TOP 2013 CANCER ADVANCES-ASCO 2013 REPORT

Clinical cancer advances made during a year-long period, which takes in much of the past calendar year, are highlighted by the American Society of Clinical Oncology in its annual progress report, published online December 10 in the Journal of Clinical Oncology.

Now its ninth year, the annual report is put together by a panel of prominent oncologists, who work through a peer-reviewed process to highlight what they consider to be the most important advances in clinical cancer made during a 1-year period (from October 2012 through September 2013).

The panel has highlighted a total of 76 advances, the most clinically relevant of which are summarized here with a link to how we reported the news on Medscape Medical News. This list includes the approval in the United Sates of 9 new drugs for cancer and the approval of extended cancer indications for another 7 drugs already on the market.

Patient Care

• Patients often do not understand goals of cancer treatment. A study of more than 1000 cancer patients found that most believed that their treatment was curative. The researchers found that 70% of those with lung cancer and 80% of those with colorectal cancer did not understand that they had incurable disease and that the aim of treatment was palliation ( N Engl J Med. 2012;367:1616-1625). ASCO says this finding "raises questions about how information is communicated and whether patients are adequately informed to make treatment decisions."
• Hospice services are underused by Medicaid patients. A study comparing rates of hospice use among patients with stage 4 lung cancer found substantially lower use among Medicare vs Medicaid patients (50% vs 25% patients used hospice) ( J Clin Oncol. 2013;31:2569-2579). ASCO draws attention to its provisional clinical opinion that recommends extending palliative care services for all patients with advanced cancer and states: "Ensuring that people live their final days in comfort and dignity is a key responsibility of cancer care providers."
• Off-label use of chemotherapy is often not supported by guidelines. A study of chemotherapy use in community oncology practice found that about 30% of chemotherapy is used off-label and that only about half of this off-label use adheres to guidelines from the National Comprehensive Cancer Network (NCCN) ( J Clin Oncol. 2013;31:1134-1139). ASCO comments that more work is needed to see how much of this non-NCCN-recommended off-label use is inappropriate or potentially harmful.
• Adherence to antibiotic use guideline improves outcomes in febrile neutropenia. A study of 25,000 patients hospitalized with febrile neutropenia between 2000 and 2010 found that adherence to guideline-recommended use of antibiotics was associated with better outcomes ( JAMA Intern Med. 2013;173:559-568). Among low-risk patients with febrile neutropenia, prompt initiation of guideline-based antibiotics significantly decreased discharge to a nursing facility and improved survival.
• Intravenous CaMg does not reduce oxaplatin-induced sensory neurotoxicity. The practice of infusing calcium and magnesium to reduce oxaliplatin-induced sensory neuropathy in patients with colorectal cancer should be stopped, according researchers who reported a study, involving 353 patients, showing that it does not work. This study was just published online December 2 in theJournal of Clinical Oncology.

Hematological Malignancies

• Ibrutinib is promising in treatment-resistant chronic lymphocytic leukemia and mantle cell lymphoma. Ibrutinib is an oral drug with a novel mechanism of action, acting as an inhibitor of Bruton's tyrosine kinase. A study in patients with relapsed or treatment-resistant mantle cell lymphoma showed results with this drug that were significantly better than what is achievable with salvage therapy options ( N Eng J Med. 2013:369;507-516) and that led to recent US Food and Drug Administration (FDA) approval of this indication. A second study in patients with relapsed or treatment-resistant chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma showed that ibrutinib led to long-lasting remissions ( N Eng J Med. 2013;369:32-42). This CLL indication for ibrutinib is still under review at the FDA.
• Engineered T cells are effective in aggressive, chemotherapy-resistant acute lymphocytic leukemia. Early results with chimeric antigen receptor–modified T cells in acute lymphocytic leukemia (ALL) were reported from small studies in adults (Sci Transl Med. 2013:5:177ra38) and in children (N Eng J Med. 2013;368:1509-1518). The latest results from these ALL studies, as well as updated results in CLL and in lymphoma, were reported just last week at the American Society of Hematology annual meeting, as reported by Medscape Medical News.
• Two new drugs were approved for chronic myeloid leukemia. The FDA granted accelerated approval to 2 new drugs: Omacetaxine mepesuccinate (Synribo) was approved for patients with chronic and accelerated-phase chronic myeloid leukemia (CML) in whom cancer has progressed after at least 2 tyrosine kinase inhibitors. Ponatinib (Iclusig) was initially approved for adult patients with chronic-phase, accelerated-phase, or blast-phase CML resistant or intolerant to prior tyrosine kinase inhibitor therapy and for patients with Philadelphia-chromosome-positive ALL. However, reports of adverse effects led to a temporary removal of the drug from the US market, followed by a review and then a return to the market, although for restricted indications and with warnings.
• Pomalidomide (Pomalyst) was approved for multiple myeloma. For patients whose disease has progressed despite at least 2 prior therapies, including lenalidomide (Revlimid) and bortezomib (Velcade).This was also an accelerated approval.
• Lenalidomide (Revlimid) was approved for mantle cell lymphoma. Specifically for patients whose disease has relapsed or progressed despite 2 prior therapies, 1 of which was bortezomib. This is an additional indication for lenalidomide, which is already marketed for multiple myeloma and myelodysplastic syndromes.

