Written by Mauricio Lema Medina based on his notes and on the slides provided by the
On his talk on “Angiogenesis, The Importance of early and continuous exposure”, Dr. Carlos Gil Ferrerira of the Instuto Nacional de Cancer of Brazil, Rio de Janeiro, discussed the biologic basis of angiogenesis as a key factor for neoplastic proliferation. The importance of angiogenesis was recognized for the first time in 1971, by Judah Folkman. The Vascular Endothelial Growth Factor (VEGF) was isolated and cloned by Ferrara en 1989. The first clinical trials with antiangiogenic therapy were conducted in the late 1990s. These were negative. Bevacizumab – a monoclonal antibody that binds to VEGF – increased the survival of patients with advanced colorectal cancer in a pivotal trial, published in 2003 (1). Bevacizumab was FDA approved in 2004 as first-line therapy for metastatic colorectal cancer (along with chemotherapy).
Dr. Ferreira discusses the importance of the angiogenic switch by which a small avascular tumor releases pro angiogenic substances that foster new vessels formation that can support an increase in tumor size, allowing cellular proliferation. Of the host of angiogenic substances, VEGFa appears to be critical for this process. VEGFa is a 45 kDalton protein, with four common isoforms: p121, p165, p189, and p206, all of which are recognized by bevacizumab.
There are three types of VEGF receptors (VEGFR) located on the cell membrane of target tissues. The VEGFR1 and 2 appear to be involved in angiogenesis, whereas VEGFR3 appears to be related to lymphangiogenesis. VEGFa is one of the ligands of VEGFR1, and is the most important ligand of VEGFR2. These receptors cause proliferation through their tyrosine-kinase activities of their intracellular domains. The activation of these signals cause proliferation of endothelial cells and new vessel formation. These new vessels are “leaky” with increased permeability, enhancing tumor spread, and decreasing tumor penetration of cytotoxic agents. VEGF acts on NORMAL endothelial cells surrounding neoplastic cells. No normal process has been recognized to be VEGF dependent in adults. These last two characteristics make the VEGF-pathway very attractive to pharmacologic manipulation.
Most human tumors express VEGF. Close to 100% of patients with colorectal cancer, breast cancer and renal-cell carcinoma, Acute myeloid leukaemia and chronic myeloid leukaemia express VEGF. More than 50% of patients with lung cancer, also express VEGF. Of even more significance, overexpression of VEGF worsens the prognosis of the vast majority of tumors.
Several therapeutic strategies have been devised to counteract angiogenesis in neoplasia. These include anti VEGFr monoclonal antibodies, small tyrosine-kinase inhibitors, ribozymes, soluble VEGRr (VEGF-TRAP), and anti VEGF monoclonal antibodies (Bevacizumab).
Bevacizumab is a recombinant, humanized, IgG1 monoclonal antibody, based on the murine anti-VEGF MAb A4.6.1. Bevacizumab is 7% murine and 93% human, and it binds to all VEGF isoforms with high affinity (Kd = 8 × 10–10M). The terminal half-life or bevacizumab is 17-21 days.
MECHANISM OF ACTION
Bevacizumab may act against tumours in 3 ways: regression of existing tumour microvasculature; normalisation of surviving tumour vasculature; inhibition of tumour-vessel regrowth and neovascularisation.
Regression: Within 24 hours, inhibition of VEGF has been shown to inhibit endothelial cell proliferation and migration and to suppress new vascular sprouting (2, 14).
Normalization: Anti-VEGF therapy reverses structural and functional abnormalities in surviving tumour vasculature: normalises vessel size, shape and permeability (3); reduces intratumoural pressure (4,5); improves oxygenation. The normalization of the surviving tumour vasculature increases the delivery of chemotherapy agents to the cancer cells.
Pre-treatment with bevacizumab has increased by 46% the delivery of irinotecan to tumor cells (6). This has led to an increase in the response rate of 10-15% for those chemotherapy-treated patients receiving bevacizumab in colorectal cancer (1, 7, 8, 9). These findings have been confirmed in metastatic breast cancer, and NSCLC (10,11).
