National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 15, 2010 • Volume 7 / Number 12

NEWS

Meeting attendees walk past a 2010 ASCO Annual Meeting banner (Photo by © ASACO/Todd Buchanan 2010)Experimental Drug Improves Survival in Advanced Melanoma

An experimental drug that targets the immune system, ipilimumab, has helped patients with advanced cases of melanoma live longer than expected. The results are from the first large randomized clinical trial to show an improvement in survival for patients with advanced melanoma whose disease had progressed on other treatments.

Patients who received ipilimumab lived nearly 4 months longer than those who received an experimental therapeutic vaccine that has shown some activity against melanoma: median survival was 10.1 months for those who received ipilimumab versus 6.4 months for those who received the vaccine. The difference was both statistically significant and, given the lack of any effective treatment options for advanced melanoma, clinically meaningful for patients, researchers said earlier this month at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.  Read more > >

COMMENTARY

Dr. Robert H. WiltroutGuest Director's Update: Pushing the Boundaries of Possibility through Strategic Collaboration

In light of the mounting evidence of cancer’s complexity presented by researchers from around the world at this year’s annual meetings of the American Association for Cancer Research and the American Society of Clinical Oncology, I remain both sober and hopeful about the future of our work. In a way, we now stand at a defining moment in the history of cancer research. Just as high-throughput technology and computing capacity made it possible to discover what exactly constitutes a human genome, it is clear that we can now harness these same techniques to determine the exact nature of cancer genomes. 

To successfully do this, though—to truly push the boundaries of the possible—we must perfect the art of strategic collaboration. Although the contributions and discoveries made by individual investigators remain the cornerstone of new knowledge, effective use of that knowledge now depends on the power of partnership and teamwork.  Read more > >

  

A MESSAGE TO READERS

Clinical Trials Featured on Cancer.gov

This month, the NCI Web site highlights the importance of clinical trials in cancer research. Read more about this topic by clicking the Cancer.gov homepage banner.

And, if you missed it, visit the NCI Cancer Bulletin special issue on clinical trials enrollment, published May 18, 2010.

IN DEPTH

UPDATES

  • FDA Update

    • FDA-ASCO Educational Module Expands Access to Investigational Drugs
  • Notes

    • NCRR and Yale Host Third Annual Clinical Research Management Workshop
    • NCAB Convenes Meeting Next Week
    • Third Telephone Workshop for Cancer Survivors Slated for June 22
    • Administrative Supplements to Increase Awareness of Pediatric Cancers
    • caBIG Annual Meeting Slated for September

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

Experimental Drug Improves Survival in Advanced Melanoma

Meeting attendees walk past a 2010 ASCO Annual Meeting banner (Photo by © ASACO/Todd Buchanan 2010)

An experimental drug that targets the immune system, ipilimumab, has helped patients with advanced cases of melanoma live longer than expected. The results are from the first large randomized clinical trial to show an improvement in survival for patients with advanced melanoma whose disease had progressed on other treatments.

Patients who received ipilimumab lived nearly 4 months longer than those who received an experimental therapeutic vaccine that has shown some activity against melanoma: median survival was 10.1 months for those who received ipilimumab versus 6.4 months for those who received the vaccine. The difference was both statistically significant and, given the lack of any effective treatment options for advanced melanoma, clinically meaningful for patients, researchers said earlier this month at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
 
“We are finally getting some good news in this disease,” said lead investigator Dr. Steven O’Day of the Angeles Clinic and Research Institute in Los Angeles during the meeting’s plenary session. The study represents an important advance for patients and the development of immunotherapies in cancer, he added.

The 676-patient trial compared outcomes in three arms: ipilimumab alone, ipilimumab plus the experimental vaccine (which targets the antigen gp100 on melanoma cells), and the vaccine alone. To their surprise, the researchers found that adding the vaccine to ipilimumab did not help patients live longer. Indeed, the median overall survival in the ipilimumab group was slightly better than that in the combination group.

