Chemotherapy Foundation Symposium Overview

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%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.”

%u25BA ADVANCES IN BREAST CANCER

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

Formal decision due in February

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—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 invitro models of angiogenesis. 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.

%u25BA ADVANCES IN LUNG CANCER

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—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.”

%u25BA ADVANCES IN COLORECTAL CANCER

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.

%u25BA ADVANCES IN RENAL CANCER

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.

%u25BA ADVANCES IN MULTIPLE MYELOMA

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.