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MAJOR ADVANCES IN CANCER IN 2011

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The annual Clinical Cancer Advances 2011 report from the American Society of Clinical Oncology (ASCO), now in its seventh year, highlights 12 major advances made in 2011 and 42 advances that it considers "notable."
The report was compiled by 18 prominent oncologists, and covers the period from October 2010 to September 2011. The research highlighted in this report is considered by the experts to have had a significant impact on the way a cancer is understood or to have had a direct effect on patient care. Most of the advances were covered by Medscape Medical News.
Major Clinical Advances
Lung cancer deaths reduced by low-dose computed tomography (CT) scanning of people at high risk. These results come from the landmark National Lung Screening Trial, which was halted early because of benefit. The study followed 53,454 people at high risk for lung cancer (they had smoked the equivalent of a pack of cigarettes a day for 30 years), and showed that anannual CT scan reduced the risk of dying from lung cancer by 20%, compared with an annual chest x-ray, over the course of 3 years (N Engl J Med. 2011:365:395-409). "This was the first randomized trial to find a definitive reduction in lung cancer deaths with screening," according to the report.
Crizotinib (Xalkori) approved for rare type of lung cancer in August 2011 by the US Food and Drug Administration (FDA). This drug, indicated for use in patients with advanced nonsmall-cell lung cancer who harbor a specific type of alternation in the anaplastic lymphoma kinase (ALK) gene, is "one of the latest examples of a successful personalized medicine approach," says the report.
Exemestane (Aromasin) reduced risk for breast cancer in high-risk postmenopausal women in the MAP.3 (Mammary Prevention Trial). The trial followed 4560 women 60 years and or older who were at high risk for breast cancer, and 3-year results showed that exemestane reduced the risk for invasive breast cancer by 65% (N Engl J Med. 2011:364:2381-2391). "This is the first conclusive evidence that an aromatase inhibitor reduced the risk of a first breast cancer," the report notes, adding that exemestane now offers an alternative to tamoxifen and raloxifene, which are approved for chemoprevention but not widely used because of concerns about toxicity.
In early breast cancer, adding regional nodal irradiation decreases recurrences. In women with early-stage breast cancer who have 1 to 3 positive lymph nodes or who are node-negative but at high risk, the addition of regional nodal irradiation reduces the risk for both local recurrence and distant metastases. These results should encourage radiation oncologists to discuss with their patients a more extended radiotherapy field to reduce the risk for recurrences, the report notes.
Vemurafenib (Zelboraf) improves survival in advanced melanoma in patients with BRAFmutations, compared with standard chemotherapy (New Engl J Med. 2011;364:2507-2516).The drug was approved by the FDA in August, and the report notes that it is "a new standard treatment" for patients with melanoma and BRAF mutations (about half of all patients with melanoma).
First-line ipilimumab (Yervoy) plus chemotherapy improves survival in metastatic melanoma in a phase 3 study (N Engl J Med. 2011;364:2517-2526). The new drug is an immunotherapeutic that activates T cells, and was approved by the FDA in March. "This is the first study showing the benefit in prolonging life by combining chemotherapy and immunotherapy in patients with advanced melanoma," the report notes.
Bevacizumab (Avastin) has been shown to delay progression in both recurrent and newly diagnosed ovarian cancer in 2 separate phase 3 trials. The report considers this to be 2 separate major clinical advances. The data in recurrent ovarian cancer come from the phase 3 OCEANS trial, and show a 52% reduction in the risk for disease progression when bevacizumab is added to chemotherapy, compared with chemotherapy alone. The other study, known as ICON 7, found an improvement in overall survival in some women with newly diagnosed ovarian cancer. The report notes that researchers are waiting for longer-term data from both of these trials.
A new high-dose chemotherapy regimen improves survival in neuroblastoma. In children with high-risk metastatic neuroblastoma, an intense dosing with busulphan plus melphalan improved the event-free survival rate to 49% at 3 years, compared with 33% with the standard regimen of carboplatin, etoposide, and melphalan. These findings establish a new standard of care, the report notes.
A new chemotherapy regimen boosts event-free survival in acute lymphoblastic leukemia (ALL). The results from a phase 3 study of nearly 2500 children and young adults showed that giving methotrexate in large consistent doses, rather than gradually increasing the dose (as happens in the standard regimen) is more effective at preventing relapses and extended survival. These findings set a new standard of care and push cure rates for pediatric patients with ALL up to more than 80%, the report notes, adding that "this disease was once considered one of the most deadly pediatric cancers, but today is seen as one of the most curable."
Imatanib (Gleevec) for 3 years improves survival in patients with high-risk gastrointestinal stromal tumors. After surgery, patients who took imatanib for 3 years had significantlyimproved overall and recurrence-free survival, compared with those who took the drug for 1 year.
