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42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-5, 2006

Research presented here indicates that the monoclonal antibody (MAb) bevacizumab may be safely and effectively combined with a variety of standard chemotherapy regimens in community-treated patients with metastatic colorectal cancer.

BEAT and BRITE Designs

Dr. Scott Berry, Assistant Professor of Medicine, University of Toronto, Ontario, and colleagues involved in the First BEAT (Bevacizumab Expanded Access Trial) found that the MAb may be combined with first-line regimens that are typically used in metastatic colorectal cancer without undue toxicity. As Dr. Berry noted, the pivotal trial showed that the addition of bevacizumab to irinotecan/bolus 5-fluoro-uracil (5-FU)/leucovorin (IFL) significantly improved overall survival (OS) by 30% compared with IFL alone (P<0.001) (Hurwitz et al. N Engl J Med 2004;350(23):2335-42).

However, by the time the study was published, “people were starting not to use IFL anymore because emerging data suggested that infusion regimens such as FOLFOX (5-FU/oxaliplatin/leucovorin) and FOLFIRI (5-FU/irinotecan/leucovorin) had slightly better toxicity profiles and in some cases better efficacy,” Dr. Berry explained. Therefore, the BEAT trial was designed to combine bevacizumab with regimens that are in more current use today, allowing physicians to choose the chemotherapy regimen they felt was best for their patient, he added. Safety data on reported serious adverse events (SAEs) requiring hospitalization on 1789 patients with metastatic colorectal cancer from 41 countries were available for the current analysis.

The most common fluoropyrimidines used in combination with bevacizumab were infusional 5-FU and capecitabine; the most common doublets consisted of bevacizumab given together with FOLFOX, FOLFIRI and XELOX (capecitabine/oxaliplatin). Median follow-up was 8.7 months. At 60 days, mortality was still low at 2.5%. SAEs were reported in 479 patients (27%) of the cohort during the course of the study, but only 9% of the reported SAEs were deemed by investigators to be related to bevacizumab. Gastrointestinal (GI) perforations were reported in 1.2% of patients and there were 11 fatal GI perforations and bleeding events. Of the 11 fatalities, three patients had GI perforation only, five had bleeding events and three had both. Rectal bleeding was seen in all eight patients who had bleeding events, in addition to hemoptysis in two patients, hematemesis in three, epistaxis in two and cerebral in one. Arterial thromboembolic events were also reported in 13 patients, two proving fatal.

“So far, we have been able to show that when you use bevacizumab in a variety of chemotherapy combinations, not just with IFL, you still have a very similar toxicity profile compared with the phase III trial with IFL. This was also in a real-world setting where patients may not be as robust as those in a randomized trial so the SAE rate is very similar to the event rate seen in the major pivotal trial and no new safety signals were identified,” Dr. Berry said.

A similar experience was reported by Dr. Mark Kozloff, Clinical Associate of Medicine, Section of Hematology/Oncology, University of Chicago, Illinois, in his presentation of updated results from the BRITE (Bevacizumab Regimens Investigation of Treatment Effects and Safety) registry, a large observational registry in the US. The BRITE observational study was initiated at the time of FDA approval of bevacizumab and was put into place to evaluate its safety and efficacy in a large, less-selected, community-based population of patients with metastatic colorectal cancer. Patients received the agent in combination with any standard first-line chemotherapy regimen and were followed for up to three years. “What we saw was that progression-free survival [PFS] was approximately 10.2 months—very similar to the pivotal study showing benefit with bevacizumab—so in a large community setting, we were able to duplicate the advantage of bevacizumab with various chemotherapy regimens,” Dr. Kozloff reported.

The “great majority” of patients tolerated the treatment exceptionally well, he added. Approximately 16% of patients developed hypertension requiring treatment. Incidence of grade 3 or 4 bleeding events was low at 2.2%, as was the incidence of GI perforation (1.7%) and arterial thromboembolic events (1.5%). Post-operative bleeding or wound-healing complications were reported in 1.4% of patients. As Dr. Kozloff noted, a causative reason for the GI perforations was identified in two-thirds of patients who developed this particular SAE.

Among the risk factors that appeared to predispose patients to develop a GI perforation on bevacizumab treatment were acute diverticulitis, intra-abdominal abscess, GI obstruction, tumour at the site of perforation and prior abdominal or pelvic radiation. “The side-effect profile is not any different from that seen in the pivotal phase III study, again making one comfortable that in a large community setting and not just in university hospitals, one can give this drug with chemotherapy to slightly older patients who may also be somewhat sicker than patients in a randomized trial, and come out with not only the same benefit but no more side effects as well,” Dr. Kozloff told delegates. Indeed, only 1.5% of patients in the BRITE registry permanently discontinued treatment with bevacizumab because of SAEs related to its use.

