Antiangiogenesis Emerges as Promising Cancer Therapy

Antiangiogenesis Emerges as Promising Cancer Therapy

May 31 June 3, 2003Chicago, ILLee  Schwartzberg MD, FACP The West Clinic

Introduction

It has long been recognized that the development of clinically relevant tumors is dependent on new blood vessel formation to sustain growth. 1 The microenvironment of a small metastatic cancer deposit disrupts the normal balance of proangiogenic and antiangiogenic forces by secreting growth factors responsible for stimulation of vessels. However, blood vessels in tumors are functionally immature and abnormal; they are disorganized, permeable, lack proper supporting cells, and express chain membrane proteins inappropriately. More importantly, unlike normal mature vascular tissue, tumor blood vessels remain dependent on cell survival factors to avoid apoptosis. Tumors elaborate vascular endothelial growth factor (VEGF) to provide the external signals which prevent apoptosis of tumor blood vessels by upregulation of anti-apoptotic genes. 2

VEGF is a member of a family of multifunctional cytokine proteins which bind to endothelial cell receptors. The interactions of VEGF and its receptors modulate multiple processes including angiogenesis, lymphangiogenesis, maintenance of immature blood vessels, and inflammation. 3,4 VEGF appears to be the central mediator for angiogenesis with normal regulation occurring through a variety of physiologic processes including pH changes, pressure changes, and oxygen level. 5,6 Moreover, VEGF is expressed in a wide variety of tumor types and tumor-associated stromal cells. VEGF also appears to be a prognostic marker for increased microvessel density, aggressive growth, and increased relapse rate. 7-9

Due to its critical role in promoting tumor growth, VEGF is an excellent anti-cancer target. The molecule was isolated and sequenced in 1989. Once pure factor became available, the development of therapeutic agents to inhibit its in vivo activity progressed rapidly. A number of antiangiogenic agents which target VEGF and other vascular growth factors have already entered the clinic. To date, somewhat contradictory results have been reported. However, data presented at ASCO 2003 clearly demonstrated a strong and clinically relevant advantage for antiangiogenesis therapy.

Bevacizumab in Colorectal Cancer

Bevacizumab (Avastin), a recombinant humanized anti-VEGF antibody, has previously been tested in phase I and a broad array of phase II studies. 10-12 Activity was demonstrated in breast, non-small cell lung, and colorectal cancers. Furthermore, an intriguing prolongation of survival time was reported in patients with metastatic renal cancer. 13 This finding is of particular interest due to the known high mutation rate of the von Hippel-Lindau gene in sporadic renal cancers, which plays a role in vascular permeability. Encouraging phase II data in colorectal cancer led to a prospective randomized phase III trial which evaluated bevacizumab when added to standard chemotherapy.

Results of this phase III study provide clear-cut proof that inhibiting angiogenesis is beneficial in colorectal cancer. 14 This study, presented by Dr. Herbert Hurwitz at ASCO 2003, involved 925 patients who were randomized to receive chemotherapy with bolus Camptosar®, 5-FU, and leucovorin (IFL) weekly or the same chemotherapy regimen plus bevacizumab at 5 mg/kg every two weeks. A third group of patients received bevacizumab plus 5-FU/Leucovorin until safety was determined. The analysis presented at ASCO concerned the 815 IFL patients in the randomized groups. Entry criteria included no prior chemotherapy for metastatic disease, prior adjuvant treatment acceptable if completed >12 months previously, and no significant atherosclerotic vascular disease. Patient pretreatment characteristics were well balanced between the arms. Patients on bevacizumab could continue treatment beyond progression with second-line chemotherapy.

The addition of bevacizumab to IFL led to a statistically and clinically significant improvement in overall survival, response rate and time to progression compared to standard chemotherapy alone (Table 1).

