1 st LINE ANTI-VEGF TREATMENT OF METASTATIC COLORECTAL CANCER (CRC)

Transcription

1 1 st LINE ANTI-VEGF TREATMENT OF METASTATIC COLORECTAL CANCER (CRC)

2 Role of the VEGF Pathway in Oncogenesis

3 The Role of Angiogenesis in Cancer Somatic mutation Small avascular tumor Tumor secretion of proangiogenic factors stimulates angiogenesis Folkman J. N Engl J Med. 1971;285: Rapid tumor growth and metastasis Angiogenic inhibitors may reverse this process

4 VEGF: A Key Mediator of Angiogenesis Increased VEGF levels Environmental factors (hypoxia, ph) Genes implicated in tumorigenesis (p53, p73, src, ras, vhl, bcr-abl) Growth factors, hormones (EGF, bfgf, PDGF, IGF-1, IL-1, IL-6, estrogen) Dvorak HF. J Clin Oncol. 2002;20: Ebos JM, et al. Mol Cancer Res. 2002;1: Ferrara N, et al. Nat Med. 2003;9:

5 The Family of VEGF and VEGFRs Epigenetic Induction Hypoxia, cytokines, sex hormones, growth factors, chemokines Genetic Induction Mutant p53, VHL, PTEN-suppressor genes, and activated oncogenes (eg, ras, src, EGFR, and erb B-2/HER2) VEGF-B PIGF VEGF-A 121 VEGF-A 165 VEGF-C VEGF-D Plasma membrane s s s s VEGFR-1 (flt-1) Endothelial cell NRP-1 Raf MEK MAPK NRP-2 PKC PLCg Host VEGF VEGFR-2 (flk-1/kdr) PI3K AKT VEGFR-3 (flt-4) Vascular permeability Proliferation Survival Migration Kerbel RS. N Engl J Med. 2008;358: Mobilization (eg, of VEGFR-2+ endothelial progenitor cells)

6 The VEGF and VEGF-Receptor Family Ligand isoforms PlGF VEGF-B VEGF-A VEGF-E VEGF-C VEGF-D VEGFR-1s VEGF-A 165 Extracellular Intracellular Receptor isoforms VEGFR-1 VEGFR-2 (Flt-1) (KDR) Angiogenesis NRP-1 VEGFR-3 (Flt-4) Lymph angiogenesis tumor metastases VEGF regulates angiogenesis via interaction with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1 Shinkaruk S, et al. Curr Med Chem Anti-Canc Agents. 2003;3: Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93.

7 Mechanism of Action of Agents Targeting VEGF Ligand

8 Methods for Inhibiting VEGF-Mediated Angiogenesis VEGF ligand blockade Antibodies targeting circulating VEGF Soluble decoy receptors targeting circulating VEGF VEGFR inhibition Antibodies against VEGFR extracellular domain Small molecule TKIs that prevent VEGFR activation Ferrera N, et al. Nature. 2005;438:

9 Agents Targeting the VEGF Pathway Small-molecule VEGFR TKIs Regorafenib Cediranib BIBF1120 Sunitinib (SU11248) Sorafenib (Bay ) Pazopanib Vandetanib Axitinib Anti-VEGF antibodies (bevacizumab) Tivozanib Motesanib VEGF P P P P P P P P VEGFR-1 VEGFR-2 Endothelial cell Soluble VEGFRs (aflibercept) Anti-VEGFR antibodies (ramucirumab) Podar K, et al. Blood. 2005:105: Gori B, et al. Ther Clin Risk Manag. 2011;7:

10 Bevacizumab Bevacizumab: a recombinant anti-vegf antibody Created by transferring the VEGF-binding regions of the murine antibody to a humanized IgG 1 framework (93% human, 7% murine) Produces a humanized IgG antibody Mediates blockade of VEGF ligand Binds and neutralizes all biologically active isoforms of VEGF FDA/EMA approved for lung cancer (NSCLC), glioblastoma, renal cancer, colorectal cancer, breast cancer, ovarian cancer, cervical cancer

11 First-line Chemotherapy + Bevacizumab in mcrc: Efficacy Comparative Regimens, Mos PFS OS IFL/Bev vs IFL [1] 10.6 vs vs 15.6 FOLFOX4/XELOX/Bev vs FOLFOX4/XELOX [2] 9.4 vs vs 19.9 FOLFOX/Bev vs FOLFIRI/Bev [3] 10.3 vs vs Hurwitz H, et al. N Engl J Med. 2004;350: Saltz LB, et al. J Clin Oncol. 2008;26: Bendell JC, et al. Oncologist. 2012;17:

12 AVF2107g: phase III trial of Bevacizumab + IFL for the 1L treatment of mcrc Previously untreated mcrc (n=923) R Bevaciz 5 mg/kg q2w + IFL (n=402) Placebo + IFL (n=411) Bevacizumab + 5-FU/LV (n=110)* Primary endpoint: OS Secondary endpoints: PFS, ORR, duration of response, safety and QoL *Pre-specified discontinuation of enrolment in arm 3 when Bevacizumab in combination with the bolus-ifl regimen was deemed no more toxic than with 5-FU/LV Hurwitz, et al. NEJM 2004

13 OS estimate PFS estimate AVF2107g: efficacy OS PFS 1.0 Bevaciz + IFL (n=402) Placebo + IFL (n=411) 1.0 Bevaciz + IFL (n=402) Placebo + IFL (n=411) 0.8 HR=0.66 p< HR=0.54 p< Time (months) Time (months) Hurwitz, et al. NEJM 2004

14 NO16966: phase III trial of Bevacizumab + FOLFOX4/ XELOX for the 1L treatment of mcrc 1,2 Recruitment June 2003 May 2004 Recruitment Feb 2004 Feb 2005 XELOX (n=317) Placebo + XELOX (n=350) Bevaciz 7.5mg/kg q3w + XELOX (n=350) FOLFOX4 (n=317) Placebo + FOLFOX4 (n=351) Bevaciz 5mg/kg q2w + FOLFOX4 (n=349) Initial 2-arm, open-label study (n=634) Protocol amended to 2x2 placebo-controlled design (n=1,400) after Bevacizumab phase III data became available 3 Primary endpoint: PFS Secondary endpoints: PFS on treatment, OS, ORR, duration of response, time to treatment failure 1. Cassidy, et al. JCO 2008; 2. Saltz, et al. JCO 2008; 3. Hurwitz, et al. NEJM 2004

15 PFS estimate OS estimate NO16966: efficacy PFS OS 1.0 Bevacizumab + XELOX/FOLFOX4 (n=699) Placebo + XELOX/FOLFOX4 (n=701) 1.0 Bevacizumab + XELOX/FOLFOX4 (n=699) Placebo + XELOX/FOLFOX4 (n=701) 0.8 HR=0.83 (97.5% CI: ) p= HR=0.89 (97.5% CI: ) p= Time (months) Time (months) Saltz, et al. JCO 2008

16 AVEX: phase III of Bevacizumab + Capecitabine for 1L treatment of mcrc patients 70 Previously untreated mcrc, age 70 years (n=280) R Bevacizumab 7.5 mg/kg q3w + Capecitabine (1000 mg/m 2 b.i.d, days 1-14) (n=140) Capecitabine (n=140) Primary endpoints: PFS Secondary endpoints: ORR, time to response, duration of response, OS, safety Cunningham, et al. ASCO GI 2013

17 PFS estimate OS estimate AVEX: Efficacy PFS OS* 1.0 Cape + Bevacizumab (n=140) Capecitabine (n=140) 1.0 Cape + Bevaciz (n=140) Capecitabine (n=140) HR 0.53 p< HR 0.79 p= Time (months) Time (months) *Study was not powered to detect differences in OS between treatment arms Cunningham, et al. ASCO GI 2013

18 p=0.137 p=0.582 p p=0.160 p= p=0.314 p=0.014 p=0.182 Median OS (months) Summary: OS in RCTs of Bevacizumab 1L 25 AVF0780g (n=104) 1 AVF2107g (n=813) 2 AVF2192g (n=209) 3 NO16966 (n=1,400) 4 AGITG MAX (n=313) 5 ARTIST (n=214) 6 AVEX (n=280) Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM 2004; 3. Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO 2008; 5. Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer 2011; 7. Cunningham, et al. ASCO GI 2013

19 p=0.005 p=0.217 p p= p= p p p Median PFS (months) Summary: PFS in RCTs of Bevacizumab 1L 15 AVF0780g* (n=104) 1 AVF2107g (n=813) 2 AVF2192g (n=209) 3 NO16966 (n=1,400) 4 AGITG MAX (n=313) 5 ARTIST (n=214) 6 AVEX (n=280) *TTP 1. Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM 2004; 3. Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO 2008; 5. Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer 2011; 7. Cunningham, et al. ASCO GI 2013

20 Bevacizumab-Associated Toxicity Adverse Event Grade 3 ATE Grade 3/4 HTN Incidence With Bev Across Indications, [1] % 2.6 GI perforations Grade 3 hemorrhagic event Wound complications Comments Risk of ATE increased in pts 65 yrs of age or older or with ATE history 5-18* Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed 15 *Predominantly grade 3. May apply more to NSCLC. When surgery conducted during bev therapy. Bev not recommended for pts with active hemorrhage Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors Discontinue 4-8 wks before surgery; resume 6-8 wks postsurgery Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others. [2,3] 1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; Nalluri SR, et al. JAMA. 2008;300; Hurwitz H, et al. J Clin Oncol. 2011;29:

21 Strategies for patients with good disease control after 1 st line chemo Continuous therapy until progression or toxicities Maintenance therapy Treatment holidays

22 Progression Progression Phase III CAIRO3 trial of continued bevacizumab + capecitabine versus observation PFS1 PFS2/ TT2P Arm A Previously untreated mcrc (n=558) Bev + CAPOX (x6) CR PR SD R Observation Bev + capecitabine PFS2: re-introduction Bev + CAPOX TT2P: any treatment combination, including Bev + CAPOX Arm B Primary endpoint: PFS after re-introduction = PFS2 Secondary endpoints: PFS1, OS, TT2P, ORR, safety Koopman, et al. ASCO 2013

23 Progression Progression CAIRO3: definition of PFS1 PFS1 Arm A Previously untreated mcrc (n=558) Bev + CAPOX (x6) CR PR SD R Observation Bev + capecitabine PFS2: re-introduction Bev + CAPOX TT2P: any treatment combination, including Bev + CAPOX Arm B PFS1: time from randomisation until first progression after observation or maintenance treatment Koopman, et al. ASCO 2013

24 PFS1 estimate CAIRO3: secondary endpoint of PFS Maintenance bevacizumab Observation Median PFS1, months Stratified HR (95% CI) 0.44 ( ) p< Adjusted* HR 0.41 p< Time (months) Pts at risk Observation Continued Bev *Adjusted for covariates with imbalances at baseline Koopman, et al. ASCO 2013

25 Progression Progression CAIRO3: definition of TT2P TT2P Arm A Observation Previously untreated mcrc (n=558) Bev + CAPOX (x6) CR PR SD R Any treatment combination, including Bev + CAPOX Bev + capecitabine Arm B TT2P: time to second progression of disease, time from randomisation to progression upon any treatment including bevacizumab + CAPOX, given after PFS1 Koopman, et al. ASCO 2013

26 TT2P estimate CAIRO3: TT2P Maintenance bevacizumab Observation Median TT2P, months Stratified HR (95% CI) 0.67 ( ) p= Adjusted* HR 0.63 p= Pts at risk Observation Continued Bev Time (months) *Adjusted for covariates with imbalances at baseline Koopman, et al. ASCO 2013

27 Maintenance Bevacizumab: MACRO Trial Patients with newly diagnosed mcrc and ECOG PS 2 Capecitabine + Oxaliplatin + Bevacizumab x 6 cycles q3w (n = 239) Capecitabine + Oxaliplatin + Bevacizumab x 6 cycles q3w (n = 241) Capecitabine + Oxaliplatin + Bevacizumab until progression Bevacizumab until progression Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.

28 Survival Probability MACRO: Overall Survival (ITT) XELOX-Bev Bev Patients, n Events, n (%) 175 (73) 174 (7%) Censored, n (%) 64 (27) 67 (28) Median (95% CI) 23.2 (19.79, ) ( ) HR: 1.05 (95% CI: ) 0.25 XELOX-Bev Bev Patients at Risk, n XELOX-Bev Bev Mos Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.

29 TRIBE: phase III trial of 1L bevacizumab + FOLFOXIRI vs bevacizumab + FOLFIRI followed by bevacizumab/5-fu/lv until progression Induction Maintenance Previously untreated, unresectable mcrc R Bevacizumab + FOLFIRI (up to 12 cycles) (n=508) Bevacizumab + FOLFOXIRI (up to 12 cycles) Bevacizumab + 5-FU/LV Bevacizumab + 5-FU/LV PD PD Primary endpoint: PFS Secondary endpoints: response rate, secondary R0 resection rate, OS, safety, biomarker evaluation Falcone, et al. ASCO 2013

30 TRIBE: FINAL OS RESULTS Cremolini et al. ASCO GI 2015

31 TRIBE: toxicity profile Grade 3/4 AE, % Bevacizumab + FOLFIRI (n=254) Bevacizumab + FOLFOXIRI (n=250) p-value Nausea Vomiting Diarrhoea Stomatitis Neutropenia <0.001 Febrile neutropenia Neurotoxicity 0 5 <0.001 Hypertension Venous thrombosis Arterial thrombosis Bleeding Safety population; yellow box indicates a difference in incidence of grade 3 AE between treatment arms of 5% Falcone, et al. ASCO 2013

