%u25BA CHEMOTHERAPY FOUNDATION SYMPOSIUM OVERVIEW

Traditional definitions of successful therapy rapidly redefined as new molecular-based therapies emerge

	This year’s Chemotherapy Foundation Symposium was held in New York City in November and was co-sponsored by the Mount Sinai School of Medicine. The meeting was titled, “Innovative Cancer Therapy for Tomorrow” and brought together experts to discuss advances in chemotherapy. The speed and sophistication of emerging therapies in the treatment of many cancers is changing the way oncologists and patients alike view the disease.

	“We’re getting access to a large number of molecular-targeted medications as we begin to better understand the process of how healthy cells are transformed into malignant ones and what specific molecular pathways are altered,” states Dr. Edward P. Ambinder, Associate Chairman of the New York—based Chemotherapy Foundation and Clinical Professor of Medicine at New York’s Mount Sinai School of Medicine. Dr. Ambinder served as Program Director of the Foundation’s Twenty-Fifth Annual Chemotherapy Symposium held in New York late last year. “We’re seeing molecular-targeted drugs capable of changing molecular pathways that are abnormally overactive or underactive in cancer cells. With certain tumors we are now fortunate to have drugs that can effectively control the cancer with very tolerable side effects.” Some innovations have also expanded to the treatment of pediatric patients, a topic which, for the first time, warranted its own session at this year’s Conference.

Definition of Successful Cancer Treatment Redefined, but Often Costly

	The age of highly targeted cancer treatments has also brought with it new definitions of what is considered a successful clinical outcome. “The standard by which we measured the success of a therapy was in overall survival rates, but now we’re looking at progression-free survival and improvement in patient quality of life,” Dr. Ambinder says.

	The monetary cost of these new, lifesaving cancer treatments is already affecting treatment decisions for both patients and oncologists. “A molecular- targeted drug, combined with different types of chemotherapy, often drives the cost of some drug regimens to upwards of $100,000 to $175,000 per year,” Dr. Ambinder says. Insurers, he says, are already shifting these expenses in the form of higher copays for patients and lower reimbursement rates for oncologists. “Even large cancer centers have suffered because of the change in drug reimbursement rates, and those of us in smaller practices are beginning to find it impossible to purchase these drugs for our patients at a price where we do not lose money.” Major industry groups representing the interests of oncology professionals, such as the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) will be actively addressing the reimbursement problem throughout the coming year, he says.

	Another dilemma oncologists face in this new age of oncology drug discovery is, ironically, the abundance of treatment options available now and in the near future—new treatment options which were once limited or nonexistent for many cancer patients. “There are probably 700 different drugs overall in the pharmaceutical pipeline now,” Dr. Ambinder says, “and about 60% of these are cancer drugs. How are we going to evaluate all of these new drugs, not only in terms of the different cancers they target, but in terms of combining them with older treatments. It’s going to be challenging for community oncologists to keep up with all of these advancements, and we hope annual events like our Symposium can help them do that.”

New Molecular “Linker” May Increase Potency of Trastuzumab While Lowering Toxicity

	Perhaps one of the biggest breakthroughs in breast cancer treatment over the past decade was the discovery of trastuzumab (Herceptin), a drug that specifically targets HER2-expressing cancer cells, an indication of an aggressive form of breast cancer likely to spread elsewhere in the body. Dosing, however, is often limited because of toxicity. Early phase I trials are underway to study the effect of a “linker” combination of compounds that may deliver trastuzumab more directly into malignant cells with less damage to healthy tissue. “A number of compounds have failed when the 'linker' has become unstable during IV drug delivery while avoiding uptake in normal cells,” Dr. Howard A. Burris III of the Sarah Cannon Research Institute of Nashville, Tennessee said during his presentation. In one small phase I trial, 24 patients aged 35 to 70 were given trastuzumab-DM1 (T-DM1), with a linker molecule (a derivative of maytansine). “The MCC linker molecule has been engineered to provide a stable bond between trastuzumab and DM1 to potentially enhance the therapeutic window of DM1 by minimizing systemic exposure to free DM1 and improving exposure to T-DM1,” Dr. Burris said, calling the antitumor activity observed in patients “quite incredible”, even in some patients with liver and lung metastases.

Alternatives to Radiation Explored for Patients With Brain Metastases From Breast Cancer

	“The spread of cancer to the brain is a therapeutic challenge for those of us who take care of those with breast cancer,” said Dr. Nancy U. Lin, Harvard Medical School, Dana-Farber Cancer Institute of Boston, Massachusetts. Historically, she said, CNS metastases has been considered “a late and uncommon event” in the treatment of patients with advanced breast cancer, yet more recent studies of HER-2 positive breast cancer patients suggest about one-third are at risk of developing brain cancer. Two small phase 1 studies may offer some other options. Some response was observed in one study that combined capecitabine (Xeloda) with temozolomide (Temodar). Another, a multinational study that studied the effect of lapatinib (Tykerb) in patients with at least one brain lesion, shows a progression-free survival rate of almost four months. “The lesson we should take away from these trials is that systemic care is feasible and very much wanted by patients and physicians,” Dr. Lin said.

Lapatinib May Help Treat Rare Breast Cancer Found in Africans and African Americans

	Inflammatory breast cancer, considered to be a relatively rare but the most aggressive form of invasive breast cancer, may be treated with lapatinib (Tykerb) alone or lapatinib/paclitaxel (Taxol) combined, according to one ongoing, international, multicenter trial. The disease is found in an estimated 25% of breast cancer patients in Tunisia and a small but growing number of African-American women in the United States. An added complication of inflammatory breast cancer is the difficulty in diagnosing it before it has progressed, according to Dr. Massimo Cristofanilli, University of Texas M.D. Anderson Cancer Center, Houston, Texas. “Mammograms really don’t help in diagnosing this disease,” he said. Clinical features upon examination of the patient, tenderness, warmth, and peau d’orange skin, “are all associated with the features of a rapidly proliferating disease,” he said. “They are all very important in making a diagnosis.” Early data emerging from the ongoing study (from 35 patients with a median age of 53) shows a response rate (defined as disappearance of invasive disease in the breast and surrounding lymph nodes) among 77% of patients with HER2 alone and HER2/EGFR (epidermal growth factor receptor) overexpression combined. (No response was seen in patients with EGFR-expression only and the arm was discontinued.) Additionally, researchers found an overexpression of p53, E-cadherin and Rho-C in almost all cases, suggesting these may be biomarkers doctors can use in making a diagnosis of inflamatory breast cancer. Future studies combining lapatinib with anthracyclines will take place early this year.

Genentech Seeks Approval for Bevacizumb for Breast Cancer

     Genentech has announced that it will seek regulatory approval for bevacizumab (Avastin) in patients with breast cancer. Genentech—the largest U.S. maker of cancer drugs&mdash;already sells one breast cancer agent, trastuzumab (Herceptin).