Table 1 Efficacy for IFL plus placebo vs IFL plus bevacizumab

The toxicities were similar in both arms with the exception of hypertension which occurred in 22.4% of the bevacizumab population compared to 8.3% in the control arm. Blood pressure was well managed with oral agents. In addition, there were six cases (1.5%) of gastrointestinal perforation when Bevacizumab was added to IFL but none in the control arm. Other grade III-IV toxicities are presented in Table 2.

Table 2: Safety for chemotherapy plus placebo vs chemotherapy plus bevacizumab

* Uncorrected for differential time on therapy

Other trials utilizing bevacizumab in conjunction with chemotherapy and colorectal cancer were also reported at ASCO 2003. Dr. A.B. Benson discussed the toxicity profile of a phase III trial comparing bevacizumab alone, FOLFOX4 (Eloxatin®, infusional/bolus 5-FU, and leucovorin) or the combination of bevacizumab and FOLFOX4 in previously treated advanced colorectal cancer. 15 All patients have previously received Camptosar® and fluoropyrimidine-based therapy. Bevacizumab was given at a dose of 10 mg/kg IV biweekly. The antibody alone had modest grade III-IV toxicity consisting mainly of hypertension (7%) and hemorrhage (3%). No increased GI or neurosensory toxicity was observed when bevacizumab was added to FOLFOX4. In addition, the chemotherapy did not seem to add to the small amount of hypertension or hemorrhage seen with the antibody. Chemotherapy induced grade IV neutropenia was reduced in patients receiving concurrent bevacizumab. Response and survival data will be forthcoming.

A phase II trial of bevacizumab added to IFL, ECOG 2200, presented by Dr. B.J. Giantonio, showed similar efficacy and toxicity findings. 16 Ninety-two patients received bevacizumab 10 mg/kg every two weeks and bolus IFL in a four of six week cycle. After toxicity review of other trials of IFL, the doses of Camptosar® and 5-FU were reduced. With median follow up of 76 months, 70 patients are available for response and 83 for toxicity. The overall response rate was 45.7% with 2.9% CR and 42.9% PR. One grade III and one grade IV bleeding episode occurred. While 9 thrombotic events were noted, including 4 grade III and 4 grade IV, both proteinuria and hypertension were infrequent.

Bevacizumab in other tumor types

Pancreatic Cancer: Pancreatic cancer is characterized by overexpression of VEGF, which may function as an autocrine tumor growth factor as well as an angiogenic stimulus. Preclinical models demonstrate anticancer activity of anti-VEGF antibodies. These observations lead to a phase II trial of bevacizumab plus Gemzar® in Stage IV pancreatic cancer patients. 17 Confirmed partial responses occurred in 6 of 16 evaluable patients (38%), while 7 patients (44%) had stable disease. The median time to progression was 5.5 months. One-year survival is 54% and median survival has not yet been reached. Grade III-IV toxicities included 50% neutropenia, 10% anemia, 5% thrombocytopenia, 15% thrombosis, and 5% hypertension. One death occurred from tumor-associated GI bleeding.

Hormone Refractory Prostate Cancer: The combination of bevacizumab and chemotherapy appears to be highly active in hormone refractory prostate cancer. 18 This combination was tested in 79 patients with hormone refractory prostate cancer. Those patients with a history of myocardial infarction, deep venous thrombosis, or anticoagulation were not eligible. Treatment consisted of estramustine day 1-5, Taxotere® day 2, and bevacizumab 15 mg/kg on day 2 repeated every 21 days. Low dose coumadin was suggested but not required. Seventeen of 32 patients with measurable disease were evaluable for response. A partial response was seen in 53% of these patients. Sustained declines in PSA of >50% were noted in 65% of all the patients on the trial. No major bleeding was reported but one stroke, one DVT, and one mesenteric vein thrombosis resulting in death were noted. Response and time to progression data are in progress.

