. 2015;33(suppl; abstr 103). Dabrafenib Trametinib EGFR RAS BRAF MEK ERK Proliferation, Survival, etc.

37 Limited Therapeutic Options in the Treatment of Patients Who Failed All Standard Therapies

38 Current Unmet Needs in the Treatment of Patients Who Failed All Standard Therapies 038 Many patients with mcrc who progress on all approved standard therapies maintain good performance status and thus remain eligible for further therapy 1 However, treatment of these patients remains challenging as viable therapeutic options are limited 1,2 Regorafenib is the only targeted agent currently approved for treatment of patients progressing on all standard therapies 2 Regorafenib provides a modest improvement in efficacy (an improvement of 1.4 months and 0.2 months in median OS and PFS, respectively) and is associated with a number of treatment-related toxicities 1,2 Most common grade 3 AEs: hand-foot skin reaction (17%), fatigue (10%), rash/desquamation (6%) In a subset analysis of 500 patients with mcrc, high-foot skin reaction (all grades): 46.6% 1. Grothey et al. Lancet Oncol. 2013;381: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V

39 Emerging Data in the Treatment of Patients With mcrc Who Failed 3 Lines of Prior Therapies

40 Phase 3 Trial of Regorafenib Monotherapy for Previously Treated mcrc (CORRECT Trial) Regorafenib Confirmed adenocarcinoma CRC Failure during or within 3 months following last administration of approved standard therapies ECOG PS 0-1 N=760 R A N D O M I S E 2:1 (160 mg once daily for 3 weeks of each 4-week cycle) + BSC until PD, death, unacceptable toxicity, withdrawal, or discontinuation n=505 Placebo + BSC Until PD, death, unacceptable toxicity, withdrawal, or discontinuation Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR, and safety n=255 Grothey et al. Lancet. 2013;381:303.

41 Efficacy of Regorafenib in Relapsed/Refractory CRC: OS and PFS 042 Median Overall Survival: 6.4 vs 5.0 mos. Median Progression-Free Survival: 1.9 vs 1.7 mos. Grothey et al. Lancet. 2013;381:303.

42 Safety Regorafenib in Relapsed/Refractory CRC: AEs Regorafenib n=500 (%) Placebo n=253 (%) Discontinued study due to AEs 42 (8) 7 (3) Dose modification 333 (67) 57 (23) Dose reductions 188 (38) 8 (3) Dose interruptions 304 (61) 55 (22%) Treatment-related AEs (grade 3) Overall 253 (51) 31 (12) AEs of higher incidence (Regorafenib vs placebo) Grothey et al. Lancet. 2013;381:303. Hand-foot skin reaction 83 (17) 1 (<1) Fatigue 46 (9) 12 (5) Hypertension 36 (7) 2 (1) Diarrhoea 35 (7) 2 (1) Rash or desquamation 29 (6) 0 Hypophosphataemia 19 (4) 1 (<1) Oral mucositis 15 (3) 0 Thrombocytopaenia 13 (3) 1 (<1) Anaemia 12 (2) 0 Hyperbilirubinaemia 10 (2) 2 (1) Proteinuria 7 (<1) 1 (<1) Voice change 1 (<1) 0 Nausea 2 (<1) 0 Vomiting 3 (1) 0 Fever 4 (1) 0 043

43 Phase 3 Trial of TAS-102 in Relapsed/Refractory mcrc (RECOURSE Trial) TAS-102 Confirmed adenocarcinoma CRC Failure of 2 prior regimens of standard chemotherapies for mcrc Known KRAS mutation status ECOG PS 0-1 N=800 R A N D O M I S E 2:1 (35 mg/m 2 /dose) 2x daily days 1-5 and 8-12 of each 28-day cycle, until discontinuation n=534 Placebo Placebo tablets 2x daily days 1-5 and 8-12 of each 28-day cycle, until discontinuation Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR, and safety n=266 TAS-102, an oral, nucleoside anti-cancer agent Mayer et al. N Engl J Med. 2015;372:1909.

44 Efficacy TAS-102 in Relapsed/Refractory CRC: OS and PFS 046 Overall Survival: 7.1 vs 5.3 mos. Progression Free Survival: 2.0 vs 1.7 mos. Mayer et al. N Engl J Med. 2015;372:1909.

45 Safety of TAS-102 in Relapsed/Refractory CRC: AEs TAS-102 n=533 (%) Placebo047 n=265 (%) Discontinued study due to AEs 19 (4) 4 (2) Dose reduction 73 (14%) Treatment-related AEs (grade 3) Overall 370 (69) 137 (52) AEs of higher incidence (TAS-102 vs placebo) Neutropaenia 200/528 (38) 0 Leukopaenia 113/528 (21) 0 Anaemia 96/528 (18) 8/263 (3) Thrombocytopaenia 27/528 (5) 1/263 (<1) Febrile neutropaenia 20 (4) 0 Nausea 10 (2) 3 (1) Vomiting 11 (2) 1 (<1) Diarrhoea 16 (3) 1 (<1) Mayer et al. N Engl J Med. 2015;372:1909.