Inhibition of tumour-vessel regrowth and neovascularisation is the third mechanism of action of bevacizumab: it has been recognized that withdrawal of bevacizumab will eventually lead to re-growth of vessels (12, 13). This continuous inhibition of tumour-vessel formation may explain the 71% increase in the progression-free survival of patients continuously treated (1), compared to the paltry 21% increase of progression-free survival observed in the Tree -1 / -2 studies also in metastatic colorectal cancer (14). This mechanism appears to be important even after PROGRESSION of disease (at least in colorectal cancer), as shown in the BRITE study: patients that continued bevacizumab after progression, had a 10 month survival advantage over those who did not (15).
In conclusion, Bevacizumab has early effects: regression of neovasculature; normalization of surviving mature vasculature. These early events increase the response rate, and improve the ability to deliver cytotoxic agents to the cancer cells, respectively (1, 2, 5, 7, 8, 9, 10, 15, 17, 21, 22).
Bevacizumab also has continued effects with inhibition of growth of recurrent and new vessels (5, 16, 17). This translates into extended survival and delay of disease progression, potential for adjuvant treatment, and maintenance of stable disease through sustained inhibition of tumour growth (1, 7, 10, 9, 17-20)
1. Hurwitz H, et al. N Engl J Med 2004;350:2335-42
2. Baluk P, et al. Curr Opin Genet Dev 2005,
3. Jain RK. Nat Med 2001;7:987-9; Jain RK. Science 2005;307:58-62
4. Lee CG et al. Cancer Res 2000;60:5565-70
5. Willett CG et al. Nat Med 2004;10:145-7
6. Wildiers, et al. Br J Cancer 2003 (INCOMPLETE)
7. Kabbinavar FF, et al. J Clin Oncol 2005;23:3697-705
8. Giantonio BJ, et al. J Clin Oncol 2005;23:1s(suppl;abs 2)
9. Miller K, Wang M, Gralow J et al. Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer N Engl J Med 2007 357: 2666-2676
10. Sandler AG, Robert PMC, Brahmer J, et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer N Engl J Med 2006 355: 2542-2550)
11. Vosseler S, et al. Cancer Res 2005;65:1294-305
12. Mancuso JCI 2008;116-2610
13. Hochster HS, et al. Proc ASCO GI Cancers Symposium 2006;abs 244
14. Grothey, et al. ASCO 2007 (INCOMPLETE)
15. Gerber HP, et al. Cancer Res 2005;65:671-80;
16. Inai T, et al. Am J Pathol 2004;165:35-52
17. Yang JC, et al. N Engl J Med 2003;349:427-34
18. Hoff PM, et al. Oncology 2004;18(6):736-46
19. Venook A. Oncologist 2005;10:250-61;
20. Mass R, et al. J Clin Oncol 2005;23:249s(suppl;abs 3514)
21. Cobleigh MA, et al. Semin Oncol 2003;30:117-24
22. Burger RA, et al. J Clin Oncol 2005;23(suppl;abs 5009)
The second lecture was imparted by Paulo M. Hoff - Diretor Executivo Centro de Oncologia Hospital Sírio Libanês São Paulo SP, Brazil on “Anti-angiogenesis in the treatment of colorectal cancer”. Doctor Hoff starts by displaying all the new agents available today for the treatment of colorrectal cancer: fluoropyrimidine derivatives such as fluoruracil, capecitabine, FUDR, UFT; oxaliplatin; irinotecan; anti-VEGF like bevacizumab; and anti-EGFR agents including cetuximab and panitumomab.
Taken from the slide: “The N9741 study, conducted by Goldberg and colleagues, was a multicenter trial comparing combinations of 5-FU/LV, irinotecan, and oxaliplatin in patients with previously untreated metastatic CRC. The original study included 3 additional patient groups treated with 5-FU/LV plus oxaliplatin, 5-FU/LV plus irinotecan, or 5-FU/LV alone. The investigators, in collaboration with the North Central Cancer Treatment Group External Monitoring Committee, made the decision to delete these 3 arms of the study due to unexpected toxicity even after dose reduction, leaving only the FOLFOX4 and IROX arms and the IFL control regimen to be examined for efficacy and toxicity. Patients were randomly assigned to receive either IFL, FOLFOX4, or IROX. Assignment of patients was based on performance status score (0, 1/2), prior adjuvant chemotherapy (yes or no), prior immunotherapy (yes or no), age (<65 years or ≥65 years), and randomizing location. Eligible patients required at least one measurable lesion (≥2 cm in diameter) or assessable disease. Patient characteristics were similar across the 3 arms” (Goldberg, et al. J Clin Oncol 2004). This trial established FOLFOX as the reference standard for metastastic colorectal cancer because of a superior response rate as compared to IFL (45% vs 31%); better time to progression (8.7 months vs 6.9 months); and better median overall survival (19.5 months vs 14.8 months).