Baseline Risk

The same anti-angiogenesis strategy appeared to improve outcomes regardless of baseline risk of patients with metastatic colorectal cancer. In a study presented by Dr. Fairooz Kabbinavar, Associate Professor of Medicine, University of California at Los Angeles, investigators performed a retrospective analysis of the registrational study by Hurwitz et al., this time evaluating the efficacy of additional bevacizumab in patients with poor prognostic risk factors, including poor performance status, presence of symptoms and the presence of cancer at multiple sites. “Irrespective of which prognostic risk group you were in, whether it was low-risk, intermediate risk or high-risk, patients who got bevacizumab did better compared with those who got chemotherapy alone, so what this tells you is that bevacizumab improves efficacy irrespective of the presence of bad prognostic features,” Dr. Kabbinavar stated.

Importantly, the toxicity was the same in all three risk categories as well. “Bevacizumab is a novel way of treating cancer—it targets the cancer indirectly by targeting the blood supply,” Dr. Kabbinavar explained. “We also think it improves the delivery of chemotherapy to the tumour bed more efficiently. So all of this put together seems to allow the drug to work in a synergistic fashion with chemotherapy.”

The AVIRI investigators also demonstrated that first-line bevacizumab can be safely given in combination with regimens containing irinotecan and infusional 5-FU (FOLFIRI). In this multicentre, open-label trial, patients were treated with six FOLFIRI cycles, although variations such as the simplified FOLFIRI or the weekly regimen were allowed, as investigators noted. Bevacizumab 5 mg/kg was given on day 1 of the regimen, every two weeks, until disease progression. A total of 209 patients with previously untreated metastatic colorectal cancer were included in the interim analysis. As presented by lead investigator Dr. Alberto Sobrero, Professor of Medical Oncology, San Martino Hospital, Genoa, Italy, over half of patients had received at least 12 administrations of bevacizumab at study end point. Approximately 45% of patients achieved either a complete response or a partial response, according to Response Evaluation Criteria in Solid Tumors (RECIST), while disease stabilized in over 45% of the cohort. Safety data were similar to those previously reported, with a 2.9% rate of arterial thromboembolic events. Two patients developed GI perforations and the 60-day mortality rate was 2%. “Preliminary data indicate that the estimated six-month PFS rate is 82%,” investigators observed, “and we found you can safely combine bevacizumab with infusional 5-FU and irinotecan with a high efficacy outcome, so it is very promising.”

Gastric Cancer

It is important to appreciate that in some parts of the world, especially Asia, gastroesophageal tumours are as common—and as lethal—as lung cancer. Thus, any treatment that better addresses the needs of patients with advanced gastric cancer has the potential to make a major impact on overall outcome. Phase II data suggested that capecitabine plus cisplatin (XP) has comparable activity to the standard regimen of 5-FU/cisplatin (FP) in advanced gastric cancer, but XP may be more convenient because it can be taken orally and does not require hospitalization for 5-FU infusions.

In a presentation by Dr. Yoon Koo Kang, Asian Medical Centre, Seoul, Republic of Korea, efficacy and safety results from a phase III trial in previously untreated patients with advanced gastric cancer confirmed promising phase II data. Patients were randomized to first-line therapy with either XP or FP. In the XP arm, patients received oral capecitabine 1000 mg/m2 b.i.d. on days 1 to 14 plus cisplatin 80 mg/m2 on day 1 every three weeks, while patients in the FP arm received 5-FU 800 mg/m2/day given as a continuous infusion on days 1 to 5, plus the same dose of cisplatin every three weeks. Patients were treated until the disease progressed or until they developed unacceptable toxicity.

The study was carried out as a non-inferiority trial and the primary end point was non-inferiority in PFS. A total of 316 patients with advanced gastric cancer were enrolled between April 2003 and January 2005 and the median follow-up was approximately 21 months in both arms. As Dr. Kang reported, median PFS was 5.6 months for patients in the XP arm and five months for those in the FP arm. Median OS was 10.5 months in the XP arm and 9.3 months in the FP arm. Based on strict RECIST criteria, the overall response rate in the XP arm was 41% compared with 29% in the FP arm, “so responses to XP were superior to those achieved with FP,” Dr. Kang observed. The most common treatment-related grade 3 to 4 adverse events included neutropenia (16% in the XP arm vs. 19% in the FP arm); vomiting (7% XP vs. 9% FP), diarrhea (5% in both arms) and anemia (5% in the XP arm vs. 3% in the FP arm). Other grade 3 to 4 adverse events occurred in fewer than 5% of patients and the incidence of all-grade hand-foot syndrome was relatively low at 22% for XP and 4% for FP.