46 Ongoing Phase 3 Trial in Patients With mcrc Who Failed All Standard Therapies

47 Mechanism of Resistance to Antiangiogenic Agents Currently available antiangiogenic therapies mainly target VEGF/VEGFR and PDGFR signalling and thus do not neutralize all relevant mechanisms involved in angiogenesis 1,2 049 Acquired resistance to VEGF-targeted therapy is a major challenge for treatment of advanced or metastatic tumours 2,3 Activation or upregulation of FGF/FGFR and PDGF/PDGFR signaling serves as a mechanism of resistance to VEGF/VEGFRtargeted therapy 4-6 The PDGF/PDGFR and FGF/FGFR pathways have been implicated in the development of resistance to antiangiogenesis through induction of epithelial mesenchymal transition (EMT) 7-9 Image obtained from 1. Rogosin et al. Clin Lung Cancer 2012;13:326-33; 2. Clarke and Hurwitz. J Gastrointest Oncol. 2013;4:253-63; 3. Ellis and Hicklin. Clin Cancer Res. 2008;14:6371; 4. Batchelor et al. Cancer Cell. 2007;11:83-95; 5. Casanovas et al. Cancer Cell. 2005;8: ; 6. Erber et al. FASEB J. 2004;18:338; 7. Eckert et al. Cancer Cell. 2011;19:372-86; 8. Jechlinger et al. J Clin Invest. 206;116; ; 9. Wu et al. Cancer Treat Rev. 2013;39:640.

48 Nintedanib: An Oral Triple Angiokinase Inhibitor Simultaneously inhibits multiple angiokinases at low nanomolar concentrations (IC 50 ) 1-3 VEGFR-1, -2, and -3 PDGFR-a/b FGFR-1, -2, and -3 BIBF 1120 Demonstrated high antiangiogenic and antitumour activity as monotherapy or in combined regimens in multiple preclinical models including bevacizumab-resistant CRC xenograft 3 Long-term treatment with nintedanib does not induce EMT in multiple preclinical models 2 1. Hilberg et al. Cancer Res. 2008; ; 2. Kutluk Cenik et al. Mol Cancer Ther. 2013;12:992; 3. Mésange et al. Oncotarget. 2014;5:4709. Nintedanib is approved in the European union (EU) under the brand name VARGATEF for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other indications.

49 Antitumour Activity of Nintedanib in mcrc 051 Confirmed mcrc (adenocarcinoma) Previously untreated patients ECOG PS 2 Adequate organ functions N=126 Study design R A N D O M I S E Primary endpoint: PFS rate at 9 months Nintedanib (150 or 200 mg bid) + mfolfox6 2:1 n=85 Bevacizumab (5 mg/kg q2wks) + mfolfox6 n= Nint + mfolfox PFS (9 mos) Activity Bev + mfolfox ORR 56.1 * *Confirmed ORs mfolfox6= oxaliplatin 85 mg/m 2, I-leucovorin 200 mg/m 2 or d,i-leucovorin 400 mg/m 2, 5-FU bolus 400 mg/m 2 followed by 2400 mg/m 2, every 2 weeks Van Cutsem E et al. Ann Oncol Aug 12. pii:mdv286. [Epub ahead of print]

50 Phase 3 Trial of Nintedanib in Relapsed/Refractory CRC (LUME-COLON 1) Currently recruiting patients Double-blind, randomised study of Nintedanib vs Placebo in Refractory CRC Confirmed adenocarcinoma CRC Progression on standard therapies or withdrawn from standard treatment due to unacceptable toxicities. Previous standard treatment must include: Fluoropyrimidine Oxaliplatin Irinotecan Bevacizumab or Aflibercept Cetuximab or Panitumumab for pts. with RAS WT tumours Prior treatment with Regorafenib allowed ECOG PS = 0-1 N=764 (estimated) R A N D O M I S E 1:1 Nintedanib (200 mg bid) + BSC in 21-day courses until PD or undue toxicity Placebo + BSC Co-primary endpoints: OS, PFS Secondary endpoints: ORR, DCR, safety (frequency and severity of AEs, lab parameters). Lenz et al. J Clin Oncol. 2015;33(suppl 3) GI Cancers Symposium. Abstract TPS Accessed August 18, 2015.

51 Where Do We Go from Here? How Do We Further Improve Patient Outcomes?

52 Identification of Potentially Novel Targetable Driver Mutations in mcrc Analysis of 224 tumour and normal pair tissue samples Cancer Genome Atlas Network. Nature. 2012;487:

53 Novel Therapeutic Approaches: Anti-PD-1/PD-L1 Agents in mcrc Nivolumab (anti-pd-1) 1,2 No activity in a Phase 1 trial with advanced tumours included 17 patients with mcrc Subsequent case report that 1/17 patients achieved CR with evidence of PD after 3 years BMS (anti-pd-l1) 3 No activity in a Phase I trial with advanced tumours included 18 patients with mcrc Atezolizumab (MPDL3280A) 4,5 1/4 patients with mcrc responded; responses seen in both PD-L1+ and PD-Ltumours MPDL3280A + bev (refractory mcrc): 8% ORR* MPLD3280A + bev + FOLFOX (oxal-naïve): 36% ORR* *Unconfirmed ORR. 1. Topalian et al. N Engl J Med. 2012;366:2443; 2.Lipson et al. Clin Cancer Res. 2013;19:462; 3. Brahmer et al. N Engl J Med. 2012;366:2455; 4. Herbst et al. J Clin Oncol. 2013;31(suppl; abstr 3000); 5. Bendell et al. J Clin Oncol. 2015;33(suppl 3; abstr 704).