Metastatic Breast Cancer: A phase III trial of Xeloda® with or without bevacizumab in heavily pretreated metastatic breast cancer patients was previously reported at the San Antonio Breast Cancer Symposium in 2002. 19 While the overall response rate was significantly higher for the combination versus Xeloda® alone (19.8% vs. 9.1%), the progression free survival was not improved. The investigators extended their observations in this trial by examining primary tumor samples from paraffin blocks for VEGF mRNA expression by in-situ hybridization. 20 Overexpression at the 2+/3+ level were observed in one-third of the patients while one-third had no VEGF expression by this technique. There was no correlation between VEGF expression in the primary tumor and response to treatment. Researchers now plan to correlate in-situ hybridization with immunohistochemistry evaluation of VEGF protein in the samples.

Combination of Bevacizumab and other biologicals

An understanding of the biological functions of VEGF allows for the development of strategies which target multiple pathways in the tumor cell machinery and a subsequent improvement in efficacy. For instance, in vitro and in vivo data indicate that epidermal growth factor receptor (EGFR) inhibition down regulates VEGF production in addition to its direct antiproliferative effect. A phase I/II trial in advanced non-small cell lung cancer is seeking to identify the maximum dose of bevacizumab with erlotinib, a small molecule targeting the EGFR. 21 Three dose levels have been explored to date. At this early phase of development, 2 of 6 pretreated patients had a partial response. Preliminary pharmacokinetic data suggests no interaction between the two agents. The combination is well tolerated with dose escalation continuing.

Investigators at Ohio State University found that an antiangiogenic strategy combining bevacizumab and low-dose interferon alpha may be useful in the treatment of melanoma. It is known that in conjunction with VEGF, basic fibroblast growth factor (FGF) is an important antiangiogenic factor in solid tumors. Dr. W.E. Carson treated metastatic malignant melanoma with a combination of bevacizumab and low-dose interferon alpha, an inhibitor of FGF. 22 Of sixteen patients accrued, two responses were observed, one a complete response. The serum VEGF levels did not correlate with clinical response but FGF levels were higher at baseline and dropped significantly in the two responders and 2 of 4 stable disease patients.

A novel use of bevacizumab is in the immunotherapy arena. VEGF inhibits dendritic cells, the critical antigen presenting cells. One approach to solid tumor vaccines is based on using ex vivo manipulated dendritic cells. Dr. B.I. Rini and colleagues at UCSF have developed a dendritic cell vaccine to prostate cancer after pulsing with a prostatic acid phosphatase-GM-CSF construct. They administered the vaccine by IV in conjunction with bevacizumab to nine hormone refractory prostate cancer patients. 23 One patient had a PSA response. In depth immunologic studies are underway and should help elucidate the role of bevacizumab in stimulating immunity in vivo.

Safety of angiogenesis inhibition

Analysis of toxicity from 4 phase II and III trials suggests that the addition of bevacizumab to chemotherapy produces tolerable side effects. Dr. R. Gray presented this data on behalf of The Eastern Cooperative Oncology Group (ECOG), a leading organization in the conduct of clinical trials with bevacizumab that has tested it in colorectal, breast, and non-small cell lung cancer. This analysis focused on three previously identified toxicities that are of potential concern: hemorrhage, thromboembolism, and hypertension. 24 The results, shown in Table 3, demonstrate a low, but increased risk of hemorrhage and hypertension in the bevacizumab arms. The relation to thromboembolism risk was not supported and proteinuria was mild and uncommon.

Table 3: Safety of bevacizumab in colorectal, breast, and non-small cell lung cancer

Thalidomide

Thalidomide is proving valuable in the treatment of various cancers. Thalidomide is an inhibitor of angiogenesis possessing other known and probable properties which lead to biological activity in the treatment of cancer. Thalidomide is known to inhibit angiogenic cytokines such as TNFa, IL-6, VEGF, and bFGF. Results reported at ASCO 2003 involve thalidomide in combination with Xeloda®, Taxotere®, DVd, Temodol®, Trisenox®, Proleukin®, or GM-CSF.