Breast Cancer

• Tamoxifen for 10 years instead of 5 years further reduces risks. In women with hormone-receptor positive early stage breast cancer treated with surgery, taking tamoxifen for 10 years, instead of the currently recommended 5 years, further reduces the risk for breast cancer recurrence and death. The finding comes from 2 large studies, known as ATLAS (Lancet. 2013;381:805-816) and aTTom (J Clin Oncol. 2013;31:6s; supplement, abstract 5).
• Paclitaxel once a week instead of every 2 weeks has the same efficacy. A randomized trial showed that administering the drug at a lower dose every week had the same efficacy and fewer adverse events than administering a higher dose every 2 weeks ( J Clin Oncol. 2013;31:51s; supplement, abstract CRA1008).
• Ado-trastuzumab emtansine (Kadcyla) was approved. For HER-2-positive metastatic breast cancer in patients who had previously received trastuzumab (Herceptin) and a taxane. It becomes the fourth targeted therapy for HER-2-positive breast cancer, joining trastuzumab, lapatinib (Tykerb), and pertuzumab (Perjeta).

Gastrointestinal Cancers

• Octreotide LA (Sandostatin LA) prolongs survival in midgut neuroendocrine tumors. Longer-term results from the PROMID study confirmed that the drug prolongs overall survival and found most benefit in patients with a low hepatic load ( J Clin Oncol. 2013;31:250s; supplement, abstract 4030). These encouraging findings will motivate physicians to start using octreotide in such patients, ASCO comments.
• Capecitabine and bevacizumab are now standard maintenance therapy in colorectal cancer.This combination has now been established as a standard maintenance therapy after showing improved survival compared with placebo in the CAIRO3 study, conducted in patients with previously untreated and inoperable metastatic colorectal cancer who had not progressed on initial treatment with capecitabine, oxaliplatin, and bevacizumab ( J Clin Oncol. 2013;31:205s; supplement, abstract 3502). Another combination of bevacizumab plus chemotherapy is alsoapproved for use in maintenance therapy of colorectal cancer (based on the ML 18147 study).
• Colorectal cancer with NRAS mutations unlikely to benefit from panitumumab (Vectibix).Patients with colorectal cancer being considered for panitumumab are already tested for KRASmutations (found in about 40%), but now they also should be tested for NRAS mutations (found in about 10%) because both of these mutations render the drug ineffective. The finding on NRASmutations comes from a new analysis of data from the PRIME study ( N Eng J Med. 2013;369:1691-1703).
• Nab-paclitaxel (Abraxane) was approved for use in pancreatic cancer. In addition, the drug's use in combination with gemcitabine was established as a new standard of care for metastatic pancreatic cancer in the MPACT trial ( N Eng J Med. 2013;369:1691-1703). Nab-paclitaxel, an albumin-bound form of the drug, is already marketed for use in breast cancer and also was recentlyapproved for nonsmall-cell lung cancer (NSCLC).
• S-1 chemotherapy improves survival in pancreatic cancer. A phase 3 trial showed that S-1 (which contains tegafur and is converted in the body to fluorouracil) substantially improves survivalwhen compared with gemcitabine in Asian patients ( J Clin Oncol. 2013;31:244s; supplement, abstract 4008). ASCO comments that the results suggest that S-1 warrants consideration as a new standard of care but points out that, so far, the drug is available only in Japan and several other countries and that previous results suggest it is more toxic in patients of European descent, requiring the use of lower doses.