Abiraterone acetate (Zytiga) was approved for prostate cancer in April by the FDA. The drug is used in combination with prednisolone in patients with metastatic prostate cancer who have previously been treated with docetaxel. According to the report, it offers a much-needed new option for these patients.
Notable Advances
Brentuximab vedotin (Adcetris) shows tumor shrinkage in lymphomas. This novel antibody–drug combination was granted accelerated approval by the FDA in August for use in refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma. This is the first drug for Hodgkin's lymphoma to be approved by the FDA in more than 30 years, the report notes.
Ruxolitinib (Jakafi) used for high-risk myelofibrosis. The drug showed increased response rates, decreased spleen size, and improved symptoms such as fatigue, night sweats, weight loss, and bone pain in the COMFORT I and II studies (2011 ASCO annual meeting, abstract 6500 andabstract LBA6501). These are the first-ever randomized trials conducted in patients with myelofibrosis, and the findings promise to change the standard of care, the report notes. Ruxolitinib, a JAK inhibitor, was recently approved by the FDA for myelofibrosis.
Treating HER2 breast cancer with drug combinations is more effective than treating with single agents. Although trastuzumab (Herceptin) is effective in treating HER2-positive breast cancer, a significant number of tumors do not respond or become resistant. Two studies have shown that adding another agent improves or extends treatment response — trastuzumab was used with lapatinib (Tykerb) in the CHER-LOB study (2011 ASCO annual meeting, abstract 507) and with docetaxel and pertuzumab (Omnitarg) in the NeoSphere study (2010 San Antonio Breast Cancer Symposium, abstract S3-2). The report notes that larger, longer-term trials (ALTTO and Neo-ALTTO) are currently evaluating whether this approach ultimately extends survival.
PARP inhibitor did not improve survival in metastatic triple-negative breast cancer. The investigational drug iniparib, which acts as an inhibitor of the PARP enzyme that is involved in tumor cell DNA repair, showed promising activity in a randomized phase 2 study (n = 123) when it was added to gemcitabine and carboplatin, increasing overall survival from 8 to 12 months. However, a larger phase 3 study (n = 519) with the same drug combination failed to show any improvement in survival (2011 ASCO annual meeting, abstract 1007). The contrasting results underscore the need to conduct carefully controlled, adequately powered studies to clarify promising results in a preliminary study, the report noted.
Gene biomarkers linked to glioblastoma survival. Analysis of data collected during a phase 3 trial of temozolomide with radiation in patients with newly diagnosed glioblastoma showed that patients with tumors that carried the "silenced" gene for methyl guanine methyltransferase (MGMT) had better overall survival. Further study revealed several more biomarkers or groups of biomarkers that could predict clinical outcome (2011 ASCO annual meeting, abstract LBA2000).
Gene deletion linked to poor glioblastoma survival. Previous studies have shown that nearly all glioblastomas have alterations in the epidermal growth-factor receptor (EGFR) gene, but drugs targeting this pathway have not been effective. One study has shown that the deletion ofNFKBIA, a gene that inhibits the EGFR signaling pathway, affects tumor formation, increases chemotherapy resistance, and worsens survival. It might provide a new target for treatment (N Engl J Med 2011; 364:627-637).
New mutation patterns were found in medulloblastoma. Researchers characterized the most common genetic alterations in medulloblastoma, making it the first pediatric solid tumor to be genetically sequenced (Science 2011;331:435-439). This might allow for better molecular classification of the disease and better prognosis, and might lead to the identification of new drug targets, the report notes.
Trastuzumab was approved for HER2-positive gastric cancer by the FDA in late 2010. The drug is indicated for use in patients with metastatic gastric cancer with tumors that express high levels of HER2 (about 15% to 18% of patients). Adding trastuzumab to chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) was shown to improve survival in the ToGA trial(Lancet 2010;376:687-697). This trial was the first to show a median survival of more than 1 year in this patient population, the report notes.
Sunitinib (Sutent) and everolimus (Afinitor) were approved for pancreatic neuroendocrine tumors in patients with unresectable or metastatic disease. Both drugs were shown to more than double the time it took for the cancer to progress, compared with placebo, the report notes, and they offer new options for the treatment of this cancer, which previously was treated with interferon and chemotherapy. The indication for pancreatic neuroendocrine tumors was approved for sunitinib and everolimus within weeks of each another in May 2010.
Cabozantinib shows benefit in advanced prostate cancer in a phase 2 trial. This investigational drug showed impressive activity in a phase 2 trial in patients with progressive metastatic hormone-refractory prostate cancer (2011 ASCO annual meeting, abstract 4516). Results from 100 evaluable patients showed tumor shrinkage in 84% and disease control in 71% of patients. In addition, the researchers reported that 56 of 65 patients (86%) with bone metastases experienced either partial or complete disappearance of the bone metastases on scans, often with a drop in blood biomarkers that are indicative of bone damage, leading to significant pain relief.