The study results, which appeared online June 6 in the New England Journal of Medicine (NEJM), will be submitted to the FDA for review. In the meantime, many patients may be interested in the experimental drug. Dr. O’Day said that ipilimumab would be available to patients at certain medical centers through a compassionate-use program. (ASCO and FDA just announced new online resources to make it easier for physicians to access the program, which makes experimental drugs available to seriously ill patients outside the context of a clinical trial.)

Also in the Journals: Combining Targeted Drugs and Immunotherapies for Melanoma

A preclinical study suggests that combining targeted therapy with a BRAF inhibitor like PLX4032 and immunotherapy such as ipilimumab or IL-2 may improve outcomes for some patients with melanoma. The study hypothesized that treating melanoma cells with a targeted agent might make the cells more vulnerable to immunotherapy, and the researchers demonstrated that this may occur through the upregulation of melanoma tumor antigens. The melanoma tumor antigens were increased up to 100-fold following treatment with targeted therapies, and this increase made tumors much more sensitive to immunotherapy.

“This study is preclinical, but it provides a rationale for combining targeted therapy with immunotherapy for treating patients with melanoma,” said lead investigator Dr. Jennifer Wargo of Massachusetts General Hospital. Further research is under way to confirm the results in patients, and clinical trials are being planned based on the study, she noted. The findings were published online today in Cancer Research.

Most patients with metastatic melanoma do not live a year after diagnosis, and the researchers noted encouraging evidence of some relatively long-term benefit. In the ipilimumab arms, the 1-year and 2-year survival rates were 46 percent and 24 percent, respectively. By comparison, 1-year survival rates in recent melanoma trials have ranged from 22 percent to 38 percent, the researchers reported.

“This is really an optimistic time for our patients with melanoma,” said Dr. Lynn Schuchter, who treats patients at the University of Pennsylvania and was not involved in the study. “This trial is a step forward.”

Although most side effects were manageable, Dr. O’Day cautioned that ipilimumab is a “powerful drug.” When the immune system is stimulated, it can attack healthy tissues, leading to complications such as rashes, colitis (inflammation of the colon), and even death. Patients need to be educated about potential side effects and should be monitored by an interdisciplinary team, the researchers said.

“Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment,” the researchers wrote in the NEJM. This is consistent with data from ongoing trials of ipilimumab and other immunotherapies, said Dr. James Gulley of NCI’s Center for Cancer Research, who has led multiple clinical studies of therapeutic vaccines for cancer. At the ASCO meeting, his group reported results from a phase I study of a different experimental vaccine combined with ipilimumab in patients with advanced prostate cancer.

“It’s been a great year for immunotherapy in cancer,” said Dr. Gulley, noting that the first therapeutic cancer vaccine, sipuleucel-T (Provenge), was recently approved for prostate cancer. With the positive results from the ipilimumab trial in melanoma and recent positive therapeutic vaccine studies, he expects growing interest in immunotherapeutic approaches for cancer from companies and academic researchers.

What’s new about ipilimumab is how it works. The drug stimulates the immune system to attack melanoma cells by removing a brake that prevents immune cells from attacking the body’s own tissues. The drug, which is an antibody, removes this check on the system by binding to a molecule on the surface of T cells called CTLA4.

In a discussion of the study at the plenary session, Dr. Vernon Sondak of the H. Lee Moffitt Cancer Center & Research Institute characterized the drug as “light at the end of melanoma’s long dark tunnel.” No improvements in survival for metastatic melanoma had been documented in 3 decades, he noted, and the last new drug for the disease, interleukin-2 (IL-2), was approved more than a decade ago.

But Dr. Sondak also cautioned that much remains to be learned about ipilimumab. Future studies will need to address how best to use the drug, whether alone or in combination with other therapies, and whether it should be a first- or second-line treatment, for instance.

In addition, markers are needed to identify which patients are likely to benefit from this and other immunotherapies. “That’s the million-dollar question—everyone is looking for markers,” said Dr. Gulley. His group is looking retrospectively for biomarkers associated with overall survival in patients who receive immunotherapies, but as yet there are no validated markers that can be used as response indicators for immunotherapy of cancer.