The next step was: “The efficacy 5-FU/LV in combination with irinotecan or oxaliplatin in patients with metastatic CRC has been well documented in various phase II trials. To determine the most effective sequence of therapy, researchers randomized patients receive either a 2-hour infusion of leucovorin (200 mg/m2 or 400 mg/m2) on day 1 and irinotecan (180 mg/m2) followed by bolus 5-FU (400 mg/m2) and a 46-hour infusion of 5-FU (2400-3000 mg/m2) every 2 weeks (FOLFIRI) or the same regimen with oxaliplatin (100 mg/m2) replacing irinotecan on day 1 (FOLFOX6). Patients received the assigned therapeutic regimen until progression or unacceptable toxicity, at which time they crossed over and received the alternate regimen. Patients in the FOLFIRI group were crossed over to receive FOLFOX6 and those in the FOLFOX6 group were crossed over to the FOLFIRI arm. Of 109 patients randomized to FOLFIRI treatment, 81 (74%) were switched to FOLFOX6. Of 111 patients randomized to FOLFOX6, 69 (62%) switched to FOLFIRI. Analyzing the results of the FOLFIRI vs FOLFOX 6 study, it appeared that neither sequence of administration appeared to convey any benefit over the other.1 First-line therapy with either FOLFOX 6 or FOLFIRI produced similar response rates (56% vs 54%, respectively). Median progression-free survival for Arm A (FOLFIRI®FOLFOX 6) and Arm B (FOLFOX 6®FOLFIRI) after first-line therapy was 8.5 and 8.0 months, respectively, and after second-line therapy was 14.2 months for Arm A and 10.9 months for Arm B; however, these differences were not statistically significant. Overall survival of patients in treatment Arm A was similar to that in treatment Arm B (21.5 vs 20.6 months, respectively). Following first-line treatment, more patients had grade 3/4 neutropenia (44% vs 25%) and neurotoxicity (34% vs 0%) with FOLFOX 6 than with FOLFIRI.2 Patients receiving FOLFIRI experienced more frequent grade 3/4 nausea (13% vs 3%), stomatitis (10% vs 1%), and grade 2 alopecia (24% vs 9%) than patients receiving FOLFOX 6. The incidence of grade 3/4 diarrhea was similar in the two arms (15% in both). Preliminary results from another, more recent trial comparing FOLFOX and FOLFIRI in patients with advanced CRC suggested little difference between the two regimens in terms of major response (36% vs 34%, respectively). FOLFIRI was associated with higher incidences of grade 3/4 diarrhea (12% vs 4%) and grade 2 alopecia (42% vs 22%), compared with FOLFOX, however, as with the Tournigand trial, more patients receiving FOLFOX experienced neurological toxicities (44% vs 0%) compared with the FOLFIRI regimen. (Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX 6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237; Hobday T, Goldberg M. Perspectives on the role of sequential or combination chemotherapy for first-line and salvage therapy in advanced colorectal cancer. Clin Colorectal Cancer. 2002;2:161-169; Colucci G et al. Preliminary results of a randomized multicenter trial of the Gruppo Oncologico Italia Meridinale (GOIM) comparing FOLFIRI vs FOLFOX in advanced colorectal cancer (ACC) patients [abstract]. Proc Am Soc Clin Oncol. 2003;22:255. Abstract 1021)
“An updated meta-analysis has confirmed their earlier report exposing patients with advanced colorectal cancer (CRC) to all active cytotoxic lines during the course of treatment improves overall survival (OS). In this report, Grothey and Sargent analyzed data from 21 arms of 11 published phase III trials, which enrolled 5768 patients and for whom data on exposure to all 3 cytotoxic agents (eg, fluorouracil, irinotecan, and oxaliplatin) were available. At the trial-arm level, the percentage of patients who received all 3 cytotoxic agents was significantly correlated with the OS for that arm (P=.0001). In multivariate analysis, survival correlated significantly with exposure to 3 drugs; however, the use of first-line doublet therapy was not significantly associated with OS. From these data, the investigators concluded that the OS of patients with advanced CRC correlates with the availability of all 3 drugs, regardless of whether single-agent or doublet therapy is used in the first-line setting. However, use of upfront doublet therapy increases the likelihood that patients will go on to received all 3 active cytotoxic agents. Use of combination regimens and multiple lines of therapy may increase risks of adverse efffects. (Grothey A. Integrating biologics and chemotherapy in the systemic treatment of colorectal cancer. American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium. General Session.Grothey A and Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23:9441-94429.”