				     Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in invitro and invivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in 

				     Bevacizumab is currently indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum, in combination with intravenous 5-fluorouracil—based chemotherapy. It is also indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, non–small cell lung cancer, in combination with carboplatin and paclitaxel.

				     In an Eastern Cooperative Oncology Group randomized trial, tumors remained stable for an average of 11 months among patients who took Avastin plus paclitaxel (N=363), compared with 6 months for those who received paclitaxel only (N=348). In addition, there was a 28% response rate for patients on bevacizumab plus paclitaxel vs. 14% for those receiving paclitaxel only. Preliminary results from the trial suggest that patients who received bevacizumab in combination with paclitaxel had a delay in worsening of their cancer by approximately 5 months, on average, compared with patients treated with paclitaxel alone. This difference was statistically significant. Study Chair Kathy D. Miller, MD remarked, “This study is the first to find a benefit of antiangiogenic therapy in patients with breast cancer, and represents a major advance in the treatment of patients with metastatic disease.”

				     Added NCI Director Andrew C. von Eschenbach, MD, “This study demonstrates that when patients with recurrent or metastatic breast cancer received bevacizumab in addition to their chemotherapy, the period of time that they lived with their cancer under control was increased. This is an important step in our journey to ultimately eliminate the suffering and death due to cancer.”

				     Patients whose tumors overexpressed HER-2 were not included in the study unless they had previously received trastuzumab or were unable to receive trastuzumab. Also excluded were patients who had received preventive chemotherapy treatment with paclitaxel within the previous 12 months, as well as patients with a prior history of blood clots or who were on blood thinners. Serious bleeding and blood clots were rare in this study. Patients who received the combination of paclitaxel and bevacizumab had slightly more neuropathy, hypertension, and proteinuria than those who received paclitaxel alone. Six of the 363 patients who received Avastin plus paclitaxel (1.7%) died, compared with none of the patients who received paclitaxel alone.

				      Unfortunately, on December 5, an FDA Advisory Committee recommended that Avastin not be approved for breast cancer. The committee cited the increased risk of adverse events such as hypertension and death with Avastin as the basis for its decision, and believed that the benefits of the drug in patients with breast cancer did not outweigh these risks.

				     The FDA is expected to render a formal decision regarding Avastin for breast cancer by February 2008. The FDA usually follows the recommendations of its advisory committees, although it is not required to do so. If, however, Avastin is approved for breast cancer, its main use would be in patients with metastatic disease. Genentech plans an ongoing dialogue with the FDA.

				      Genentech and various research groups are testing Avastin in approximately 300 clinical trials worldwide, in 20 different tumor types. The company plans to ask for FDA approval of the drug soon for patients with kidney cancer, and plans to discuss positive results from a brain cancer study with regulators as well.

	Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is the most common form found in smokers. Drugs that inhibit the expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in tumors are being closely studied for their ability to control the progression of NSCLC, although concerns about toxicity and low response rates remain. Several leading oncologists foresee a day where individualized therapy for NSCLC patients will be the standard of care.

Oncologists Foresee Treatment ‘Beyond Bevacizumab’ for NSCLC

	Lung cancer specialists are eagerly awaiting the results of several large phase II and phase III trials that build upon the success of adding bevacizumab (Avastin) to standard chemotherapy. Bevacizumab is a biologic therapy that has been successfully used to target VEGF in many types of solid tumor cancers and, in 2004, became the first angiogenesis inhibitor approved by the FDA.

	“We are headed toward the era of individualized therapies and proper patient selection,” said Dr. Chandra Belani, Penn State Cancer Institute in Hershey, Pennsylvania. Agents such as vandetinib (ZD6474), sunitinib (Sutent), sorafenib (Nexavar), vatalanib (PTK/ZK) and axitinib (AG-013736) are currently being studied in phase II trials. The results of two other later-stage trials, according to Dr. Belani, are being eagerly anticipated. “Progression-free survival from the Avastin in Lung (AVAiL) study are positive but not compelling,” he said. “Survival data from the AVAiL study are pending and critical.” Data from this study, scheduled to be available later this year, will be especially looked at for toxicity in doses of 7.5mg/kg or 15mg/kg when bevacizumab is combined with cisplatin/gemcitabine chemotherapy. The results of the phase III “ESCAPE” trial (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC [ESCAPE] trial of gemcitabine [Gemzar] and cisplatin [Platinol] with or without sorafenib), described by Dr. Belani as the first definitive study to measure how combination chemotherapy regimens differ from bevacizumab plus chemotherapy, are also due later this year. “Multiple agents that target VEGFR TKIs (tyrosine kinase inhibitors) have demonstrated single-agent activity against NSCLC, so we are looking forward to those results as well,” Dr. Belani said.

Can Molecular Biomarkers Help Tailor NSCLC Treatment?

	Molecular biomarkers may be a more reliable predictor of whether a NSCLC treatment will work as opposed to clinical features of patients, Dr. Paul A. Bunn Jr., University of Colorado Health Science Center, Aurora, Colorado said. These predictors may be especially important when selecting first-line therapy for advanced NSCLC and adjuvant therapy for early stage disease.

	Dr. Bunn examined the possibility of identifying key molecular biomarkers, including the presence of specific EGFR mutations, K-ras mutations, EGFR gene copy number (i.e., whether flourescent in situ hybridization [FISH] positive or negative), EGFR protein expression by immunohistochemistry, expression of epithelial markers such as E-cadherin and the ex- pression of downstream activation proteins such as pakt as part of choosing the right therapy for NSCLC. “This is, in my opinion, the future of lung cancer,” Dr. Bunn said. “When a patient has an initial diagnosis, we are going to be able to look at the properties of the tumor—much like we do with breast cancer today&mdash;before we even start treating patients.” Such an advancement may one day be able to cut down on the level of toxicity and side effects that often accompany many lung cancer treatments. In two large, randomized trials comparing erlotinib and gefitinib with placebo, increased EGFR copy number (as shown by FISH) was associated with significantly improved response, time to progression, and survival. Additionally, certain EGFR mutations were associated with improved survival in studies involving placebo or EGFR TKI therapy. The next task, Dr. Bunn said, is to study these biomarkers individually in terms of their response to certain drugs. “All of these have been retrospective studies,” he said. “We now need prospective studies.”

Skin Reactions, Genetic Mutation, May Be Important Predictors in Colorectal Cancer Treatment

	Clinical and molecular differences may also signal whether a particular course of therapy is working in colorectal cancer treatment. One finding emerging form the CRYSTAL trial (Cetuximab combined with iRinotecan in first-line therapy for metaSTatic colorectAL cancer) last year, for example, showed patients who had cetuximab added to their regimen and who exhibited skin reactions did experience higher toxicity but also showed a better cancer response. Another study, according to Dr. Howard S. Hochster, MD, professor of medicine at the NYU Cancer Institute, New York City, is data from last year’s 600-patient panitumumab (Vectibix) pivotal trial, which indicated patients with a wildtype mutation in the K-ras gene (a gene in the EGFR signaling pathway) showed a better response—so much so that efforts are underway in Europe to approve panitumumab only in those with a K-ras “wild type” mutation. “This is quite a remarkable finding and I think at ASCO later this year we’ll see similar findings coming out of CRYSTAL,” Dr. Hochster said.