Some researchers have questioned the selection of gp100 for the study’s control group because the vaccine alone may not have much activity in the disease, said Dr. Claudio Dansky Ullmann of NCI’s Division of Cancer Treatment and Diagnosis, who was not involved in the study. But he added that there is not really an established or preferred standard treatment comparison in this setting.

Dr. Dansky Ullmann, who oversees melanoma trials for NCI Cooperative Groups, said that the Institute has an active portfolio of trials looking at ipilimumab alone or in combination with other immunotherapies that will likely expand to other combinations, such as with targeted agents. He pointed out that the dose of ipilimumab used in this study is now considered relatively low compared with what will be used in future studies, so there is certainly the potential for better outcomes.

Ipilimumab could potentially be combined with a molecularly targeted drug, such as a BRAF inhibitor like PLX4032. In early-phase clinical trials of patients with advanced melanoma, 70 percent of patients responded to that drug. But most responses last only about 6 to 8 months. By comparison, about 20 to 30 percent of patients respond to ipilimumab, but the responses seem to be more durable, according to Dr. O’Day.

Certainly, a few years ago it wasn’t possible to even consider combining melanoma therapies in this way. Dr. O’Day attributed the recent advances in treatment for melanoma to a much better understanding of the biology of the disease and its genetic pathways.

“And now the whole field of immunotherapies has broken wide open,” he added. “I think of it as going from darkness to light.”

—Edward R. Winstead

Cancer Research Highlights

Trials Point to More Treatment Options for Chronic Myeloid Leukemia

Short-term results from two phase III clinical trials suggest that patients with chronic myeloid leukemia (CML) may have new options for the initial treatment of their cancer. It’s still unclear, though, whether there will be a longer-term survival benefit from the drugs compared with the standard first-line treatment, imatinib (Gleevec). Some researchers said this information will be important in determining the optimal treatment for patients with newly diagnosed CML.

Data from both trials were presented last week at the ASCO annual meeting in Chicago and published online June 5 in the New England Journal of Medicine (NEJM).

The trials compared the drugs dasatinib (Sprycel) and nilotinib (Tasigna), respectively, with imatinib. Both drugs are second-generation agents that, like imatinib, target the molecular driver of CML, a fusion of the genes BCR and ABL. This fusion gene produces a protein that spurs the overdevelopment of white blood cells that is the hallmark of CML. In both trials, patients who received one of the new drugs had higher rates of complete cytogenetic response, meaning a complete disappearance of cells that contain the chromosome (known as the Philadelphia chromosome) that harbors the BCR-ABL fusion gene, than patients who received imatinib. They also had higher rates of major molecular response, a disappearance of virtually all cancerous cells.

In the 519-patient trial that pitted dasatinib against imatinib, dubbed DASISION, at the 12-month follow-up point the confirmed complete cytogenetic response rate was 77 percent for patients treated with dasatinib compared with 66 percent for patients who received imatinib. The rates of major molecular response were 46 and 28 percent, respectively.

The 846-patient trial involving nilotinib, dubbed ENESTnd, compared two different doses of nilotinib with imatinib. The confirmed complete cytogenetic response and major molecular response rates for patients who received either nilotinib dose or imatinib were very similar to what was seen in the DASISION trial. In both trials, the side effects were considered minimal and manageable.

Both drugs—which are already approved by the FDA to treat CML that no longer responds to or is resistant to imatinib—are more potent than imatinib. In addition, fewer mutations in the BCR-ABL target appear capable of conferring resistance to these drugs than to imatinib, explained Dr. Charles Sawyers, whose research helped lead to the development of imatinib, one of the first and most successful molecularly targeted cancer therapies.

“The data regarding response and side effects in the two studies certainly make a strong case for dasatinib or nilotinib as first-line therapy over imatinib,” Dr. Sawyers wrote in an accompanying editorial in NEJM. But because imatinib will be available as a generic drug in several years and given “the rising pressure to balance cost and efficacy,” he noted, imatinib may remain a first-line option.

