A look at 10 of the most significant advances of the past year—progress that stands to benefit patients now and lays the foundation for future breakthroughs
By Mia James
Each year the American Society of Clinical Oncology (ACSO) publishes a review in the Journal of Clinical Oncology of its choices for the most meaningful advances in cancer research and treatment. In this year’s “Clinical Cancer Advances 2015,” ASCO highlighted a range of significant developments—from progress in the treatment of rare cancers to innovations in care for diseases with a broad impact, such as breast and lung cancers.1
The following 10 advances from ASCO’s review of the past year represent some of most important current advances in cancer research and treatment. They highlight how far we have come in cancer care, with innovations in treatments such as immunotherapy and targeted therapy transforming patient outcomes; they also show how continuing research will deliver new options in the coming years.
- Promising Advances For Patients With Chronic Lymphocytic Leukemia
Patients with chronic lymphocytic leukemia (CLL) are among the biggest beneficiaries of progress in cancer treatment in 2015. The US Food and Drug Administration (FDA) has approved new treatments for both those with untreated and previously treated CLL. Importantly, these new therapies are easier to tolerate, which means potential options for patients who have been unable to tolerate standard CLL therapies.
- For Patients with Previously Untreated Chronic Lymphocytic Leukemia
Gazyva® (obinutuzumab) was approved for use in combination with Leukeran® (chlorambucil) in people with previously untreated CLL in late 2013. In 2015 the FDA updated the approval of Gazyva plus Leukeran with a supplemental biologics license application (sBLA)—a submission that contains specific information about the manufacturing processes, chemistry, pharmacology, clinical pharmacology, and medical effects of the biologic product. The sBLA for Gazyva plus Leukeran included the following information about improved survival for patients with CLL:2
- Gazyva plus Leukeran helped people with previously untreated CLL live nearly a year longer without a worsening of disease compared with the standard CLL treatment Rituxan® (rituximab) plus Leukeran.
- With Gazyva plus Leukeran, nearly three times the number of people had a complete response compared with Rituxan plus Leukeran.
This past year the FDA also issued an sBLA for Arzerra® (ofatumumab) in combination with Leukeran in previously untreated patients with CLL—specifically for patients who are not candidates for treatment with chemotherapy that contains the drug Fludara® (fludarabine).3
This most recent approval of Arzerra (a monoclonal antibody that targets a molecule known as CD20, which is found on the surface of B-cells) was based on the results of a Phase II trial. The multicenter, randomized, open-label trial included 447 patients for whom Fludara-based therapy was considered inappropriate (because of advanced age or other health conditions). Researchers randomly selected patients to receive Arzerra plus Leukeran or Leukeran alone.
Patients who received Arzerra plus Leukeran had a significantly improved median progression-free survival compared with those who received Leukeran alone (22 months versus 13 months).
- For Patients with Previously Treated Chronic Lymphocytic Leukemia
While the approvals for both Gazyva and Arzerra stand to benefit patients with untreated CLL, there is also important progress for patients with previously treated CLL. Two biological therapies that block the growth of cancer—Imbruvica® (ibrutinib) and Zydelig® (idelalisib)—demonstrated important survival improvements for these patients.4,5
In a multicenter trial of 48 patients with previously treated CLL and an average age of 67 years, patients who received Imbruvica had an overall response rate of 58 percent. These responses lasted from about six to 24 months.
Zydelig also proved safe and effective for the treatment of previously treated CLL, based on findings from a clinical trial that included 220 patients. Participants were assigned treatment with Zydelig and Rituxan or with a placebo and Rituxan. At the first planned follow-up, the researchers found that participants treated with Zydelig and Rituxan lived almost 11 months without disease progression compared with about six months for those treated with placebo and Rituxan. At the next follow-up, they continued to see significant survival benefits with Zydelig and Rituxan over placebo and Rituxan.