Trial Findings Offer New Hope, Treatment Options, for Non-Clear Renal Cell Carcinoma

	Trials examining the efficacy of sunitinib (Sutent) and sorafenib (Nexavar), two oral, multi-targeted tyrosine kinase inhibitors approved for the treatment of advanced renal cell carcinoma several years ago, may give new treatment options to those with non—clear cell carcinoma. In one large sunitinib trial some clinical benefit was seen in those with brain metastases, non–clear cell carcinoma patients and patients older than 65 years at rates similar to the overall group. While 88% of patients studied were clear cell patients, 12% had non–clear cell renal cancer. “These were patients that would generally not be included in a clinical trial,” Dr. Janice P. Dutcher, Mount Sinai School of Medicine, New York, said.

	Sorafenib may also treat non—clear cell renal cancer patients. The ARCCS trial (Advanced Renal Cell Carcinoma Sorafenib Expanded Access Program in North America) showed an 80% clinical benefit in stabilizing the progression of the disease, including patients with clear cell and non–clear cell disease, those with brain metastases, and those who had received prior bevacizumab. While Dr. Dutcher noted the majority of patients in the ARCCS enrolled in the final two months of the study, clinical benefit was still seen. “These agents seem to have the same activity in clear cell and non–clear renal cell carcinoma,” Dr. Dutcher said.

Lenalidomide/Steroid Combination Shows Promise in Treating Multiple Myeloma

	Several new agents, including a regimen combining a derivative of thalidomide and a steroid, are showing promise in helping people with multiple myeloma.

	The Eastern Cooperative Oncology Group (ECOG) study, sponsored by the National Cancer Institute, showed some patients who were given a regimen of lenalidomide (Revlimid), a derivative of thalidomide, along with low doses of the steroid dexamethasone (Decadron) could achieve one-year survival rates of up to 96%. This was compared with an earlier study where patients received standard (higher) doses of the lenalidomide/dexamethasone combination, where survival rates were about 10% lower.

	“The take-home message here is that newly diagnosed multiple myeloma patients should not get more than 40 mg of dexamethasone a week if they’re also going to be on lenalidomide,” said Dr. David H. Vesole, St. Vincent’s Comprehensive Cancer Center, New York City.

	Thalidomide, banned decades ago, was resurrected about two years ago by the Food and Drug Administration as one of the few treatments available for multiple myeloma other than bone marrow transplant. “Thalidomide is now considered almost an old and antiquated drug even though it was only approved [for the treatment of multiple myeloma] two years ago.” Still, Dr. Vesole added, thalidomide may still be a viable therapy early in the disease, showing a 65% to 70% response rate. Major side effects remain a problem with thalidomide, however, the worst being neuropathy. This complication led researchers to consider the lenalidomide/dexamethasone combination as a possible alternative.

	Other studies are looking at the efficacy of a melphan/prednisone/lenalidomide combinations. More data should be available later this year.

Articles

Chemotherapy Foundation Symposium Overview

49th Annual Meeting of the American Society of Hematology

Focus of hematological malignancies and notable research

The American Society of Hematology (ASH) held its 49th Annual Meeting at the Georgia World Congress Center in Atlanta in December. The Society's annual meeting provides a forum for hematologists from around the world to discuss critical issues in hematology.

Roughly 20,600 clinicians, scientists, and other hematology professionals hailing from over 100 countries attended the four-day meeting, which consists of educational programs and scientific sessions that address a wide range of issues relating to and covering the entire spectrum of hematological disorders.

In addition, the annual meeting features oral and poster presentations, chosen by peer-reviewers from abstracts submitted prior to the meeting, that feature the latest breaking developments in scientific research. For the 2007 meeting, 3,745 abstracts from 46 countries were accepted for presentation.

Mitchell Weiss, MD, PhD, Children’s Hospital of Philadelphia, Pennsylvania, and Scientific Co-Chair of ASH 2007, summarized its value in the following terms: “If you’re a practicing hematologist/oncologist, ASH is a very important meeting covering diverse topics. The educational and scientific sessions provide overviews of what’s hot in the field. So it’s a good place for clinicians to brush up the latest, newest emerging concepts that they might not see all the time. One can find out what the state of the art research is that will be coming into clinical practice five years from now. ASH offers a very comprehensive global view, from practical, clinical issues to cutting-edge research. Everything is important (in terms of) current clinical practice, clinical practice alterations, and things that are going to become clinical practice.”

The following highlights provide summary coverage of meeting highlights, primarily focusing upon notable research breakthroughs relating to hematological malignancies.

Second in prevalence only to non-Hodgkin’s lymphoma, multiple myeloma (MM) is one of the most common hematologic malignancies in the United States. This severe form of bone marrow cancer is also one of the most

difficult to treat. Traditionally, MM outcomes have been poor. Survival rates for MM have not been promising: most patients die within two to three years after diagnosis. In 2007, an estimated 10,790 fatalities were attributed to the disease in the United States. However, over the past decade, survival rates have risen dramatically. Recent analyses delivered by numerous presenters at the 49th Annual American Society of Hematology meeting suggest that this trend may be attributed to new types of drugs, new treatment combinations and aggressive therapeutic interventions such as stem—cell transplantation (SCT).

Bortezomib-Melphalan-Prednisone Associated with Improved Efficacy Endpoints Compared With Melphalan-Prednisone in Newly Diagnosed Multiple Myeloma

Jesus San-Miguel, MD, Hematology Department Head, University Hospital of Salamanca, Salamanca, Spain, presented results from a 682-patient, randomized, Phase III trial comparing bortezomib (Velcade)-melphalan (Alkeran)-prednisone (Meticorten) (BMP) versus melphalan-prednisone (MP) in the treatment of patients with newly diagnosed MM who were ineligible to receive SCT.

Patients in the BMP arm of the study received bortezomib at 1.3 mg/m

 twice weekly in weeks one, two, four and five for four six-week cycles (eight doses per cycle), followed by once weekly on weeks one, two, four and five for five six- week cycles (four doses per cycle) in combination with melphalan at 9 mg/m

 once daily on days 1 through 4 of each cycle. Patients in the MP arm received nine six-week cycles of MP once daily on days 1 through 4. For both groups, treatment continued for a maximum of 54 weeks (52 vials) with a median number of 46 weeks (44 vials) reported in the trial. The safety profile of BMP was as expected, based on the known safety profile of each of the three individual agents in the combination. Adverse events included neutropenia, thrombocytopenia, anemia and peripheral neuropathy. Discontinuation because of adverse events was low and similar in both arms.