Genitourinary Cancers

• Cabozantinib shows impressive activity in prostate cancer.This includes the disappearance of bone metastases on scans (J Clin Oncol. 2013;31:314s; supplement, abstract 5026),described as unprecedented. However, there were also adverse events seen at higher doses, and more research is needed, ASCO comments; larger phase 3 trials that will collect survival data are in progress. Cabozantinib (Cometriq), a multireceptor tyrosine kinase inhibitor, is approved for use in medullary thyroid cancer.
• Direct comparison in metastatic renal cell carcinoma shows that pazopanib and sunitinib have similar efficacy. However, sunitinib has more adverse effects ( N Eng J Med. 2013;369:722-731).
• Immunotherapy shows promising activity in renal cell carcinoma. Patients who had progressed despite several treatments showed encouraging responses to the anti-PD-LI antibody MPDL3280A ( J Clin Oncol. 2013;31:391s; supplement, abstract 5026); the drug has also shown activity in several other tumor types.
• Radium223 (Xofigo) was approved for advanced prostate cancer. This novel alpha-emitting radiopharmaceutical was approved by the FDA for patients with advanced prostate cancer and symptomatic painful bone metastases.
• Abiraterone (Zytiga) was approved for first-line use in prostate cancer. This approval expands the drug's indication in the treatment of this disease; it was already approved for use after chemotherapy.

Gynecologic Cancers

• Selumetinib shows promising activity in serous ovarian cancer ( Lancet Oncol. 2013;14:134-140). This investigational agent, a novel MEK inhibitor, has also shown activity in several other tumor types and is the first drug shown to work in uveal melanoma.
• Bevacizumab plus chemo improves survival in advanced cervical cancer. GOG 240 was a landmark trial ( J Clin Oncol. 2013;31:6s; supplement, abstract 3), ASCO comments, but bevacizumab is not approved for this use (as yet).

Lung Cancer

• Afatinib (Gilotrif) was approved for NSCLC. Specifically for first-line treatment for patients harboring EGFR mutations, after a study showed a 4.2-month improvement in disease-free progression compared with chemotherapy.
• Erlotinib (Tarceva) was approved for first-line use in EGFR+ve NSCLC. On the basis of a study that showed a 5.2-month improvement compared with chemotherapy, erlotinib was approved for first-line use in EGFR+ve NSCLC, and at the same time, the FDA approved a companion diagnostic test. This is an extension of its indication, as erlotinib was already marketed for use in NSCLC, but the approved indication had previously stipulated its use as a second- or third-line agent.

Melanoma

• Dabrafenib (Tafinalar) and trametinib (Mekinist) were approved for melanoma. Dabrafenib is a BRAF inhibitor and was approved for use in melanoma patients harboring BRAF V600E gene mutations, whereas trametinib is a MEK inhibitor and was approved for use in melanoma patients with BRAF V600E or V600K gene mutations.
• Encouraging results were seen with new PD1-targeted immunotherapies in melanoma. Here, the ASCO report highlights findings with several investigational agents, including nivolumab, lambrolizumab (MK-3475), and MPDL3280A, as well as a study ( N Eng J Med. 2013;369:122-133) using the combination of ipilimumab with nivolumab, which showed "truly remarkable" responses.