The duration of oxaliplatin-based chemotherapy in metastatic colorectal cancer has been the subject of the OPTIMOX trials. In the OPTIMOX-1, 626 patients were randomized to either FOLFOX4 administered every 2 weeks until progression or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7. No difference in survival or response rates was observed between the treatment arms. Therefore, a shorter duration of oxaliplatin-based therapy followed by maintenance therapy could preserve survival benefit while limiting toxicity and reducing costs compared with continuing FOLFOX4 until progression (Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394-400). In the OPTIMOX2 trial, however, patients who received a complete chemotherapy-free holiday were compared with the 5-FU maintenance approach of OPTIMOX1 in 200 patients. Compared with patients receiving maintenance therapy, those who received a chemotherapy-free holiday had shorter progression-free and overall survival rates (36 vs 29 weeks; 26 vs 19 months, respectively) Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): a GERCOR study. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 4013.
The OPTIMOX strategy was not a part of Dr. Hoff’s presentation, but it is of importance, and it would be in this position in this lecture.
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Falcone devised FOLFOXIRI, a regimen that incorporates irinotecan, oxaliplatin, and fluoruracil. Response rate to FOLFOXIRI was 60%, with a progression-free and overall-survival of almost 10 months, and 22.6 months, respectively (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: 1670-1676). No further benefit with conventional cytotoxic agents is expected in metastatic colorectal cancer (at least with the available agents).
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In the CRYSTAL study, 1217 chemo-naïve patients with metastastic colorectal cancer were randomized to FOLFIRI or FOLFIRI + Cetuximab (A monoclonal antibody against the Epidermal Growth Factor Receptor). The response rate was higher in the cetuximab-containing group (46.9% vs 38.7%, respectively). The median progression-free survival, the main study outcome, was also superior in the cetuximab-containing group (8.9 vs 8 months, respectively; p = 0.04). (Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 4000).
The results of the CRYSTAL trial were not a part of Dr. Hoff’s presentation, but they are important, and it would be in this position in this lecture.
The benefit of anti-EGFR therapy appears to be confined to those patients harboring wild-type K-RAS; mutated K-RAS is associated with significant resistance to these agents. No single standard K-RAS assay has been adopted as a gold-standard, so it is not ready for prime-time (Finocchiaro G, Cappuzzo F, Jänne PA, et al. EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 4021; Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166-1169)
Dr. Hoff briefly reviews the basis for anti-angiogenic therapy in colorectal cancer including bevacizumab and its mechanism of action. Dr. Hoff underscored the feasibility and safety of a short infusion for this agent (5 mg/kg/10 minutes), based on several reports (Saltz LB, Chung KY, Timoney J, Park V and Hollywood E. Simplification of bevacizumab (bev) administration: Do we need 90, 60, or even 30 minute infusion times? J Clin Oncol 2006;24(June 20 Suppl.):156s (Abstract 3542; Reidy D, Chung KY, Timoney J, et al. Bevacizumab 5mg/kg can be safely infused over 10 minutes. J Clin Oncol 2007;25(June 20 Suppl.):197s (Abstract 4135)).
The toxicity profile of Bevacizumab does not overlap with that of conventional cytotoxic agents and include: hypertension, proteinuria, arterial thromboembolic events, gastrointestinal perforation, minor bleeding (eg: epistaxis), wound-healing problems.