Responses were evaluated by the commonly used M-protein levels measured in serum or urine by a centralized laboratory as well as the most stringent European Group for Blood and Marrow Transplantation (EBMT) criteria. Key findings reported by Dr. San-Miguel included: an immunofixation-negative complete remission (CR) rate of 35% in the BMP arm compared with 5% with MP (

 < 0.000001); a CR rate of 30% in the BMP arm compared with 4% with MP; a 24-month median duration of response for patients with CR in the BMP arm compared with 13 months in the MP arm; a 24-month time-to-disease progression (TTP) in the BMP arm, compared with 17 months with MP (

= 0.0000001); and a statistically significant demonstration of overall survival associated with the BMP arm (a 40% reduction in risk of death (

= 0.0078) was observed in the patient cohort undergoing BMP therapy).

According to researchers, the BMP arm of the clinical trial achieved significant improvement across all efficacy endpoints that were analyzed, most notably CR and long-term survival. Commenting on the results, Dr. San Miguel, the trial’s principal investigator, stated, "The goal of therapy is long-term survival and complete remission is a well-known indicator for survival. Data from this rigorously controlled trial clearly show that Velcade-based therapy should be a standard of care for previously untreated patients, who are not able to receive stem-cell transplantation."

Bortezomib-Thalidomide-Dexamethasone Yields Superior Response Compared With Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma

Michele Cavo, MD, Seragnoli Institute of Hematology, University of Bologna, Bologna, Italy, presented the results of a multicenter, randomized Phase III trial comparing a combined regimen of bortezomib (Velcade)-thalidomide (Thalomid)-dexamethasone (Decadron) (BTD) with thalidomide-dexamethasone (TD) combination therapy, incorporated into autologous stem-cell transplantation (ASCT) for newly diagnosed multiple myeloma.

In the trial, initiated in May 2006 by the Italian Myeloma Network (GIMEMA), both BTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan (Alkeran) 200 mg/m

. In both the BTD arm (arm A) and TD arm (arm B) of the study, induction therapy consisted of three 21-day courses of therapy (totaling 63 days).

The primary end point of the study was complete response (CR) [either immunofixation-negative CR or immunofixation-positive (nCR)] to induction therapy. Secondary study end points included CR+nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned, to be performed after one year from study initiation, to assess efficacy and toxicity of induction therapy.

As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive BTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR+nCR to BTD was 38% versus 7% to TD (

< 0.001) 60% of patients in BTD arm and 25% of patients in the control group attained at least a very good partial response ( 

<0.001). Patients who failed at least a partial response to BTD were signifi- cantly less than those who failed on TD (7% versus 21%, respectively; 

Adverse events were similar in both arms, with the exception of (grade 3 or higher) skin rash (6.5% in BTD arm versus 1% in TD arm; 

= 0.04). Treatment discontinuation resulting from adverse events was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase.

A subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR+nCR to melphalan was significantly higher in the BTD arm than in the control group (

= 0.05 for CR+nCR comparison between the two treatment arms).

Preliminary analysis of this study provides demonstration that BTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR+nCR rate compared with TD both before ASCT and after the first autologous transplantation with melphalan.

Principal trial investigator Dr. Cavo commented, "This Velcade-based induction regimen achieved a fourfold increase in the complete remission rate. Complete remission is widely recognized as a predictor for long-term survival. These exciting results demonstrated that adding Velcade to the standard induction therapy prior to stem cell transplantation improves the response rate dramatically."

Lenalidomide Plus Low-Dose Dexamethasone Demonstrates Superior Overall Survival Compared With Lenalidomide Plus High-Dose Dexamethasone

S. Vincent Rajkumar, MD, Mayo Clinic, Rochester, Minnesota, reported the results of a randomized trial comparing lenalidomide (Revlimid) plus high-dose dexamethasone (Decadron) combination therapy with lenalidomide plus low-dose dexamethasone in patients with newly diagnosed multiple myeloma. Findings, drawn from a second preplanned interim analysis, indicated that overall survival was significantly superior in the subject cohort that received low-dose dexamethasone combination therapy (

One-year survival rates observed in patients undergoing lenalidomide plus low-dose dexamethasone were 96% (compared with 87% survival in patient receiving lenalidomide plus high-dose dexamethasone). Survival rates after 18 months yielded similar results: patients taking lenalidomide plus low-dose dexamethasone were more likely to survive than their high-dose dexamethasone counterparts (survival rates of 91% and 80% were observed, respectively). The low-dose dexamethasone combination maintained its favorable survival rate across the span of patient age groups. Differences in favor of the low-dose dexamethasone cohort were seen both in patients under the age of 65 (97% versus 92% at one year, 

= 0.022) and in patients over the age of 65 (94% versus 83% at one year, 

In addition, the low-dose dexamethasone combination was associated with decreased mortality. Of the 61 patients who perished over the duration of the study period, 42 were in the high-dose dexamethasone arm. The higher mortality incidence evidenced in the high-dose dexamethasone cohort was attributed to disease progression and increased toxicity.

Patients who underwent lenalidomide plus high-dose dexamethasone therapy experienced a markedly higher rate of serious adverse events, including deep vein thrombosis/pulmonary embolism (DVT/PE) (25% versus 9%, 

 < 0.001), grade 3 or higher nonhematologic events (49% versus 32%, 

< 0.001), grade 4 or higher nonhematologic events (20% versus 9%, 

< 0.001), and death in the first 4 months (5% versus 0.5%,

This study demonstrated that in patients with newly diagnosed multiple myeloma, lenalidomide plus low-dose dexamethasone combination therapy, as compared with lenalidomide plus high-dose dexamethasone combination therapy, is associated with superior overall survival, decreased toxicity, and decreased mortality.

“This is a major advance and gives researchers a new direction to explore—that more is not necessarily better,” commented Dr. Rajkumar.

Pegylated Liposomal Doxorubicin in Combination With Bortezomib May Provide an Advantage for High-Risk Patients Relapsing Within 12 Months of Stem-Cell Transplant

Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, Minnesota, presented results of a retrospective analysis of a large, phase III study (DOXIL-MMY3001) (Orlowski et al. JCO 2007), which demonstrated that the combination of pegylated liposomal doxorubicin (Doxil) (PLD) plus bortezomib (Velcade)(B) improved time to progression (TTP), compared with B monotherapy, in patients with multiple myeloma (MM) who relapse within 12 months of autologous stem-cell transplantation (ASCT).

The present analysis examined the 12-month post-randomization survival of 646 patients who had early (less than 12 mo) versus late (12 mo or later) relapse following ASCT, as well as the effect of PLD+B versus B alone in patients who had relapsed early.