Cabozantinib shows significant effect in melanoma and other cancers. The same investigational agent showed impressive activity in another phase 2 trial — this time in patients with a variety of advanced solid tumors (including liver, ovarian, and prostate cancer) and in melanoma (2011 ASCO annual meeting, abstract 3010). Cabozantinib, which also showed suppression of bone metastases, is a novel multitargeted agent, with activity against MET, VEGFR2, RET, KIT — protein kinases that are involved in the development and progression of many cancers, the report notes.
Axitinib (Inlyta) used as second-line therapy for advanced kidney cancer. Results from the phase 3 AXIS trial of 723 patients with metastatic renal cell carcinoma in whom previous treatment had failed showed that axitinib improved progression-free survival to 7 months, compared with 5 months with sorafenib (Nexavar) (2011 ASCO annual meeting, abstract 4503). Axitinib is not marketed yet, but an FDA Oncologic Drugs Advisory Committee recently voted unanimously to recommend its approval for second-line treatment in renal cell carcinoma.
Denosumab (Xgeva) prevents skeletal-related events in metastatic cancer patients. This novel bone drug, a monoclonal antibody that targets a protein (RANK ligand) involved in cancer-related bone destruction, was approved by the FDA in November 2010 for preventing skeletal-related events in cancer patients with solid tumors and bone metastases. In 2 clinical trials, denosumab was significantly better at reducing skeletal-related events in patients with advanced breast and prostate cancer than the bisphosphonate zoledronic acid (Zometa).
The Cancer Genome Atlas provides details on ovarian cancer and points to potential drug targets. The first comprehensive effort to map the genome of ovarian cancer focused on serous ovarian adenocarcinoma (which accounts for about 70% of deaths), and found several molecular features: TP53 mutations in 96% of cases, BRCA mutations in 22%, and defects that interfere with DNA repair (which could be susceptible to PARP inhibitors) in about 50% of tumors (Nature. 2011;474:609-615). These findings reinforce the promise of ongoing research on PARP inhibitors, which are being evaluated in late-stage clinical trials in ovarian cancer, the report notes.
PARP inhibitors and maintenance therapy used in ovarian cancer. A phase 2 study of 265 women with relapsed high-grade serous ovarian cancer showed that the investigational PARP inhibitor olaparib used after standard chemotherapy improved progression-free survival to 8 months, compared with 5 months for placebo (2011 ASCO annual meeting, abstract 5003). If these results are confirmed in larger trials, which are underway, olaparib could become an important treatment for women with advanced or high-risk ovarian cancer, the report notes.
The Lung Cancer Mutation Consortium matched tumor mutation to drug selection. Aprospective study identified at least 1 of 10 recognized "driver" mutations in tumors of nearly two thirds of patients with adenocarcinoma, many of which are targeted with drugs that are already marketed or in clinical trials. As a result of this program, "multiplex testing" for many tumor mutations at the same time is now routine at some of the 14 American centers that took part, and is also applicable to other cancers, the report notes.
Maintenance pemetrexed extends survival in advanced lung cancer. The phase 3 PARAMOUNT study showed that after initial treatment with pemetrexed and cisplatin, patients who continued on maintenance pemetrexed had a longer progression-free survival than those who did not (4 vs 3 months). This is the first trial to show that longer-term maintenance with one of the drugs used in the initial treatment can improve outcomes, the report notes. Pemetrexed maintenance was recently approved in Europe and has been approved in the United States since 2009, after a previous trial showed benefit.
Combination of investigational oral therapies used in melanoma. A phase 1/2 trial showed that a combination of 2 oral targeted therapies — the MEK inhibitor GSK1120212 and the BRAF inhibitor GSK2118436 — appears to have substantial antitumor activity in advanced melanoma. The results suggested promising synergistic anticancer activity (2011 ASCO annual meeting,abstract CRA8503).
Pazopanib (Votrient) and brivanib show benefit in advanced sarcoma. Pazopanib is already marketed for advanced kidney cancer, but has also shown benefit in patients with metastatic soft-tissue sarcoma in the phase 3 PALETTE trial. Second-line pazopanib improved progression-free survival, compared with placebo (5 vs 2 months) (2011 ASCO annual meeting,abstract LBA10002). The investigational drug brivanib, which blocks both vascular endothelial growth factor and the fibroblast growth factor, significantly improved progression-free survival, compared with placebo, in a phase 2 discontinuation study (2011 ASCO annual meeting,abstract 10000).
Other Notable Advances
Other notable advances covered in the report are related to strides that have been made in advanced cancer care, in patient and survivor care, and in prevention and screening.

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