A study of 800 patients investigated the efficacy and safety of bevacizumab (BV) in combination with bolus IFL as first-line therapy for metastatic colorectal cancer. Patients were randomized to receive one of 3 treatment strategies: IFL plus placebo with no BV allowed, even after disease progression (n=412), IFL plus BV with optional BV after disease progression (n=403), or 5-FU/LV plus BV with optional BV after disease progression (n=110). IFL treatment included bolus 5-FU (500 mg/m2), LV (20 mg/m2), and irinotecan (125 mg/m2) administered on weeks 4 and 6. 5-FU/LV treatment included bolus 5-FU (500 mg/m2) and LV (500 mg/m2) administered on week 6 and 8. BV (5 mg/kg) was administered every 2 weeks. The primary endpoint for the study was duration of survival. Secondary endpoints included response rate (PR + CR), PFS, QOL, and safety. Bevacizumab reached its primary end points in this trial, resulting in improved survival, PFS, ORR, and duration of response. Median survival: 15.6 months with IFL + placebo vs 20.3 months for IFL + bevacizumab (P=0.00004).
PFS: 6.24 months with IFL + placebo vs 10.6 months for IFL + bevacizumab (P<0.00001). ORR: 35% with IFL + placebo vs 45% for IFL + bevacizumab (P=0.0036). Duration of response: 7.1 months with IFL + placebo vs 10.4 months for IFL + bevacizumab (P=0.0014). Interestingly, the increase in ORR was similar to the increase in ORR in the phase III bevacizumab trial in patients with MBC (10%).
The success of this trial may be due in part to tumor type, combination therapy used, or the stage of disease. Agents that block angiogenesis may have more clinical benefit when administered earlier in disease progression, before tumor vasculature becomes entrenched.
Progression-free survival was also significantly increased by 71% in the IFL plus Avastin arm (10.6 [95% CI 9.0–11.0] vs 6.2 [95% CI 5.6–7.7] months, p<0.001).
The stratified HR for disease progression or death during first line therapy in the IFL plus Avastin arm relative to the IFL plus placebo arm was 0.54 (95% CI 0.45–0.66).
It is interesting to note that the difference in overall and progression-free survival between the two treatment arms is relatively constant at 4.7 and 4.4 months.
Together with the study design, in which the treatment arms differed only with the addition of Avastin to IFL, this suggests that the increase in survival is due to the addition of Avastin. (Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42).
The addition of Avastin 5mg/kg every 2 weeks to 5-FU/LV significantly improved progression-free survival compared with chemotherapy alone (8.8 vs 5.6 months, respectively; p=0.0001), with a 37% decrease in the risk of progression.1
The absolute improvement in progression-free survival, at 3.2 months, is similar to that in overall survival (3.3 months), suggesting that the benefit is due to the addition of Avastin to chemotherapy. The inclusion of IFL-treated patients in the control arm biases against seeing a benefit of adding Avastin to 5-FU/LV. Data pooled from 2107, 0780 and 2192 (Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23:3706–12).
The use of Bevacizumab with FOLFIRI was explored in a Phase IV Clinical Trial in 209 chemo-naïve metastatic colorectal cancer patients. The Avastin plus FOLFIRI regimen has been generally well tolerated, with a similar safety profile to that of Avastin plus IFL reported in the pivotal trial.1 The most common adverse events of special interest for Avastin were hypertension (5%), ATEs (4%) and bleeding (4%). A total of 117 (56%) deaths were reported, the majority of which were due to progressive disease. The remaining 13 deaths were due to pulmonary embolism (n=2); myocardial infarction (n=1); anal fistula (n=1); aortic dissection (n=1); cardiac arrest (n=1); hepatic failure (n=1); large intestinal perforation (n=1); neutropenic sepsis (n=1); small intestinal obstruction (n=1); tumour haemorrhage (n=1); and unknown cause (n=2). Overall, 24% of patients had an adverse event leading to discontinuation of treatment. The most common events leading to discontinuation were gastrointestinal disorders. Additionally, adverse events leading to dose modification or treatment interruption of any component occurred in 77% of patients. The 60-day mortality rate was 2%. These data support the use of Avastin in combination with FOLFIRI for the first-line treatment of patients with metastatic CRC. At the time of reporting, 111 (53.1%) patients have had an objective response, including eight (3.8%) complete and 103 (49.3%) partial responses. Stable disease has been seen in 68 (32.5%) patients. Median progression-free and overall survival were 11.1 months and 22.2 months, respectively, which are comparable to that observed with Avastin plus IFL (10.6 months and 20.3 months) in the pivotal trial. Median progression-free survival in the ITT population was 11.1 (95% CI: 10.3–12.1) months. Median overall survival in the ITT population was 22.2 (95% CI: 20.5–25.9) months. (Ackland S, Clarke S, Perez-Carríon R, et al. Updated efficacy data from AVIRI, a large phase IV trial of first-line bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer. Presented at: 2008 Gastrointestinal Cancers Symposium; 25–27 January 2008; Orlando, Fl. Abstract 463. Available at: http://www.asco.org. Accessed 30 January 2008).