Sarcomas

• Retreatment with imatinib (Gleevec) in gastrointestinal stromal tumors (GIST) offers modest gains. A study from South Korea reported, for the first time, results from retreatment with imatinib in patients with advanced GIST who had progressed after first-line imatinib or sunitinib (Sutent). The results show that retreatment offers modest gains, ASCO comments, showing a small but significant improvement in progression-free survival (1.8 vs 0.9 months on placebo), as well as overall survival (8.2 vs 7.5 months with placebo) (J Clin Oncol. 2013;31:632s; supplement, abstract LBA 10502).
• Regorafenib (Stivarga) was approved for treatment-resistant GIST. The approval was specifically in patients with advanced and inoperable disease who had progressed despite treatment with imatinib and sunitinib. The approval was based on a study showing a nearly 4-fold improvement in progress-free survival (4.8 vs 0.9 months on placebo). This is an additional indication for regorafenib, which was already marketed for colorectal cancer.
• Denosumab (Xgeva) was approved for giant cell tumor of the bone. The drug offers a new treatment option for patients whose tumors cannot be surgically removed, and in clinical trials, it resulted in tumor shrinkage in 47% of patients. This is an additional indication for denosumab, which is already marketed for osteoporosis and for use in cancer patients with bone metastases.

Other Cancers

• Sorafenib (Nexavar) stalls growth of treatment-resistant thyroid cancer. The drug also showed an improvement in progression-free survival in the DECISION trial ( J Clin Oncol. 2013;31:6s; supplement, abstract 4). On the basis of this study, sorafenib was recently approved for the treatment of metastatic differentiated thyroid cancer, becoming the first drug for this indication in 40 years. The product was already marketed for liver and kidney cancers.
• Late results show therapy benefits in oligodendroglioma. Results from a long-term follow-up of 2 studies in anaplastic oligodendroglioma showed what earlier results did not: a significant improvement in survival when chemotherapy was added onto radiation. This benefit may be limited to patients with 1p/19q deletions ( J Clin Oncol. 2013;31:344-350), but for this patient subgroup, these results will change the standard of care, ASCO comments.
• Crizotinib (Xalkori) shows promising activity in pediatric patients. Specifically, in young patients with treatment-resistant solid tumors that harbor ALK gene alterations, including neuroblastoma, inflammatory myofibroblastic tumors, and anaplastic large-cell lymphoma (ALCL). Some patients (eg, 7/9 patients with ALCL) experienced complete remissions ( Lancet Oncol. 2013;14:472-480).

Prevention and Screening

• Daily multivitamins modestly reduce the risk for cancer in men. The finding comes from an analysis of the Physicians Health Study II, which involved 14,641 male physicians aged 50 years or older ( JAMA. 2012;308:1871-1880) and which found that after a median follow-up of 11 years, men who took multivitamins had a small but significant reduction in the incidence of cancercompared with those taking placebo (17.6% vs 18.8%). "A broader combination of low-dose vitamins and minerals may be more effective than high doses of individual vitamins," ASCO comments.
• Increase in HPV cancers, but HPV vaccine coverage uneven across the United States. The Annual Report to the Nation ( J Natl Cancer Inst. 2013;103:175-120) noted that from 2000 to 2009, there was a decrease in cervical cancer but an increase in several cancers associated with the human papilloma virus (HPV), including oropharyngeal cancer in white men and women, anal cancer among white and black men and women, and vulvar cancer among black and white women. That same report noted that only 32% of girls aged 13 to 17 years had completed the full course of 3 vaccinations with HPV and that vaccinations rates were significantly lower among the uninsured (14.1%) and in some Southern states (20.0% in Alabama and Mississippi).
• Chemoprevention of prostate cancer with finasteride not approved. This issue has run on for years: the data to support this use come from the Prostate Cancer Prevention Trial, which showed a 25% reduction in prostate cancer in men taking finasteride compared with those receiving placebo, but at the same time, it found an increase in high-grade cancers in the finasteride group. As a result, the chemoprevention indication for finasteride (and a related drug, dutasteride) was not approved. Now, long-term follow-up during a median of 18 years has found that overall survival was identical in the finasteride and placebo groups ( N Engl J Med. 2013;369:603-610).
• An inexpensive, vinegar-based screening for cervical cancer was developed in India ( J Clin Oncol. 2013;31:5s; supplement, abstract 2). The screening can be carried out by health workers after only 4 weeks of study. This is an "important step forward in reducing the cervical cancer burden in India and other low-resource countries," ASCO comments.

"Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society on Clinical Oncology." J Clin Oncol. Published online December 10, 2013. Full text