In February, the FDA granted “priority review” for nilotinib, which is manufactured by Novartis, as a first-line CML treatment. In a news release, Bristol-Myers Squibb, which manufactures dasatinib, said the company is “in the process of submitting the DASISION data to worldwide health authorities this year” for approval of the drug as a first-line CML treatment.

Partial Breast Irradiation Safe for Some Women with Invasive Breast Cancer

In a randomized trial performed at 28 treatment centers in nine countries, women with breast cancer who received a single dose of radiation during breast-conserving surgery had the same likelihood of local disease recurrence as women who received a standard, weeks-long course of whole-breast external-beam radiation therapy (EBRT) after surgery. Results from the trial, dubbed TARGIT-A, were published June 5 in the Lancet.

The researchers, led by Dr. Jayant Vaidya of University College of London, randomly assigned 1,113 women to receive a single dose of approximately 20 Gy of intraoperative partial breast irradiation using a device called the Intrabeam and 1,119 to receive EBRT at a dose of 40 Gy to 56 Gy given in 15 to 25 fractions (with an optional booster dose at the end of treatment). All of the women were 45 years of age or older and eligible for breast-conserving surgery for a single invasive tumor. Patients with known lobular carcinoma were excluded from enrollment, but patients in the intraoperative treatment group who were found to have lobular carcinoma or other high-risk disease during surgery (about 15 percent of the intraoperative group) later received additional EBRT. Hormone therapy and chemotherapy were given to women in both groups as needed.

At 4 years after treatment, six women in the intraoperative radiotherapy group and five women in the EBRT group had experienced a recurrence of their cancer in the treated breast. The researchers will continue to follow both groups of patients to monitor for local recurrences and new primary tumors outside the area treated.

Tumor recurrence, the need for radiation therapy, and speed of recovery are all factors that patients take into account when choosing treatment, explained the authors. “Because the definitive treatment with radiation can be completed at the time of the surgery or shortly afterwards in a single session with targeted intraoperative radiotherapy,” they wrote, “two of the patients’ major concerns are immediately addressed, and perhaps fewer patients should feel obliged to choose mastectomy over breast-conserving surgery either because they live far away from a radiotherapy facility or to avoid prolonging their treatment.”

Chemotherapy Combo Improves Survival in Elderly Lung Cancer Patients

Survival can be improved in older patients with advanced non-small cell lung cancer (NSCLC) with the use of two chemotherapy drugs as opposed to a single agent, French researchers reported at the ASCO annual meeting. The findings come from a phase III clinical trial of 451 patients between the ages of 70 and 89, the first lung cancer trial to enroll strictly older patients. The trial was stopped early when an interim analysis showed a more than 4-month improvement in overall survival in patients receiving the chemotherapy “doublet” of carboplatin (Paraplatin) and paclitaxel (Taxol) compared with those receiving single-agent treatment with either gemcitabine (Gemzar) or vinorelbine (Navelbine).

In addition to improved overall survival, patients in the trial who were randomly assigned to receive both chemotherapy drugs had longer progression-free survival and higher tumor response rates than patients who received single-agent treatment, reported the trial’s lead investigator, Dr. Elisabeth Quoix of University Hospital in Strasbourg, France. The beneficial effect was seen “in most subgroups tested,” she explained during a press briefing, including patients with a poorer prognosis, such as smokers and those of more advanced age.

When the trial was launched in 2005, ASCO clinical guidelines recommended single-agent chemotherapy to treat advanced lung cancer in older patients, Dr. Quoix noted. These new findings establish “a new [treatment] paradigm for elderly patients with NSCLC,” she said.

Median overall survival in the combination therapy arm was 10.4 months, compared with 6.2 months in patients who received a single agent. One-year survival was 45 percent and 27 percent, respectively. The combination therapy was, however, associated with greater side effects, including a nearly fourfold increase in neutropenia, a dangerous decline of white blood cells.