The combination of Avastin with first-line FOLFIRI has also been investigated in a US-based, single-arm phase II study in patients with metastatic CRC. A total of 43 patients received FOLFIRI (irinotecan 180mg/m2, bolus 5-FU 400mg/m2 and leucovorin 400mg/m2, followed by infusional 5-FU 2,400mg/m2 over 46 hours). Avastin 5mg/kg was given every 2 weeks. The primary endpoint was progression-free survival. Preliminary data for all 43 patients show that the median progression-free survival is currently 12.5 months. A total of 26 (60%) patients had a response to therapy (all partial responses), with a median time to response of 4 months. Five (11%) patients had stable disease. The median progression-free survival, at 12.5 months is superior to FOLFIRI alone (8.5 months)2 and compares favourably with Avastin plus IFL in the pivotal phase III trial (10.6 months).3 Data for median overall survival are not mature; the 12- and 20-month survival rates are 95% and 75%, respectively (Kopetz S, Glover K, Chang DZ, et al. Phase II study of infusional-5FU, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer. J Clin Oncol 2007;25(June 20 Suppl.):185s (Abstract 4089)).
In second-line chemotherapy, the combination of bevacizumab + FOLFOX exhibits superior progression-free (4.8 vs 7.2 months) and overall survival (10.8 vs 12.9 months) (Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)).
The addition of bevacizumab to FOLFOX or XELOX in first-line chemotherapy does not appear to increase the response rate (47% vs 49%) No explanation for this observation has been found. Despite this finding, bevacizumab appears to significantly increase progression-free survival (8 vs 9.4 months, p=0.02). Patients treated with bevacizumab show a trend towards better overall survival (19.9 vs 21.3, 0.07) when added to oxaliplatin-based chemotherapy (Saltz L, Clarke S, Díaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/ NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. J Clin Oncol 2007;25(June 20 Suppl.):170s (Abstract 4028)). It has been speculated that the sub-optimal survival achieved in this trial can be explained by the short exposure to bevacizumab, of about 5-6 months (bevacizumab was discontinued with XELOX or FOLFOX), as compared to other studies in which bevacizumab was continued until disease progression.
Bevacizumab in combination with XELOX or XELIRI appears to yield equivalent results, as shown by the AIO trial: a randomized phase II trial for first-line metastatic colorectal cancer patients.
In the BOND II trial, a non-chemotherapy arm with Bevacizumab and Cetuximab was compared with the addition of irinotecan to both monoclonal antibodies. The response rate, and the time to progression was superior in the group treated with the three agents.
Other trials involving of FOLFOX plus the combination of monoclonal antibodies with cetuximab and bevacizumab are underway. The preliminary results show a response rate of 56%, with a median progression-free survival that exceeds 8 months (Ocean AJ, O’Brien K, Lee J, et al. Phase II trial of FOLFOX6, bevacizumab and cetuximab in patients with colorectal cancer. J Clin Oncol 2007;25(June 20 Suppl.):182s (Abstract 4075)). A large study, the CALGB 80405, is expected to settle this issue in the future.
The First-BEAT study is a Phase IV, prospective, observational study of international (non-US) patients receiving bevacizumab plus chemotherapy in first-line metastatic colorectal cancer. About 1965 patients have been enrolled, with a median follow-up of more than 22 months. The observed progression-free survival was 10.9 months. The overall survival after 822 events is about 22.7 months (Berry S, Van Cutsem E, Michael M, et al. Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and fluoropyrimidines for mCRC: First BEAT. Presented at: 2008 Gastrointestinal Cancers Symposium; 25–27 January 2008; Orlando, Fl. Abstract 350. Available at: http://www.asco.org. Accessed 30 January 2008). This trial replicates in the community the findings of phase III trials. In this trial, close to 12% underwent hepatic metastatectomies. Those patients treated with oxaliplatin-based chemotherapy plus bevacizumab had a higher success rate in achieving an R0 state in the liver. Although preliminary, the KM curves of patients with successful metastatectomy are excellent with an almost flat line over the 80% survival (Cunningham D, Michael M, Kretzschmar A, et al. Efficacy and safety of surgery with curative intent in patients treated with first-line bevacizumab with for mCRC: First BEAT. Presented at: 2008 Gastrointestinal Cancers Symposium; 25–27 January 2008; Orlando, Fl. Abstract 445. Available at: http://www.asco.org. Accessed 30 January 2008).