- “Precision Medicine” Moves Forward For More-Personalized Care
Precision medicine (also known as targeted therapy) is an approach where treatments are matched to the genetic makeup of the patient and his or her tumor. These treatments are designed to fight disease more directly and effectively while reducing the incidence of harsh side effects, such as those associated with chemotherapy.
In 2015 the following seven targeted drugs became available to patients, based on 2014 FDA approvals. These therapies are promising for patients with hard-to-treat cancers:
- Arzerra is approved in combination with the chemotherapy drug Leukeran for the treatment of previously untreated patients with CLL who are not eligible for Fludara-based therapy.
- Cyramza® (ramucirumab) is approved for the treatment of advanced gastric cancer or gastro-esophageal junction adenocarcinoma.
- Sylvant® (siltuximab) is approved for the treatment of multicentric Castleman’s disease (a rare disease of lymph nodes that is similar to cancer of the lymph nodes, or lymphomas) who do not have human immunodeficiency virus and human herpesvirus-8 infection.
- Zykadia™ (ceritinib) is approved for the treatment of patients with metastatic non– small cell lung cancer (NSCLC) that is caused by a defect in a gene called ALK (anaplastic lymphoma kinase) whose disease has worsened after taking Xalkori® (crizotinib) or cannot tolerate Xalkori.
- Beleodaq® (belinostat) is approved for the treatment of peripheral T-cell lymphoma that comes back or does not respond to treatment.
- Zydelig is approved to treat patients with three types of blood cancers: chronic lymphocytic leukemia that has returned (relapsed), relapsed follicular B-cell non-Hodgkin’s lymphoma, and relapsed small lymphocytic lymphoma.
- Keytruda® (pembrolizumab) is approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following treatment with Yervoy® (ipilimumab) and, if BRAF V600 mutation positive, treatment with a BRAF inhibitor.
- Combination Of Radiation And Chemotherapy Improves Survival For Certain Types Of Brain Cancer
Patients with a low-grade Stage II gliomas may live up to five and a half years longer when treated with chemotherapy following radiation therapy compared with radiation therapy alone. Until now the median survival time after diagnosis has been 15 months with standard care, with only 10 percent of patients surviving more than five years—statistics that have left much room for improvement.6
In a trial that enrolled 251 patients with low-grade Stage II gliomas, researchers found that patients who received chemotherapy with Matulane® (procarbazine), CeeNU® (lomustine), and Oncovin® (vincristine)—in combination, known as PCV—following radiation had an improved overall survival and progression-free survival compared with those who received chemotherapy alone. Patients who received PCV lived 5.5 years longer than those who received radiation alone. Given these impressive results, the combination of PCV chemotherapy and radiation will likely become a standard approach to treatment for certain patients with low-grade Stage II gliomas—especially as future research helps identify which individuals are likely to benefit the most.
- Survival Improved In Advanced Prostate Cancer With Early Treatment With Chemotherapy Plus Hormonal Therapy
In a study conducted by researchers at the Dana-Farber Cancer Institute, the chemotherapy drug Taxotere® (docetaxel) administered with androgen-deprivation therapy (ADT), also called hormonal therapy, to metastatic prostate cancer patients was found to extend overall survival by more than 13 months.7
Historically, chemotherapy for men with newly diagnosed prostate cancer would be given only after the disease worsened despite ADT. New findings, however, suggest that starting chemotherapy earlier can substantially improve outcomes.
The study included 790 men with hormone-sensitive metastatic prostate cancer, or prostate cancer that is stimulated to grow with exposure to the male hormone testosterone. Patients were assigned to receive either standard ADT or ADT plus Taxotere.
The trial was stopped early when researchers noted significant differences in survival between the two treatment groups. After almost two and a half years, 136 more patients receiving ADT alone had died compared with those receiving ADT plus Taxotere—136 versus 101 patients, respectively. Men in the ADT/Taxotere arm had a median overall survival that was almost 14 months longer than those in the ADT-only arm—57.6 months versus 44 months, respectively. Other markers of the disease—prostate-specific antigen response, time to castration resistance, and time to progression prostate—were also improved in the ADT/Taxotere group.