According to a recent study, most elderly patients with advanced NSCLC don’t receive any chemotherapy, and those who do usually receive only single-agent therapy, explained Dr. Martin Edelman of the University of Maryland Greenebaum Cancer Center, during the plenary session presentation of the trial results. Dr. Edelman noted some concerns about the trial design, including the combination regimen that was chosen and its dosing schedule. Nevertheless, he continued, data from this trial and other clinical trials support the benefit of platinum-based combination chemotherapy in elderly patients and “should change day-to-day practice.”

Dr. Mark Kris, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, agreed. “Patients over the age of 70 should be treated just like anyone else,” Dr. Kris said during a press briefing, with therapy decisions guided by factors such as comorbidities and patient preference, among others.

Adding Radiation to Hormone Therapy Improves Survival in Locally Advanced Prostate Cancer

Results from an international phase III trial show that adding radiotherapy to androgen deprivation therapy (ADT) reduced the risk of death from prostate cancer by 43 percent in men with locally advanced disease. The data were presented last week at the ASCO annual meeting in Chicago.

Between 1995 and 2005, 1,205 men were randomly assigned to receive ADT plus radiation or ADT alone. Most of the men had stage T3/T4 disease. After a median follow-up of 6 years, 51 of the 603 men who received the combined modality therapy had died, compared with 89 of the 602 men who received ADT alone. Fewer than 2 percent of patients in either group experienced significant gastrointestinal toxicities. However, patients receiving radiation had more low-grade diarrhea and rectal bleeding.

“These results suggest that adding radiation therapy to the treatment plan for these patients could become part of standard therapy and should be considered,” said lead researcher Dr. Padraig R. Warde of Princess Margaret Hospital and the University of Toronto.

The researchers projected that fewer men who received ADT plus radiation would die from their prostate cancer over 10 years than would men who received ADT alone (15 percent versus 23 percent). Final results are expected in the next few years.

Known as Intergroup T-94-0110, the study was coordinated by the National Cancer Institute of Canada with participation by the Medical Research Council of the United Kingdom and the Southwest Oncology Group in the United States. Though the study was originally designed in 1993, “We believe the results are still relevant in 2010,” said Dr. Warde. “Close to 50 percent of patients with high-risk disease are [still] managed with ADT alone.” In fact, he said, the benefit of adding radiation may be underestimated because changes in technology over the last decade have enabled oncologists to deliver “much higher doses of radiation into the prostate than used in this study.”

Also in the News: Selenium Does Not Protect Against Second NSCLC Tumors

Study results presented at the American Society of Clinical Oncology (ASCO) annual meeting revealed that selenium is not effective for preventing a second primary lung tumor in patients treated surgically for early-stage non-small cell lung cancer (NSCLC). An estimated 1 to 2 percent of NSCLC patients develop a second primary tumor in the first year after surgery.

Patients in the double-blind intergroup study, led by the Eastern Cooperative Oncology Group, were randomly assigned to take a placebo or 200 mg of selenized yeast daily for 48 months. The study was launched in 2000 and spanned nearly a decade before being stopped early, in November 2009, after the independent data and safety monitoring board reviewed the data and found that selenium supplementation was unlikely to produce the anticipated benefit.

“This study reminds us that supplements are medicines, and we know if they work only if they are rigorously tested,” said Dr. Mark Kris, of Memorial Sloan-Kettering Cancer Center, at the ASCO press briefing.

Guest Director's Update

Pushing the Boundaries of Possibility through Strategic Collaboration

Dr. Robert H. Wiltrout Dr. Robert H. Wiltrout

In light of the mounting evidence of cancer’s complexity presented by researchers from around the world at this year’s annual meetings of the American Association for Cancer Research and the American Society of Clinical Oncology, I remain both sober and hopeful about the future of our work. In a way, we now stand at a defining moment in the history of cancer research. Just as high-throughput technology and computing capacity made it possible to discover what exactly constitutes a human genome, it is clear that we can now harness these same techniques to determine the exact nature of cancer genomes. 