A similar observational study was performed in the US, the BRiTE study. The Kaplan-Meier estimate for median overall survival for the different subgroups of patients with metastatic CRC in the BRiTE study. Data show that median overall survival is superior in patients who received Avastin post progression compared with patients who did not receive Avastin or any other therapy post progression. Similarly, survival beyond first progression was better in patients who received Avastin post progression. These are the first data to show an improvement in overall survival in patients who received first-line Avastin and continued with Avastin-based therapy post progression. (Grothey A, Sugrue M, Hedrick E, et al. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC): Results from a large observational study (BRiTE). J Clin Oncol 2007;25(June 20 Suppl.):172s (Abstract 4036)). Folfox is the combination chemotherapy favored by American oncologists (56%), followed by Folfiri (14.3%). At data cut off (September 5, 2007), preliminary median PFS and OS in the overall population was 9.9 months (95% CI, 9.5–10.3) and 23.5 months (95% CI, 22.5–25.1), respectively.
Safety data for all patients and age subgroups are available.1 Serious adverse events of special interest for Avastin in the overall group included gastrointestinal perforation (2.0%), grade 3/4 bleeding (2.6%), arterial thromboembolic events (1.8%) and new/worsening hypertension (20.7%). In addition, 60-day mortality in all patients was 2.1%. Generally the rates of adverse events were consistent across the age subgroups; however, the incidence of arterial thromboembolic events were considerably greater in patients aged ≥75 years (3.9%) and ≥80 years (3.7%). Although the crude rate of arteria thromboembolic events was higher in the ≥75 years group, the risk of these was not significantly greater than that in the <65 years group after adjustment for baseline risk factors (ECOG performance status and history of arterial thromboembolic events). These data show that the incidence of adverse events observed in clinical practice is similar to that observed in clinical trials of Avastin, even though Avastin was combined with a variety of different chemotherapy regimens in this study (Kozloff M, Sugrue MM, Berlin J, et al. Safety and effectiveness of bevacizumab and chemotherapy in elderly patients with mCRC: results from the BRiTE observational cohort study. Presented at: 2008 Gastrointestinal Cancers Symposium; 25–27 January 2008; Orlando, Fl. Abstract 454. Available at: http://www.asco.org. Accessed 30 January 2008).
Bevacizumab in the adjuvant setting: The phase III BO17920 trial is looking at FOLFOX versus FOLFOX plus Avastin versus XELOX plus Avastin in 3,450 patients with high-risk stage II or stage III colon cancer. The aim is to show an improvement in disease-free survival at 3 years for patients with stage III disease with the addition of Avastin to the current standard of care (FOLFOX4) and the likely future standard of care (XELOX). Primary endpoint is disease-free survival; secondary endpoints are safety, overall survival, pharmacoeconomic issues and pharmacodynamics.
Accrual was completed in Q2 2007. The results of this study are expected by 2010.
Bevacizumab has proven the benefit of targeting angiogenesis in colorectal cancer. Bevacizumab plus either irinotecan- or oxaliplatin-based chemotherapy increases progression-free survival. Response rate and overall survival are also increased in patients receiving irinotecan-based chemotherapy, but no similar results have been observed in oxaliplatin-based combinations in first-line chemotherapy. Interactions between the agents and schedules need to be taken into consideration. Although encouraging, the place of bevacizumab in the therapy of metastatic and non-metastatic colorectal cancer needs to be defined. Choosing the patient most likely to benefit from this (and other) agents appears to be elusive, so far.
In the next lecture, Antonio Buzaid explored the issue of anti-VEGF therapy in metastatic breast cancer.