Thalidomide and Xeloda® for Hepatocellular Carcinoma (HCC): Thalidomide and Xeloda® appear effective and well tolerated for the treatment of advanced HCC. Xeloda® was administered orally at 750 mg/m2 twice daily and thalidomide was administered orally at 400 mg at bedtime to patients with unresectable, recurrent, or metastatic HCC. Among 11 patients evaluable for response, one achieved a complete response lasting 5 months, one achieved a partial response lasting over 4 months, and 5 achieved stable disease for at least 3 months. Grades 3 or greater toxicities included transient hyperbilirubinemia in 5 patients and one patient each had diarrhea, vomiting, hand-foot syndrome, and somnolence. 25

Thalidomide and Taxotere® for Prostate Cancer: Studies have demonstrated significant microvascular density in prostate cancer, indicating a possible role for thalidomide. Additionally, Taxotere® has clearly demonstrated activity in the treatment of prostate cancer. The addition of thalidomide to Taxotere® appears to improve responses in patients with hormone refractory prostate cancer (HRPC), as indicated by PSA reduction. Patients in this study had an ECOG performance status of zero or one and had a median age of 65 years. Fifty-five patients were randomized to receive thalidomide plus Taxotere® (arm A) or Taxotere® alone (arm B). A reduction of PSA by 50% or more occurred in 66% of patients in arm A and only 32% of patients in arm B. Grade 2 or greater neutropenia and thrombocytopenia occurred in 5 and 3 patients, respectively. Two patients in arm A developed D.V.T. which cleared shortly following anticoagulant therapy. 26

DVd-T for Multiple Myeloma: Liposomal doxorubicin, vincristine, and reduced frequency dexamethasone (DVd) is a well tolerated and effective therapeutic option for the treatment of multiple myeloma. Thalidomide (T) has also demonstrated activity as a single agent in multiple myeloma. Based on historical comparison, the addition of thalidomide to DVd appears to enhance the quality of response in patients with multiple myeloma with minimal toxicity. This finding was produced in a trial conducted by the Cleveland Clinical Myeloma Program. The trial involved 25 patients with a median age of 60 years. DVd was repeated every 4 weeks for a minimum of 6 cycles and 2 cycles following best response. Thalidomide was initiated at 50 mg/day and increased to 400 mg/day. Patients were then maintained until disease progression on 50 mg of prednisone every other day plus maximum tolerated thalidomide. The overall response rate was 88%, with 24% of patients achieving remission according to SWOG criteria. A complete response plus a greater than 90% reduction in M-protein occurred in 40% of patients. Three of 14 patients developed DVT, but no infection or grade 3 neuropathy was noted. 27

Temodol® and Thalidomide for Glioblastoma (GBM): Although the combination of Temodol® and thalidomide has a safe toxicity profile in pre-irradiated patients with GMB who underwent aggressive surgical resection, daily treatment with this combination does not appear to be effective. Following treatment with Temodol® and thalidomide, none of the first 7 patients recruited in this trial demonstrated a disease response or stabilization, so the trial was prematurely closed. Clearly, new directions in the treatment of GBM are needed, particularly since the average survival of GBM is less than 12 months. 28

Trisenox® and Thalidomide for MDS: Previous results have demonstrated that thalidomide provides improved survival in responding patients compared to non-responders in the treatment of MDS. Based on the findings of a recent study, Raza et al believe that the combination of arsenic Trisenox® and thalidomide for the treatment of MDS is worth pursuing in further studies. Trisenox® was given at 0.25 mg/kg IV over 2 hours on a 2 weeks on and 2 weeks off schedule. Thalidomide dosing was oral 100 mg/day, increased as tolerated to 300 mg/day. Twenty-seven patients have been entered on the study, with 10 presently evaluable. Of the evaluable patients, half demonstrated hematologic improvement and 3 became transfusion independent. Three of 4 patients considered to have a poor prognosis due to high pre-therapy Evi-1 expression responded to therapy as demonstrated through quantitative RT-PCR. 29

Thalidomide and Proleukin® for Renal Cell Cancer (RCC): RCC is one type of cancer that often responds favorably to immunomodulatory agents, making thalidomide a perfect candidate for its treatment. Additionally, thalidomide is thought to enhance the activity of Proleukin®. Results from a recent clinical trial indicate that the combination of thalidomide and Proleukin® appears to be tolerable and active in patients with metastatic RCC.