32 Bevacizumab + chemotherapy & potentially curative resection of liver mets Study Experimental arm n R0 resection rate (%) ORR (%) NO Bevacizumab + XELOX/FOLFOX NR First-BEAT 1 Bevacizumab + chemotherapy NR ETNA 2 Bevacizumab + chemotherapy NR Gruenberger* 3 Bevacizumab + XELOX BOXER 4 Bevacizumab + XELOX GONO 5 Bevacizumab + FOLFOXIRI Trials in patients with borderline resectable disease NR = not reported *Patients borderline resectable based on multiple risk factors for early recurrence ; NR in patients with liver-only metastases 1. Okines, et al. Br J Cancer 2009; 2. Smith, et al. ESMO Gruenberger, et al. JCO 2008; 4. Wong, et al. Ann Oncol Masi, et al. Lancet Oncol 2010

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34 Aflibercept (VEGF-Trap) Fully human fusion protein consisting of VEGFR-1 Ig domain 2 VEGFR-2 Ig domain 3 Human IgG1 Fc ~ 110,000 MW Kd = 0.5 pm for VEGF 164 Blocks VEGF and PlGF Stronger binding than Bev t 1/2 ~ 17 days In phase III development VEGFR-1 K d pm The Structure of VEGF Trap VEGFR-2 K d pm Fc VEGF Trap K d < 1 pm t 1/2 ~ 25 days VEGF-Trap is a fusion protein consisting of VEGFR-1 Ig domain 2 and VEGFR-2 lg domain 3 bound to human IgG1 Fc. VEGF-Trap contains all human amino acids and has a K d of 0.5 pm for VEGF 165.

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36 Role of VEGF Pathway in Tumor Growth VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGF-A Ramucirumab VEGFR2 VEGFR2 Endothelial cell membrane VEGF-A VEGF-C VEGF-D Ramucirumab binds to VEGFR2, blocks VEGF ligand binding Ligand binding activates VEGFR2 and p44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vessel formation and tumor growth

37 Multiple signaling pathways activated in CRC

38 3 rd LINE 2 nd LINE E3200 ML18147 Chemo +Bevacizumab vs Chemo +Placebo months months VELOUR FOLFIRI +Aflibercept vs FOLFIRI +Placebo 13.5 months 12.0 months RAISE FOLFIRI +Ramucirumab vs FOLFIRI +Placebo 13.3 months 11.7 months CORRECT Regorafenib vs Placebo 6.4 months 5.0 months

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41 RAISE: SAFETY ANALYSIS Addition of Ramucirumab to FOLFIRI associated with: Higher incidence of hypertension Severe neutropenia: 38.4% vs 23.3%), Severe fatigue: 11.5% vs 7.8% Severe thrombocytopenia: 3.0% vs 0.8% Severe proteinuria: 3.0% vs 0.2% Ramucirumab did not appear to increase febrile neutropenia: 3.6% vs 2.7%

42 CORRECT: Common Adverse Events Treatment-related adverse events occurring in >10% of patients in either group from start of treatment to 30 days after end of treatment Regorafanib (n=500) Placebo (n=253) Any Gr Gr 3 Gr 4 Any Gr Gr 3 Gr 4 Fatigue, n (%) 237 (47) 46 (9) 2 (<1) 71 (28) 12 (5) 1 (<1) Hand-foot skin reaction, n (%) 233 (47) 83 (17) 0 19 (8) 1 (<1) 0 Diarrhea, n (%) 169 (34) 35 (7) 1 (<1) 21 (8) 2 (1) 0 Anorexia, n (%) 152 (30) 16 (3) 0 39 (15) 7 (3) 0 Voice changes, n (%) 147 (29) 1 (<1) 0 14 (6) 0 0 Hypertension, n (%) 139 (28) 36 (7) 0 15 (6) 2 (1) 0 Oral mucositis, n (%) 136 (27) 15 (3) 0 9 (4) 0 0 Rash or desquamation, n (%) 130 (26) 29 (6) 0 10 (4) 0 0 Nausea, n (%) 72 (14) 2 (<1) 0 28 (11) 0 0 Weight loss, n (%) 69 (14) (2) 0 0 Thrombocytopenia, n (%) 63 (13) 13 (3) 1 (<1) 5 (2) 1 (<1) 0 1. Grothey A, et al. Lancet [epub].

43 Approx. Prices per month Bevacizumab -> 1, /month Aflibercept -> 2, /month Regorafenib -> 3, /month Ramucirumab -> ~10,000 /month (?)

44 Overall survival in phase III trials 1997 ~12 months 1* 2007 >20 months >30 months 6,7 *Based on a meta-analysis of >19 trials of 5-FU/LV 1. Thirion, et al. JCO 2004; 2. Hurwitz, et al. NEJM Van Cutsem, et al. NEJM 2009; 4. Van Cutsem, et al. JCO Goldberg, et al. Oncologist 2007; 6. Falcone, et al. ASCO 2013; 7. Takahari, et al. ASCO 2013