Of the 359 patients who had previously received stem-cell transplant, 114 (32%) relapsed within 12 months. The median age, gender distribution, time from diagnosis, trial enrollment, measures of disease burden (M-Protein levels and B2M) and renal function were comparable between the early- and late-relapse groups. There was no difference in overall response rates [complete + partial response (CR+PR)] or very good partial response (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early versus late relapse groups (hazard ratio = 0.94). Twelve-month survival from randomization was significantly lower in the early relapse group as compared with late relapse (83% versus 92% respectively, 

However, within the early-relapse group, the 12-month post-randomization survival rate was significantly superior following treatment with PLD+B as compared with B alone [52 of 56 patients (93%) versus 43 of 58 patients (74%) respectively, 

= 0.01]. (Patients received intravenous B, 1.3 mg/m2 on days 1,4,8 and 11 of every 21-day cycle with or without PLD, 30 mg/m

 on day 4.) Correspondingly, TTP was better in this group with PLD+B versus B alone (276 days versus 205 days respectively, 

 = 0.13). Overall, the toxicity profiles of the combination and B alone were comparable regardless of early or late relapse following ASCT.

According to the researchers, results demonstrate that PLD+B may provide an important therapeutic advantage for high-risk MM patients who experience early relapse following ASCT.

Safety and Efficacy of Lenalidomide, Bortezomib, and Dexamethasone as Front- Line Therapy for Multiple Myeloma

Paul Richardson, MD, Dana- Farber Cancer Institute, Boston, presented preliminary results from a Phase I/II study designed to determine the maximum tolerated dose (MTD), and assess the safety and efficacy of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron) as combination therapy in newly diagnosed multiple myeloma (MM) patients.

Patients received lenalidomide 15—25 mg on days 1–14, bortezomib 1.0–1.3 mg/m

 on days 1, 4, 8, 11, and dexamethasone 40/20 mg (cycles 1—4/5–8) on days 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-day cycles, initially at four planned dose levels (lenalidomide/bortezomib: 15/1.0, 15/1.3, 20/1.3, and 25/1.3).

Dose escalation proceeded depending on dose-limiting toxicities (DLTs). Based on safety data, the maximum planned dose level (4M) was added with a reduced dexamethasone starting dose (lenalidomide/bortezomib 25/1.3, dex- amethasone 20 mg in all cycles). Patients with Grade 2 or higher peripheral neuropathy (PNY) were excluded.

Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform criteria. Patients with complete response—either immunofixation negative (CR) or immunofixation positive (nCR), very good partial response (VGPR) or partial response (PR) could proceed to autologous stem-cell transplantation (ASCT) after four or more cycles.

To date, 33 patients (median age 56 years, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled in dose levels 1—4 and at the maximum planned dose level (4M), respectively, including 10 patients enrolled at the maximum planned dose level (4M). Patients have received a median of five cycles; nine patients have completed all eight cycles. Two DLTs of Grade 3 hyperglycemia caused by high-dose dexamethasone were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for lenalidomide in nine pts, bortezomib in seven patients, and dexamethasone in 17 patients, with three dose reductions having occurred in dose level 4M.

Reported toxicities have been manageable. Only 1 Grade 4 toxicity (thrombocytopenia) has been reported, plus 1 Grade 3 deep venous thrombosis (DVT) (reversed with low molecular-weight heparin (LMWH) (Fragmin)), and no Grade 3 or higher PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable patients, including 35% CR/nCR/VGPR.

After median follow-up of three months, median duration of response, TTP, progression-free survival, and overall survival have not been reached; all responders except one remain in remission, with two patients proceeding to ASCT.

Preliminary results of the study demonstrated the combination of lenalidomide/bortezomib/ dexamethasone is very active and well tolerated in newly diagnosed MM patients. The maximum planned dose has been reached at lenalidomide 25 mg, bortezomib 1.3 mg/m2, and dexamethasone 20 mg, with Phase 1 enrollment now complete using the lower dose of dexmethasone. Enrollment to the Phase 2 component is ongoing.

Together, the multiple diseases that encompass leukemia—the four major types of which are acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML)&mdash;represent the most common form of blood cancer. Roughly $2.6 billion is spent each year in the United States on leukemia treatment. Despite this abundance of resources, leukemia incidence and mortality rates have remained relatively unchanged for more than the past two decades. At the most recent ASH annual conference, however, researchers sounded a hopeful tone, citing numerous examples of diagnostic and therapeutic progress.

According to Richard A. Larson, MD, University of Chicago, and moderator of an ASH press conference on 2007 research findings, “Every year, scientists are continually making advances in learning more about what causes normal bone marrow cells to become cancerous on the genetic level. Through this cutting edge research, we are finding more effective combination therapies and developing new targeted cancer agents that help extend the lives of our patients with leukemia. Research presented at this year’s meeting focuses on many of these innovative treatment advances.”

One of the topics that generated significant interest and attention at ASH 2007 was imatinib (Gleevec) therapy and the emerging, increasingly viable niche of replacement therapies for imatinib in cases where patients demonstrate therapeutic resistance or intolerance to imatinib.

Intensive Imatinib in Combination With High Dose Chemotherapy Yields Improved Early Event-Free Survival in Children With Philadelphia Chromosome- Positive ALL

Kirk R. Schultz, MD, Children's Oncology Group, Arcadia, California, reported on results of Children’s Oncology Group (COG) Study AALL0031, which demonstrated an association between intensive imatinib (Gleevec) therapy in conjunction with high-dose chemotherapy and improved early event-free survival in children with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).

The COG AALL0031 protocol (open 2002 —2006) gave imatinib at 340 mg/m

 for an increasing number of days in combination with an intensive chemotherapy backbone. Cohorts received 42 days of imatinib exposure (Cohort 1, N=8), 63 days (Cohort 2, N=12), 84 days (Cohort 3, N=11), 126 days (Cohort 4, N=12) and 280 continuous days (Cohort 5, N=50) prior to maintenance therapy. If an HLA-identical sibling donor was available, a bone marrow transplant (BMT) was performed after the first two cycles of therapy postinduction otherwise chemotherapy was continued. The BMT patients received imatinib starting 4—6 months post-BMT for a 6-month duration. Ninety-three patients were treated, 10 of whom had failed induction (induction failures were removed from the following analyses).