- Encouraging News For Patients With Treatment-Resistant Lung Cancer
Although lung cancer is still a deadly disease—responsible for more than 150,000 deaths each year in the United States alone—there is some remarkably good news when it comes to lung cancer treatment. As researchers learn more about how the disease grows, they are finding promising therapies for even the most challenging lung cancers to treat.
Targeted therapies have been an important advance in the treatment of patients with non–small cell lung cancer, the most common type of lung cancer. These drugs target specific mutations found in patients with NSCLC—namely, in the epidermal growth factor receptor (EGFR) gene and in the ALK gene. The targeted drugs block, or inhibit, the effects of these mutations and cause tumors to shrink as a result. They can be effective at first, but patients eventually become resistant to them, meaning they no longer cause the tumors to shrink. As a result, patients with NSCLC need effective new treatment options.
Fortunately, scientists increasingly understand why patients become resistant to targeted therapies and how they can develop drugs that overcome this resistance. As a result, in recent years they have made promising discoveries in treatment for NSCLC that is resistant to both EGFR and ALK inhibitors.
Scientists have made important steps in overcoming resistance to EGFR inhibitors by discovering another mutation that they believe causes a cancer’s resistance to EGFR-targeted therapy: the T790M mutation. They have been testing two experimental drugs— AZD929118 and CO-1686— designed to target T790M. Results so far are promising: in early studies approximately 50 percent of T790M-positive patients who received AZD9291 and close to 60 percent of those who received CO-1686 experienced tumor shrinkage. A significant next step in research will be to see if these drugs improve long-term survival for patients with NSCLC that is resistant to EGFR inhibitors.8
Researchers have also found encouraging activity in the treatment of NSCLC that is resistant to ALK inhibitors. The investigational compound Zykadia appears highly active in patients with advanced ALK-positive NSCLC.9
Zykadia is an ALK inhibitor but so far appears more effective than one of the standard treatments for advanced ALK-positive NSCLC, Xalkori. In early trials Zykadia has shown greater anti-tumor activity than Xalkori. In one trial, where patients (most of whom had ALK-positive NSCLC) received the maximum tolerated dose of Zykadia (as determined in an earlier study), the majority of participants experienced a clinical response to Zykadia. The overall response rate among patients with ALK-positive NSCLC was 58 percent, and the median progression-free survival was seven months.
- Patients With Early-Stage Melanoma And Lung Cancer Among Those Standing To Benefit From Immunotherapy
Immunotherapy, a type of biological therapy, is among the most promising areas of cancer treatment advances. This approach uses substances to stimulate or suppress the immune system to help the body fight cancer. Patients with early-stage melanoma and lung cancer are among those who are particularly benefiting from immunotherapy.
The first trial of the immunotherapy Yervoy conducted in patients with Stage III melanoma appears promising, demonstrating an improvement by delaying cancer recurrence and improving survival. Yervoy targets a molecule known as CTLA4, which is found on the surface of T-cells and is thought to inhibit immune responses. By targeting this molecule, Yervoy may enhance the immune system’s response against tumor cells.10
A Phase III trial evaluated Yervoy as adjuvant therapy (in addition to surgery) and found that immunotherapy both reduced the risk of melanoma recurrence and improved the duration of survival. Overall 46 percent of patients treated with Yervoy were free of disease recurrence compared with 35 percent of patients treated with placebo. Patients survived without cancer recurrence an average of 26 months when treated with Yervoy compared with only 17 months for placebo.
For lung cancer patients, advances in immunotherapy are improving outcomes with several treatment approaches. Specifically, PD-1 inhibitors—drugs that block the action of PD-1, a protein that inhibits certain types of immune responses—are producing favorable outcomes in research. As a result, these drugs may enhance the immune system’s ability to fight cancer.
For example, findings from an ongoing Phase IB study show that for patients with previously untreated Stage IV NSCLC, the experimental anti-PD-1 antibody Keytruda results in high response rates and slows cancer progression.11
The researchers reported an overall response rate of 26 percent in previously untreated NSCLC patients. This compares quite favorably with any known chemotherapy regimens in similar patient populations. Importantly, the investigators report that responses are ongoing in 100 percent of responders.