This trial involved 15 patients who had not received prior chemotherapy or immunotherapy for RCC. Thalidomide was initiated at 200 mg and increased to 400 mg after 48 hours. Proleukin® was given at 7 mlU/m2 subcutaneously on days 1-5 of weeks 1-4, with rest from Proleukin® during weeks 5 and 6. Eight patients demonstrated a response in the first phase of the trial. Six of these responders continued on treatment for 12+ to 18+ months. In the second phase of the trial, 36 of 37 patients were evaluable. One patient achieved a complete response, 14 patients achieved a partial response, and 11 patients achieved disease stabilization. Ten patients progressed. Twenty-six patients (69%) remain on therapy with maintained responses or stabilization. Overall, the range of time on therapy was 3 to 15 months. Most side effects were grades I-II, with the most common including somnolence, rash, constipation, flu-like symptoms, fluid retention, hypotension, hypothyroidism, and deep vein thrombosis. Due to these results, a phase III randomized trial will be developed by a cooperative group which will compare thalidomide plus Proleukin® to Proleukin® alone and thalidomide alone. 30

Thalidomide and GM-CSF for Melanoma: Thalidomide is thought to possess synergistic activity with GM-CSF as well as enhance activity of Proleukin®. This activity would induce T-cell co-stimulation and Proleukin® mediated T-cell proliferation. Results of a recent phase I/II trial indicate that thalidomide and GM-CSF is a well tolerated combination for high-risk melanoma patients and may provide a treatment alternative to those who cannot tolerate interferon.

Patients in this trial had high-risk melanoma and were not eligible for, or refused treatment with interferon. Treatment consisted of daily GM-CSF at a dose of 125 mcg/m2 administered subcutaneously for 14 days every 28 days plus thalidomide daily, with dose escalation from 50 mg to 400 mg. All patients were free of disease upon entry of the trial and 11 were evaluable for response. Three patients are alive and disease free, 8 patients had disease progression either before or after discontinuation of therapy, and 2 patients died from progressive disease. Discontinuation of therapy occurred due to the following reasons: disease progression in 5 patients, non-compliance in 1 patient; syncope in 1 patient; grade III rash in 1 patient; transportation difficulties in 1 patient and change of physician in 1 patient. Most common toxicities included fatigue, dizziness, somnolence and constipation. 31

Other Angiogenesis Agents in Development

In addition to the promising data on bevacizumab and thalidomide reported at ASCO, several other angiogenesis agents were reported to have encouraging anticancer activity and acceptable safety profiles. Mature survival data of these agents, particularly those in phase III clinical trials, may ultimately provide significant contributions to current standard practices of oncology.

Neovastat: Neovastat (AE-941) is a standardized shark cartilage extract, possessing pleotropic properties including antiangiogenesis. Neovastat activity includes inhibition of VEGF signaling and MMP activity as well as induction of endothelial cell apoptosis. Preclinical and phase I/II trials have demonstrated no dose-limiting toxicities of Neovastat and a survival benefit in refractory RCC with increased doses (240 ml/day vs. 60 ml/day). Preliminary results from a phase III prospective, randomized, placebo-controlled clinical trial evaluating Neovastat as monotherapy in the treatment of metastatic renal cell carcinoma (RCC) refractory to immunotherapy were presented at the 2003 ASCO meeting. 32 This trial involved 302 patients with an average age of 61 years. According to an independent Data Safety Monitoring Board review, there has been no significant toxicity in either arm. Survival data are not yet mature; however, the forthcoming results will provide great insight into the true clinical benefit of Neovastat as monotherapy for refractory RCC and may ultimately provide this group of patients with an effective treatment option. Currently, there are no approved therapies for treatment of refractory RCC, clearly indicating a need for an effective therapeutic option.