Researchers observed that minimal residual disease (MRD) positivity (<0.01%) was significantly lower (

= 0.0002) after consolidation block 1 and after consolidation block 2 (

= 0.007) in Cohorts 3—5 (imatinib in consolidation blocks 1&2) versus Cohorts 1 and 2 combined (no imatinib in consolidation blocks 1&2). Early event-free survival (EFS) improved with increasing imatinib exposure with a one-year EFS of 70.6±11.1% for Cohorts 1 & 2, 90.9±6.4% for Cohorts 3&4, and 95.3±3.6% for Cohort 5 (

= 0.02). The one year EFS for Cohort 5 was significantly higher than for historical controls from previous COG studies (N=56; one-year EFS 65.7±6,4%; 

= 0.006). Twenty-one patients had matched sibling transplants (8 of 43 in Cohorts 1—4 and 13 of 44 in Cohort 5). Eleven of 83 (13%) patients were removed from protocol by treating institutions for alternative donor BMT. Intent-to-treat analysis does not show a statistically signifi- cant difference in early outcome between those patients in Cohort 5 treated without sibling donor BMT compared with patients who received a matched sibling donor BMT (

The related donor BMT group treated with 6 months of imatinib post BMT had a higher one-year EFS compared with a comparable historical BMT group receiving no imatinib on prior pediatric cooperative group protocol with a one-year EFS 78%. Cohort 5 chemotherapy treatment group outcomes were not significantly affected after removal of patients receiving off protocol BMT.

Schultz and colleagues concluded that imatinib given in combination with intensive chemotherapy resulted in a significant improvement in early EFS and reduction in early MRD. Post-BMT imatinib also improved early outcome in related donor BMT. Intensive imatinib with intensive chemotherapy gives equivalent early EFS to patients treated with allogeneic-related or alternative- donor BMT. According to researchers, longer observation will be required to see if this results in a difference in long term EFS.

Currently, Ph+ ALL remains one of the highest risk subsets of childhood ALL.

Outcome in patients on Children's Oncology Group protocol, AALL0031

Intent-to-treat analysis - Cohort 5 chemotherapy with continuous-dosing imatinib

				(includes 6 patients removed from study for alternative donor BMT) specifi city

Intent-to-treat analysis - Sibling BMT (all Cohorts)

The American Society of Hematology (ASH) held its 49th Annual
Meeting at the Georgia World Congress Center in Atlanta in December. The following reports provide summary coverage of meeting highlights,
primarily focusing upon notable research breakthroughs relating
to hematological malignancies.

American Society of Hematology Meeting Highlights

New research and Emerging Trends from the San Antonio Breast Cancer Symposium

The 30th Annual Charles A. Coltman, Jr. San Antonio Breast Cancer Symposium (SABCS) was held December 13—16, 2007, at the Henry B. Gonzalez Convention Center, San Antonio, Texas. The scientific program consisted of invited lectures and mini-symposia by experts in clinical and basic research, selected slide and poster presentations chosen from the submitted abstracts, and case discussions.

The SABCS is a division of the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio. The CTRC is an independent, nonprofit institution directed by a volunteer Board of Governors committed to providing the highest quality cancer treatment, research, and education. Its objective is to provide state-of-the-art information on the experimental biology, etiology, prevention, diagnosis, and therapy of breast cancer and premalignant breast disease to an international audience of academic and private physicians and researchers.

This symposium is directed primarily toward academic and private physicians and researchers involved in breast cancer in medical, surgical, gynecologic, and radiation oncology, as well as other appropriate health care professionals. The majority of participants are physicians and researchers, with a smaller representation of affiliated health care professionals.

CTRC-AACR San Antonio Breast Cancer Symposium

At this most recent SABCS, the CTRC and the American Association for Cancer Research (AACR) announced a collaboration for future symposia, the result of which will be renamed the 

 beginning in 2008. As stated in the announcement, “Complementing the clinical strengths of the highly regarded annual San Antonio Breast Cancer Symposium, the AACR’s scientific prestige in basic, translational, and clinical cancer research will create a unique and comprehensive scientific meeting that will advance breast cancer research for the benefit of patients.”

Patient Characteristics and Time Course of CNS Metastases In Patients with HER2-Positive Metastatic Breast Cancer: Results of a Prospective, Observational Study of More Than 1,000 Patients

Clinically apparent central nervous system (CNS) metastases are reported to occur in 6% to 16% of women with metastatic breast cancer. The true incidence is not known, as autopsy series have revealed CNS metastases in 18% to 34% of patients with metastatic breast cancer. The development of brain metastases has been associated with young age, HER2-positive status, estrogen receptor—negative status, and basal phenotype.

Patients with HER2-positive metastatic breast cancer are much more likely to develop CNS metastases than those with HER2-negative metastatic breast cancer, with estimates of the incidence ranging from 23% to 48% based on retrospective reviews of trastuzumab trials and single institution experiences. Predictors of CNS metastasis are not well characterized.

Denise A. Yardley, MD, from the Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, Tennessee, presented the results of an analysis of RegistHER data performed to characterize the incidence and predictors of CNS metastases among patients with HER2-positive metastatic breast cancer.

RegistHER is an observational cohort of 1,030 women with HER2-positive metastatic breast cancer treated in community and academic settings. Patients were enrolled in the RegistHER study between January 2003 and February 2006. This analysis was restricted to patients with metastatic breast cancer diagnosed on or before July 1, 2005 (N = 772). The median follow-up from diagnosis of metastatic breast cancer was 20 months at the time of data cutoff (December 30, 2006).

A total of 173 patients (22.4%) developed CNS metastases, of whom 35 (4.5%) had CNS metastases at the time of diagnosis, and 138 (17.9%) developed CNS metastases as a later site of disease progression. Patients who developed CNS metastases were younger (<50 yr of age, 46% vs. 39%), had disease that was hormone receptor— negative (52% vs. 40%) and had a greater disease burden (>2 metastatic sites at initial diagnosis, 60% vs. 52%), compared with patients without CNS metastases.

Among patients who later developed CNS metastases, the CNS was the only site of disease progression in 50 (36.2%) and was a first site of progression in conjunction with other sites in 14 (10.1%). Median time to CNS progression among patients without CNS disease at baseline was 12.1 months.

The brain is the first metastatic target of the HER2-positive cells in about 50% of patients, rather than a late occurrence, said Dr. Yardley. On the other hand, treatment with trastuzumab appears to extend survival in women with brain metastases, even though the drug does not cross the blood-brain barrier.

Gemcitabine/Docetaxel Versus Capecitabine/ Docetaxel in Patients With Anthracycline-Pretreated Metastatic Breast Cancer: New Phase III Data Demonstrate Similar Efficacy and Suggest Better Tolerability for Gemcitabine/Docetaxel

Gemcitabine, capecitabine, and docetaxel are highly active agents in anthracycline-pretreated metastatic breast cancer. A comparison of gemcitabine plus docetaxel (GD) and capecitabine plus docetaxel (CD) would provide valuable information for the clinician to help guide treatment decisions.

Stephen Chan, MD, MRCP, FRCR, Head of the department of clinical oncology at Nottingham City Hospital, Nottingham, United Kingdom, presented survival results of a phase III study comparing GD and CD in anthracycline-pretreated patients with metastatic breast cancer. Patients with histologically confirmed metastatic breast cancer who relapsed after an anthracycline- based regimen (either in neoadjuvant or first-line metastatic disease) were randomized to GD (G 1000 mg/m

 d1) q21 days. Neoadjuvant pretreatment with taxanes was allowed if completed more than six months before entry. In a previous analysis

, GD demonstrated similar efficacy to CD, but with a better non-hematologic toxicity profile.