As in other tumors, VEGF levels correlate inversely with prognosis (Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997;89:139–47; Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R. Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 2000;18:1423–31)
Bevacizumab at 10 mg/kg every two weeks was chosen for further study in metastatic breast cancer after a dose-finding study that showed similar results with 3 mg/kg and 20 mg/kg. The response rate with single-agent bevacizumab was 9.3%, including 1 complete response. The toxicity profile found is typical to anti-angiogenic therapies: hypertension in about 20%, proteinuria in 2%, thrombosis in 2-5%, severe headache in 19% - all in the 20 mg/kg dose; cardiomyopathy in 2-6% (Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30(5 Suppl. 16):117–24).
BEVACIZUMAB WITH CYTOTOXIC CHEMOTHERAPY, INCLUDING METRONOMIC CHEMOTHERAPY
Several phase II trials involving patients with metastatic breast cancer explored the addition of bevacizumab to several chemotherapeutic agents including: capecitabine, vinorelbine, docetaxel, docetaxel + capecitabine. The response rates range from 31%-52%. One interesting randomized Phase II trial enrolled 41 patients to bevacizumab combined with metronomic chemotherapy (Low dose oral methotrexate and cyclophosphamide) and 21 patients to chemotherapy without bevacizumab. Of the 34 patients enrolled to bevacizumab + chemotherapy, 10 had a partial response, and 14 had stable disease, with a 5.5 months median time to disease progression (Burstein HJ, Spigel D, Kindsvogel K, et al. Metronomic chemotherapy with and without bevacizumab for advanced breast cancer: a randomized phase II study. Breast Cancer Res Treat 2005;94:S6 (Abstract 4)). Cyclophosphamide 50 mg QD and Capecitabine 500 mg TID + Bevacizumab 10 mg/kg every two weeks is another “metronomic” chemotherapy with a 48% response rate, with very low toxicity in heavily pretreated metastastatic breast cancer patients.
BEVACIZUMAB IN INFLAMMATORY BREAST CANCER
Bevacizumab appears to be active in inflammatory breast cancer (Avastin 15mg/kg, doxorubicin 50mg/m2, docetaxel 75mg/m2 every 3 weeks). Twenty-one patients in total were enrolled. Partial response was found in 66.7%, and stable disease in 23.8; with a median survival of 25.3 months (Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumour effects of bevacizumab in inflammatory and locally advanced breast cancer patients. J Clin Oncol 2006;24:769–77).
BEVACIZUMAB IN HER2 POSITIVE BREAST CANCER
Synergy of anti HER2 and anti-angiogenic therapy has been suggested by pre-clinical data (Epstein e t al. Breast Cancer Res Treat 2002;76:S143. Abstract S70). An ongoing Phase II trial is enrolling HER2 positive metastatic breast cancer patients and treating them with bevacizumab + trastuzumab. The objective response rate so far has been 19 partial responses out of 37 patients.
PHASE III TRIALS OF BEVACIZUMAB IN METASTATIC BREAST CANCER
Capecitabine vs Capecitabine + Bevacizumab was explored in 462 patients with metastatic breast cancer in the AVF2119g trial. The response rate was higher in the Bevacizumab treated group, but the progression-free-, and overall- survival was no different in both groups (Miller KD, Chap LI, Holmes FA, et al. Randomised phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9).
Weekly paclitaxel (90 mg/m2 every week x3 of a 4 week cycle) with or without bevacizumab was studied in 722 patients with metastatic breast cancer in first line in the ECOG 2100 Trial. The response rate increased from 16.4% to 36.2%. The progression-free survival increased from 6.7 months to 13.3 months. No difference in overall survival was observed. But the primary end-point was reached. Neuropathy, neutropenia and fatigue were slightly more severe in the bevacizumab arm; the usual anti-angiogenic toxicities were also observed. This study led to the approval of bevacizumab in metastatic breast cancer both in Europe, and in the US.
ADJUVANT BEVACIZUMAB IN BREAST CANCER
Several ongoing trials are exploring bevacizumab in the adjuvant setting (eg: E2104, E5103). The results of these trials will settle this issue.
Dr. Buzaid ends his talk with a pretty simple algorithm for the initial management of patients with metastatic breast cancer that require chemotherapy: if the patient is HER2 positive, she should be treated with chemotherapy plus trastuzumab. If, on the other hand, she is HER2 negative, bevacizumab plus chemotherapy is indicated.