- Researchers Are Hopeful For Breakthrough In Treatment Of Relapsed Leukemia
Patients with B-cell acute lymphoblastic leukemia (ALL), the most common type of ALL, have limited treatment options after the cancer becomes resistant to chemotherapy. Researchers, however, are now finding promise in a new type of immunotherapy: chimeric antigen cancer cells and T-cells receptor-modified (CAR) T-cell therapy. The therapy might be helpful in ALL as well as in CLL.12
In CAR T-cell therapy, doctors genetically modify a patient’s T-cells to express a CAR that is designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. As a result, the reprogrammed T-cells, or CAR T-cells, make protein that find and attach to antigens on cancer cells to help destroy the cancer cells.
In studies to date, CAR T-cell therapy directed against the CD19 antigen on B-cells appears effective in the treatment of relapsed ALL. Two studies have produced favorable results. In one trial 88 percent of participants experience a complete cancer remission. In another, which tested a different form of CD19-directed CAR T-cell therapy, 14 of the first 20 patients treated in the study experienced complete remission of the disease.
- Hormone Drug Arimidex® (Anastrozole) Cuts Postmenopausal Breast Cancer Risk By Half
The aromatase inhibitor Arimidex has been found to reduce the risk of breast cancer by 53 percent in high-risk postmenopausal women. Aromatase inhibitors, which block the production of estrogen in postmenopausal women, are commonly used in the treatment of hormone receptor–positive breast cancer but may also have a role in breast cancer prevention—particularly in women at high risk of the disease.13
A study that included more than 3,000 postmenopausal women at high risk of breast cancer compared daily Arimidex with placebo, taken for five years for breast cancer prevention. After a median follow-up of five years, 40 women in the Arimidex group (2 percent) and 85 women in the placebo group (4 percent) had developed breast cancer. The researchers predicted that the overall incidence of all breast cancers after seven years was close to 6 percent in the placebo group compared with just under 3 percent in the Arimidex group.
- Important Step Toward Widespread Use Of Low-Dose Computed Tomography Lung Cancer Screening In The United States
One strategy for reducing the death rate from lung cancer is to increase the rate of early detection so that cancers are found when they are most treatable. Currently, only 25 percent of patients are diagnosed with early-stage disease. The US Preventive Services Task Force (USPSTF) has made a significant step toward this goal by recommending screening with annual low-dose computed tomography (CT) scans for people who are at high risk of lung cancer.14
Low-dose CT scans are a type of imaging that can identify smaller nodules than can chest X-rays, making them a strong candidate for lung cancer screening. They may be best used on high-risk individuals (smokers and older individuals, for example), as CT scans can have false-positive results, which can lead to unnecessary invasive procedures. In high-risk populations, however, the benefits of screening with low-dose CT scans may outweigh the harm.
After reviewing the evidence, the USPSTF concluded that it makes sense to screen people ages 55 to 80 who have a 30-pack-year or greater history of smoking, who are either current smokers, or who have quit in the past 15 years. A “pack-year” refers to someone who has smoked an average of one pack of cigarettes per day for a year. Someone who smokes a pack a day will take 30 years to reach 30 pack-years; however, someone who smokes two packs a day will take only 15 years to reach that limit.
These recommendations are an important step toward the eventual widespread implementation of low-dose CT lung cancer screening in the United States and securing related health insurance coverage, both of which would have a dramatic impact on reducing lung cancer deaths.