Between October 2002 and March 2004, 305 patients were randomized. The treatment arms were well balanced. Median age was 55 years; 86% of enrollees had visceral disease; 81% had two or more metastatic sites; 67% were estrogen receptor/progesterone receptor—positive; 17% were HER2 over-expressed; 17% received prior taxane treatment; and 34% received prior chemotherapy for metastatic disease.

In the current analysis (median follow-up, 19.2 mo), median overall survival (OS) was 19.3 months in the GD group, compared with 21.5 months in the CD group (

 = 0.983). Grade 3/4 hematologic toxicity was similar in both arms, except for grade 3/4 thrombocytopenia (11% in the GD arm vs. 3% in the CD arm; 

 = 0.014). Nonhematologic toxicities were low in both arms, but significantly different grade 3/4 toxicities were more pronounced in the CD arm. These included diarrhea (8% in the GD arm vs. 18% in the CD arm; 

 = 0.0088), mucositis (4% in the GD arm vs. 15% in the CD arm; 

 = 0.0008), and hand-foot syndrome (0% in the GD arm vs. 26% in the CD arm; 

 < 0.0001). Thirteen percent of patients discontinued therapy because of an adverse event in the GD arm, compared with 30% of those in the CD arm. Dr. Chan stated, “These data suggest that the two regimens are comparable in OS; however, a more favorable toxicity profile on the GD arm may be a determining factor in selecting a better treatment option.”

Quality of Life in Patients With Node-Positive and Those With Node-Negative, HER2-Positive Early Breast Cancer Treated with Docetaxel- and Trastuzumab (Herceptin)-Based Regimens

In a poster session, Heather-Jane Au, MD, MPH, Department of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada, presented the results of the Breast Cancer International Research Group (BCIRG) Study 006, which assessed quality of life in patients with node-positive and those with node-negative, HER2-positive early breast cancer treated with docetaxel- and trastuzumab-based regimens.

BCIRG 006 was a large-scale (N = 3,222), randomized, controlled trial comparing adjuvant doxorubicin plus cyclophosphamide (AC) for four cycles, followed by either docetaxel for four cycles (AC-T) or one of two trastuzumab-containing regimens—AC followed by T with trastuzumab for one year (ACTH) or T with carboplatin for six cycles with trastuzumab for one year (TCH) in patients with node-positive or high-risk, node-negative, HER2- positive early breast cancer.

The European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaires C-30 and BR-23 were administered at baseline; mid-chemotherapy; end of chemotherapy; and at six, 12, and 24 months after chemotherapy. The primary endpoint for quality of life compared Physical Function, Global Health Status, Systemic Therapy Side Effects, and Future Perspective mean changes from baseline to mid-chemotherapy, end of chemotherapy, and 12 months post-chemotherapy using a two-sample t-test. Owing to the three-arm comparisons, 

 < 0.017 was considered statistically significant.

Physical Function change scores were —7.2 for TCH, –5.2 for AC-TH, and –5.9 for AC-T at mid-chemotherapy (

 = 0.0081 TCH vs. AC-TH); —8.9, –8.9, and –10.1, respectively, at end of chemotherapy (

 > 0.017); and —0.5, –1.7, and –1.5, respectively, at 12 months post-chemotherapy (

 > 0.017). Global Health Status change scores were —6.8 for TCH, –5.4 for AC-TH, and –7.2 for AC-T at mid-chemotherapy (

 > 0.017); —6.7, –8.4, and –8.6, respectively, at end of chemotherapy (

 > 0.017); and 3.6, 2.8, and 4.1, respectively, at 12 months post-chemotherapy (

 > 0.017). Systemic Therapy Side Effects change scores were 25.4 for TCH, 25.0 for AC-TH, and 26.7 for AC-T at mid-chemotherapy (

 > 0.017); 20.2, 25.1, and 28.8, respectively, at end of chemotherapy (

 < 0.0001 for TCH vs. AC-TH and TCH vs. AC-T; 

 = 0.0007 for AC-TH vs. AC-T); and 3.6, 5.1, and 4.2, respectively, at 12 months post-chemotherapy (

 > 0.017). Future Perspective change scores were similar between arms, improving at each time point: 3.0 to 4.9, 3.3 to 5.8, and 10.7 to 14.8 at mid-chemotherapy, end of chemotherapy, and 12 months post-chemotherapy, respectively.

The Systemic Therapy Side Effects change scores were significantly better for TCH patients compared with AC-TH and AC-T patients at the end of chemotherapy and by response analysis, supporting the conclusion that this regimen was better tolerated. Physical Function was slightly worse at mid-chemotherapy for TCH patients compared with those just starting their taxane on AC-TH, but otherwise was similar between arms. Dr. Au stated that all arms had recovery of the deterioration in Physical Function, Global Perspective, and Systemic Therapy Side Effects quality-of-life scales by one year.

New Data Support the Pharmacokinetic Profile, Tolerability, and Preliminary Antitumor Activity of Sequential Administration of Sunitinib (Sutent) and Docetaxel (Taxotere) in Patients With Advanced Breast Cancer

Sunitinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), the cytokine receptor KIT, the receptor tyrosine kinase—encoding proto-oncogene RET, and the receptor tyrosine kinase FLT3. Sutent is currently approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate. In mouse xenograft models of breast cancer, sunitinib has been shown to enhance the antitumor activity of docetaxel.

In a poster session moderated by Luca Gianni, MD, Head of the Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, results of a phase I study evaluating the pharmacokinetic profile, tolerability, and preliminary antitumor activity of sequential administration of sunitinib and docetaxel in patients with advanced breast cancer were presented.

Patients with unresectable, locally recurrent, or metastatic breast cancer who relapsed after anthracycline-based chemotherapy in the adjuvant setting were eligible for the study. The primary objective was to study the pharmacokinetic profile of sunitinib and docetaxel. Secondary endpoints were the safety and the preliminary activity of the combination. Patients received intravenous docetaxel 75 mg/m

 on day 1 and oral sunitinib 37.5 mg/day for two weeks starting on day 2 of a three-week cycle. After discontinuation of docetaxel, responsive patients (those achieving partial response or stable disease) could continue sunitinib as a single agent until progression of disease.

Twenty-two patients received 75 mg of intravenous docetaxel three times a week in addition to sunitinib 37.5 mg/day, administered in a dosing schedule of two weeks on treatment, followed by one week off. Dosing of docetaxel was reduced to 60 mg in six patients and delayed in 10 patients, while dosing of sunitinib was reduced to 25 mg/day in three patients, and escalated to 50 mg/day in one patient. Dosing of sunitinib was interrupted in 13 patients. After discontinuation of docetaxel, patients who responded to treatment continued on sunitinib as a single-agent until the disease progressed.