54 Ongoing Trials With Anti-PD-1 Agents in mcrc Trial Study Title Treatment 1 Endpoint Status Phase 2 NCT Phase 2 NCT Phase 2 NCT Phase 1/2 NCT Phase 1/2 NCT Phase 1/2 NCT Phase 1/2 NCT Assess the Efficacy of Pembrolizumab Plus Radiotherapy or Ablation in Metastatic Colorectal Cancer Patients Study of Pembrolizumab in Combination With Chemotherapy for Patients With Advanced Colorectal Cancer A Phase 2 Study of Pembrolizumab in Combination With Azacitidine in Subjects With Chemo-refractory Metastatic CRC Pembrolizumab and Monoclonal Antibody Therapy in Advanced Cancer Phase I/IIA Study MK-3475 With Chemotherapy in Patients With Advanced GI Cancers (MK-3475 GI) A Study of the Safety, Tolerability, and Efficacy of INCB24360 Administered in Combination With Nivolumab in Select Advanced Cancers Study of Nivolumab Plus Chemotherapy in Patients With Advanced Cancer (NivoPlus) Combination Radiation Therapy or Ablation Plus Pembrolizumab Combination FOLFOX6 Chemotherapy with Pembrolizumab Response Rate PFS Recruiting Recruiting Combination Azacitidine with Pembrolizumab Response Rate Recruiting Combination of Pembrolizumab with Trastuzumab, ado-trastuzumab emtansine, or Cetuximab Combination FOLFOX6 Chemotherapy with Pembrolizumab Combination with INCB24360 (IDO1 Inhibitor) with Nivolumab Combination of Nivolumab with Temsirolimus or Irinotecan or Irinotecan plus Capecitabine RP2D Safety Phase 1: Safety (DLT) Phase 2: Response Rate & Overall Survival RP2D Recruiting Recruiting Recruiting Recruiting PFS, Progression free survival; RP2D, Recommended phase 2 dose; DLT, dose limiting toxicities. Accessed Sept. 3, 2015.

55 Anti-PD-1/PD-L1 in mcrc: The Need to Identify the Right Patient Population Phase 2 trial of pembrolizumab in 41 patients with progressive metastatic carcinoma with or without mismatch repair deficiency PFS OS Not reached Not reached 2.2 months 5.0 months ORR/SD Mismatch repair deficient (n=10): 40%/50% Mismatch repair proficient (n=18): 0/11% Ongoing Phase 2 trial in mismatch repair deficient or microsatellite (MSI)-high mcrc patients (NCT ) Le et al. N Engl J Med. 2015;372:2509.

56 Ongoing Trials With Anti-PD-1 Agents in MMR and MSI-high mcrc Trial Study Title Treatment Study of Pembrolizumab as Phase 2 Monotherapy in Participants NCT With Previously-Treated Locally 8 Advanced Unresectable or Metastatic Colorectal Cancer (KEYNOTE-164) Phase 2 NCT Phase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors Phase 1/2 A Study of Nivolumab and NCT Nivolumab Plus Ipilimumab in 8 Recurrent and Metastatic Colon Cancer (CheckMate 142) Pembrolizumab Monotherapy Pembrolizumab Monotherapy Nivolumab Alone or in Combination with Ipilimumab 1 Endpoint Response Rate IR-PFS & Response Rate Response Rate Status Recruitin g Recruitin g Recruitin g IR-PFS, immune-related progression free survival Accessed September 3, 2015.

57 Summary/Conclusion 059 Management of CRC involves multimodality strategies combining surgery, radiation therapy, and chemotherapy Neoadjuvant/adjuvant chemotherapy for Stage II/III is an area of active study particularly in rectal cancer Significant advances have been made over the last two decades in the treatment of mcrc mos for fluoropyrimine monotherapy: 12 months mos for targeted agent + combination chemo: >25 months However, a number of challenges still remain (eg, treatment-emergent resistance, the need for better tolerated, and effective therapy in later-line settings) More efforts are needed to better understand the underlying disease mechanisms of mcrc and to identify novel, targetable driver mutations in order to improve disease management

58 BACKUP 060

59 Treatment of Stage II/III Colon Cancer (NCCN Guidelines): The Role of Adjuvant Chemotherapy 061 Stage II Stage III Currently, there s no role of targeted agents associated with chemotherapy in the adjuvant setting for colon cancer NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V

60 Treatment of Stage II/III Rectal Cancer (NCCN Guideline) 062 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Rectal Cancer V