An Added Benefit Of Stepping Up Lung Cancer Screening
In addition to catching lung cancer in its early and most treatable stages, lung cancer screening may have another major impact: it may help encourage people to quit smoking. Research has found that when screening detects changes that look suspicious for lung cancer, a person is more likely to quit smoking.15
- Kyprolis® (Carfilzomib) Appears More Effective Than Velcade® (Bortezomib) In Patients With Relapsed Multiple Myeloma
When researchers with a Phase III trial directly compared Kyprolis in combination with low-dose Decadron® (dexamethasone) versus Velcade and low-dose Decadron in patients with relapsed multiple myeloma, they found that patients treated with Kyprolis lived twice as long without a worsening of disease.16
Patients with multiple myeloma who have become refractory—or resistant—to the drugs Revlimid® (lenalidomide) and Velcade have limited treatment options. This makes Kyprolis an intriguing treatment option. It belongs to a class of drugs known as proteasome inhibitors, which work by preventing the breakdown of protein in cancer cells, triggering their death.
Results from a worldwide multicenter study found that patients with relapsed multiple myeloma treated with Kyprolis lived twice as long without a worsening of disease compared with Velcade. Kyprolis-treated patients survived on average almost 19 months compared with only nine months for those receiving Velcade.
- Masters GA, Krilov L, Bailey HH, et al. Clinical cancer advances 2015: Annual report on progress against cancer from the American Society of Clinical Oncology. Journal of Clinical Oncology. 2015;33(7):786-809. doi: 10.1200/ JCO.2014.59.9746.
- FDA approves Gazyva for chronic lymphocytic leukemia [news release]. US Food and Drug Administration website. Available at: http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm. Accessed October 16, 2015.
- GSK and Genmab receive FDA approval for Arzerra® (ofatumumab) as first-line treatment in combination with chlorambucil for patients with Chronic Lymphocytic Leukaemia (CLL) for whom fludarabine-based therapy is considered inappropriate [news release]. GlaxoSmithKline website. Available at: http://www.gsk.com/ media/press-releases/2014/gsk-and-genmab-receive-fda-approval-for-arzerra-ofatumumab. html. Accessed October 16, 2014.
- FDA expands approved use of Imbruvica for chronic lymphocytic leukemia. US Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm406916.htm. October 16, 2015.
- FDA approves Zydelig for three types of blood cancers. US Food and Drug Administration website. Available at: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm406387.htm. Accessed October 16, 2015.
- Buckner JC, Pugh SL, Shaw EG, et al. Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. Journal of Clinical Oncology. 2014;32:5s (suppl.). Abstract 2000.
- Sweeney C, Chen Y-H, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. Journal of Clinical Oncology. 2014;32:5s (suppl.). Abstract LBA2.
- Sequist LV, Soria JC, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). Journal of Clinical Oncology. 2014;32:5s (suppl.). Abstract 8010.
- Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-small-cell lung cancer. New England Journal of Medicine. 2014;370(13):1189-1197. doi: 10.1056/NEJMoa1311107.
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of Stage III melanoma: Initial efficacy and safety results from the EORTC 18071 Phase III trial. Journal of Clinical Oncology. 2014;32:5s (suppl.). Abstract LBA9008.
- Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). Journal of Clinical Oncology. 2014;32:5s (suppl.). Abstract 9000.
- Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine. 2014;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
- Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): An international, double-blind, randomised placebo-controlled trial. The Lancet. 2014;383(9922):1041- 1048. doi: 10.1016/S0140-6736(13)62292-8.
- U.S. Preventive Services Task Force Recommends Lung Cancer Screening for High-Risk Populations in Final Statement [news bulletin]. USPSTF website. Available at: http://www. uspreventiveservicestaskforce.org/Page/Name/ newsroom#2013. Accessed October 16, 2015.
- Tammemägi MC, Berg CD, Riley TL, Cunningham CR, Taylor KL. Impact of lung cancer screening results on smoking cessation. Journal of the National Cancer Institute. 2014;106(6):dju084. doi: 10.1093/jnci/dju084.
- FDA Grants Priority Review for Amgen’s Supplemental New Drug Application for Expanded Labeling of Kyprolis® (Carfilzomib) in Relapsed Multiple Myeloma [news release]. Amgen website. Available at: http://www. amgen.com/media/media_pr_detail.jsp?releaseID=2088926. Accessed October 16, 2015.