Of 18 evaluable patients, 13 (72%) have experienced an objective response to date, all of which were partial responses, as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Nine of these patients—several of whom had visceral disease&mdash; experienced decreases in tumor size after two cycles of therapy.

In this exploratory study, the combination of sunitinib and docetaxel demonstrated preliminary activity with no pharmacokinetic drug—drug interaction. Treatment with the combination was generally well tolerated, with most adverse events proving mild or moderate in severity. The most commonly reported severe adverse event was transient neutropenia (grade 4); however, the investigators concluded that sunitinib can be given among patients with grade 3–4 neutropenia, with no need for dose interruption. Grade-3 adverse events were few and included one case each of fatigue, diarrhea, stomatitis, and hand– foot syndrome. Eleven patients discontinued treatment for reasons including lack of efficacy (5 pts), adverse events (2 pts), and non–treatment- related discontinuations (4 pts).

Dr. Gianni summarized the results by stating, “Previous studies have shown sunitinib malate to be well tolerated in combination with standard of care chemotherapy regimens—including paclitaxel and capecitabine&mdash;in patients with advanced breast cancer. Based on these and other evolving data, this compound is continuing to be evaluated both as a single agent and in combination with other agents to treat metastatic breast cancer.”

A phase III study of sunitinib plus docetaxel compared with docetaxel alone in the first-line treatment of advanced breast cancer is currently underway. The results of this trial are eagerly anticipated.

Two-Year, Phase III Study Looks at Denosumab in Preventing Bone Loss Caused by Aromatase Inhibitors

The aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor—positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, aromatase inhibitors are associated with significantly more osteoporotic fractures and greater bone mineral loss. Furthermore, adjuvant therapy with aromatase inhibitors is well established in postmenopausal women with hormone receptor– positive breast cancer, but may be complicated by accelerated bone loss and increased risk of fracture. Strategies for the identification and management of treatment-induced bone loss are currently being defined.

A late-breaking presentation moderated by Georgiana K. Ellis, MD, Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington, highlighted the results of a phase III, randomized, double-blind, placebo-controlled study evaluating the effect of denosumab therapy on bone mineral density (BMD) in women receiving aromatase inhibitors for non-metastatic breast cancer. Denosumab is a fully human antireceptor activator of nuclear factor κB (RANK) antibody. It is also known as RANK ligand (RANKL), and is an essential mediator of osteoclast formation, function, and survival that is expressed on osteoblasts and stromal cells. RANKL is a member of the tumor necrosis factor (TNF) ligand family, which is essential for this process. RANKL attaches to RANK, a receptor on the cell surface of osteoclasts and osteoclast precursors, to stimulate proliferation and differentiation of cells to form the osteoclast phenotype and inhibit apoptosis. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. Since denosumab is highly specific, the chance of systemic effects in other parts of the body is low, so patients do not need routine laboratory monitoring.

To test the effectiveness of denosumab in preventing bone loss caused by aromatase inhibitors, a clinical trial recruited 252 patients who had been treated for early-stage breast cancer and for whom treatment with anastrozole, an aromatase inhibitor, was planned. Eligible patients were 18 years of age or older with histologically confirmed, HR+, nonmetastatic breast cancer. Enrollees were stratified by duration of AI therapy (≤6 vs. >6 mos) and received placebo (N = 125) or denosumab 60 mg (N = 127) subcutaneously every six months for four doses. All patients were instructed to take daily doses of calcium and vitamin D.

At enrollment, all patients had evidence of bone loss, but no one had osteoporosis or T scores less than —2.5 at the lumbar spine, total hip, and femoral neck. The primary endpoint was percentage change from baseline to Month 12 in lumbar-spine BMD, based on dual-energy x-ray absorptiometry measurement.

The study lasted for two years. At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab and placebo groups (

 < 0.0001 at both time points). These increases were not influenced by duration of AI therapy. Increases in BMD were also observed consistently at the total hip and total body, and at predominantly cortical sites at the femoral neck and distal third of the radius, at 12 and 24 months (

 < 0.0001). Greater proportions of the denosumab-treated patients than those who received placebo had preservation of lumbar spine BMD (>0% change from baseline) at 12 (97% vs. 36%; 

Overall, by the end of the first year, the bone density of the women receiving denosumab had increased by nearly 5%, while the women who did not receive denosumab had bone density decreases of almost 1%. By the end of the second year, the difference was even greater: In the women receiving denosumab, bone density had increased by almost 6%, while the bone density of the women who did not receive denosumab decreased by nearly 2%. Side effects of denosumab were similar to those reported in the control group.

The investigators concluded that in women with nonmetastatic breast cancer who had low bone mass and were receiving adjuvant AI therapy, twice-yearly administration of denosumab consistently increased BMD over 24 months at trabecular and cortical bone sites, with overall adverse event rates similar to placebo.

Based on these results, denosumab appears to be a safe and effective treatment for preventing bone loss in women taking AIs, offering an attractive alternative to existing therapies, such as oral or intravenous bisphosphonates.

Docetaxel-Based Chemotherapy Significantly Improves Overall Survival Compared With Standard Anthracycline-Based Chemotherapy in Early-Stage Breast Cancer

In an oral presentation given by Steve E. Jones, MD, Medical Director of US Oncology Research, Inc., Houston, Texas, seven-year results of US Oncology Adjuvant Trial 9735 were reported. The new data update the five-year data reported previously.

 This trial compares docetaxel (Taxotere)/ cyclophosphamide (TC) with standard chemotherapy doxorubicin/cyclophosphamide (AC) in women with node-negative (~50%) and node-positive early breast cancer. Dr. Jones was the principal investigator of the study.

Patients were eligible if they had Stage I—III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and Dec-ember 1999, 1,016 patients were assigned to four cycles of either standard-dose AC (60/600/mg/ m

) (N = 506), by intravenous infusion every three weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor—positive disease, were given after completion of chemotherapy.

In the updated analysis, overall survival (OS) at seven years was statistically greater among women treated with TC compared with those treated with AC (87% vs. 82%). The 31% reduction in the risk of death was statistically significant (

 = 0.032). At seven years, disease-free survival (DFS) was also statistically greater among women treated with TC than among those treated with AC (81% vs. 75%). The 26% reduction in the risk of cancer recurrence among women treated with TC was statistically significant (

 = 0.033). The DFS benefit seen in elderly patients (≥65 yr; 31% risk reduction of recurrence) is consistent with that in the overall patient population.

The 30th Annual Charles A. Coltman, Jr. San Antonio Breast Cancer
Symposium (SABCS) was held December 13-16, 2007, at the Henry
B. Gonzalez Convention Center, San Antonio, Texas. Our editors highlight the newest research and emerging trends in treatment and care. 

Oncology & Biotech News Editors

Articles

Chemotherapy Foundation Symposium Overview

American Society of Hematology Meeting Highlights

Highlighting Advances in Breast Cancer