“The primary objective of the study was met and response rates were superior with XP than for FP,” Dr. Kang concluded, adding that “XP avoids the inconvenience and complications associated with infusional 5-FU. Therefore, XP should become the new standard of care in advanced gastric cancer.”

Another phase III trial evaluating the safety of XELOX compared with intravenous bolus of 5-FU/LV, given in the adjuvant setting for patients with stage III colorectal cancer, showed that the XELOX regimen is feasible in this setting. Indeed, the XELOX regimen appeared to cause less myelosuppression and stomatitis than 5-FU/LV, although it was associated with more skin and neurosensory toxicity. As lead author Dr. Hans-Joachim Schmoll, Martin Luther University, Halle, Germany, noted, the study was an open-label, randomized, phase III trial involving 1861 patients who were randomized to either XELOX (n=937) or 5-FU/LV (n=924). Efficacy data will not be available until 2007. However, the safety data reported in this presentation showed that 22% of patients withdrew from the XELOX regimen due to toxicity as did 9% of those randomized to the alternative arm. A small number of patients required either interruption in treatment delivery, a reduction in the dose or a delay in cycle delivery of either capecitabine or cisplatin, as did a small number receiving 5-FU/LV. Less grade 3 to 4 hematologic toxicity was reported with the XELOX regimen (9%) than with 5-FU/LV (16%) and XELOX was associated with a lower rate of febrile neutropenia at less than 1% than 5-FU/LV at 4%. Otherwise, the rate of AEs with XELOX and 5-FU/LV was similar, “suggesting that XELOX has a comparable safety profile to bolus 5-FU/LV in adjuvant therapy in patients with stage III colon cancer,” the authors noted.

A cost analysis of capecitabine in the adjuvant setting for stage III colon cancer showed that while it has more direct costs than 5-FU, its incremental cost falls well within the acceptable range based on quality-adjusted life-years when indirect costs are taken into account. As presented by Dr. Kiran Virik, Assistant Professor of Medicine, Dalhousie University, Halifax, Nova Scotia, researchers undertook a cost minimization analysis of capecitabine and 5-FU, both of which were given in combination with leucovorin. Direct costs included treatment acquisition costs, supportive medications, laboratory investigations and health resource utilization, while indirect costs included travel and opportunity cost based on the average provincial wage and participation rates. “The Markov model developed used a hypothetical cohort of 1000 patients with stage III colon cancer and projected costs and outcomes over five years,” investigators observed.

Compared with 5-FU, total direct costs for capecitabine were higher at $9693 vs. $3490 but total indirect costs were much higher for 5-FU at $3288 vs. $824 for capecitabine. The model also showed that capecitabine is potentially cost-effective at five years using a conservative approach, in which it was assumed (based on clinical trial data) that capecitabine would lead to a 10% lower relative risk of recurrence than 5-FU. Using this data, investigators concluded that capecitabine is a cost-effective alternative to 5-FU when the rate of relapse-free survival is as reported in the pivotal trial by Twelves et al. (N Eng J Med 2005;352(26): 2696-704).

Questions and Answers

The following question-and-answer section was conducted with Dr. Fairooz Kabbinavar, Associate Professor of Medicine, University of California at Los Angeles, and Dr. Alberto Sobrero, Professor of Medical Oncology, San Martino Hospital, Genoa, Italy.

Q: Can you combine bevacizumab with any standard chemotherapy regimen used for colorectal cancer?

Dr. Kabbinavar: Yes, it appears to be compatible with every chemotherapy regimen with which it has been combined, and it does not increase the side effects of chemotherapy, either. Its own side effects are manageable as well.

Q: Are targeted therapies finally coming into their own after all these years?

Dr. Kabbinavar: Absolutely correct. We have heard and talked about targeted therapies for a long while and bevacizumab is an example of a targeted therapy that has delivered on the promise that was seen in the laboratory setting.

Q: What is it about bevacizumab that allows it to work so well across all patient groups with metastatic colorectal cancer?

Dr. Sobrero: This is an agent that slows disease progression, and in randomized comparisons—whether it is in colorectal or lung cancer—you get an additional 10% to 15% gain in your response rate with the addition of bevacizumab. In the face of that 10% to 15% gain, you get a huge gain in PFS—on the order of 60% to 70% over what is possible with chemotherapy alone. So you have to look at it this way to appreciate how dramatic the impact of this treatment is. In fact, I would say that bevacizumab is the most promising drug to come along in colorectal cancer because it is associated with a 70% prolongation in PFS and a 35% prolongation in overall survival.