An additional NCI-sponsored intergroup trial evaluating Neovastat for the treatment of NSCLC is currently in the process of recruiting patients. 33 This placebo-controlled trial will compare induction chemotherapy and concomitant chemoradiotherapy (CRT) with Neovastat or placebo for stage III unresectable NSCLC. Interim toxicity data of approximately 90 patients (of 200 currently recruited) indicates that overall toxicity appears acceptable.

Recombinant Human (rh) Endostatin : RhEndostatin is an antiangiogenic agent that has demonstrated the ability to inhibit endothelial cell proliferation and inhibit tumor growth in the preclinical setting. Treatment for neuroendocrine tumors (NET) with traditional chemotherapy results in limited benefit coupled with significant toxicity. However, a recent phase II trial demonstrated minimal toxicity associated with rhEndostatin in the treatment of advanced NET.

This trial involved 41 patients with advanced NET (25 carcinoid/16 pancreatic) with a median age of 55 years. Patients self-administered rhEndostatin via subcutaneous injections. Escalating doses were administered if tumor regression was not 50% or greater following 8 weeks of treatment. Thirty-seven patients were evaluable. Eleven patients remained at the initial dose level of 60 mg/m 2 /d, 21 were escalated to 90 mg/m2/d, and 5 dropped out of the study due to disease progression. The median follow-up was 39 weeks. Median time to tumor progression was 35 weeks, with 62% of patients experiencing disease stabilization and 32% of patients progressing. Toxicity typically consisted of grade I/II injection site reaction, which was reported in 90% of patients. 34

COX-2 Inhibitors : The inhibition of cyclooxygenase-2 (COX-2) is gaining momentum as providing potential therapeutic benefit in several cancers. COX-2 is upstream of prostaglandin E2 (PGE2) in the hormone cascade, which is a product of COX-2. PGE2 is involved in the stimulation of VEGF, the reduction of immune recognition, the reduction in apoptosis, and the potential increase of invasive properties. In addition, COX-2 is being implicated in several lines of tumor induction and/or progression. Celecoxib is a COX-2 inhibitor that has demonstrated additive anti-cancer effects when coupled with Taxotere® against NSCLC in the preclinical setting.

Preliminary results from an ongoing phase II trial indicate that the combination of celecoxib and Taxotere® reduces VEGF and PGE2 levels and appears to provide activity in recurrent NSCLC. The accrual goal of 65 had not yet been reached, but preliminary data from 33 patients was presented at the 2003 ASCO meeting. Partial responses were observed in 4 patients, disease stabilization in 8 patients and progressive disease in 21 patients. Two patients are alive and receiving maintenance therapy on celecoxib over 18 months from treatment. Serum VEGF and intratumoral PGE2 levels decreased markedly following treatment, compared to pre-treatment levels. While these preliminary findings are encouraging, longer follow-up and additional trials will be necessary to determine whether celecoxib is effective in the treatment of NSCLC. 35

Conclusion

In conclusion, bevacizumab has substantial activity in conjunction with chemotherapy in colorectal cancer. There are intriguing preliminary response and clinical benefit data in breast cancer, prostate cancer, pancreatic cancer, and kidney cancer. The side effects of the antibody are manageable and do not appear to be synergistic with the chemotherapy regimens tested to date. With the demonstration of a survival advantage for patients receiving chemotherapy and anti-VEGF antibody, the promise of thirty years of antiangiogenesis research has finally been fulfilled.

Data on other antiangiogenic agents including thalidomide, neovastat, RhEndostatin, and celecoxib indicate potential therapeutic benefit, with a trend towards acceptable toxicity profiles. The anticipated data that could potentially indicate a survival advantage with these treatments will provide direction for future clinical trials.

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