To successfully do this, though—to truly push the boundaries of the possible—we must perfect the art of strategic collaboration. Although the contributions and discoveries made by individual investigators remain the cornerstone of new knowledge, effective use of that knowledge now depends on the power of partnership and teamwork.

At one time, it was the norm for scientists to work independently in relative isolation. Today we understand that we can accomplish more, and make every dollar go further, if we communicate and collaborate. Researchers and the work we do are made better by having other scientists around us, especially those in other disciplines.

University of Maryland (UMD) President Dr. C. D. Mote, Jr., looks on as Dr. Robert Wiltrout, director of NCI’s Center for Cancer Research, and Dr. Melvin Bernstein (right), vice president for research at UMD, sign an agreement establishing the Collaborative Research and Graduate Partnership Program in Cancer Technology. University of Maryland (UMD) President Dr. C. D. Mote, Jr., looks on as Dr. Robert Wiltrout, director of NCI’s Center for Cancer Research, and Dr. Melvin Bernstein (right), vice president for research at UMD, sign an agreement establishing the Collaborative Research and Graduate Partnership Program in Cancer Technology.

Toward this end, our leadership in NCI’s Center for Cancer Research (CCR) has made significant advances in building strong scientific partnerships with public and private institutions as we strive to translate new scientific discoveries for the benefit of patients. We are shifting our culture in many ways to make sure we are facilitating strategic collaborations. One of the most challenging aspects of our transition to team science is that it requires researchers to share scientific recognition and credit in a new way. For decades, scientists have largely been recognized and rewarded for individual accomplishment, which has an impact on tenure decisions, grant submissions, promotions, scientific awards, and acceptance to prestigious organizations. In order to enable change, so that our collaborations can be limitless and more successful, we continue to pursue paradigm shifts among both our scientific teams and the organizations that recognize their achievements.

Capitalizing on the idea that solutions to fundamental questions in cancer research will be facilitated by approaches and input from experts in complementary disciplines, we have recently established the Collaborative Research and Graduate Partnership Program in Cancer Technology with the University of Maryland (UMD) departments of Physics and Mathematics and the Institute for Physical Sciences and Technology. This agreement allows qualified UMD graduate students from the participating departments to conduct research under the joint supervision of CCR and UMD faculty and enables new collaborations between CCR researchers and UMD faculty.

Research enterprises like NCI and pharmaceutical companies are also becoming natural scientific allies, since the science needed to support successful drug development can be too complex to undertake independently. To enable further alliances with the pharmaceutical industry, we have established an umbrella Cooperative Research and Development Agreement (CRADA) that streamlines our collaborations, and we have used that vehicle to enter into collaborative agreements between CCR investigators and industry. Currently, CCR has more than 100 active CRADAs, and CCR’s technologies can be found in over 200 licensed products, including several FDA-approved products that were dependent upon contributions from CCR laboratories. We hope a new culture of collaboration and partnership will further increase these practical accomplishments.

To foster collaboration even further, five Centers of Excellence have been established in CCR to promote interactions among investigators at NCI and other NIH institutes, extramural scientists, and the private sector across the country and around the world. Each center serves as a locus of resources and infrastructure aimed at accelerating the discovery, development, and delivery of interventions for preventing, diagnosing, and treating cancer and HIV/AIDS.

Within our clinical program, collaborations are equally expansive. Broad national and international partnerships are enabling new trials in which treatment of individual patients is guided by genomic information, or in which diagnoses based on genomic profiles inform new strategies for intervention, all while minimizing the use of inappropriate approaches.

In the next few years, the convergence of a vast body of new knowledge and insights about cancer genomes, with the rapidly evolving culture of cross-disciplinary partnerships, promises to revolutionize the translation of basic discoveries to clinical application.

Dr. Robert H. Wiltrout
Director, NCI Center for Cancer Research

Spotlight

For Lung Cancer, a New Drug and a Way Forward

The phone call that would change Dr. Michael Weitz’s life came from his mother. In June 2009, she tuned in to the evening news and learned about an experimental cancer drug that had made a patient’s lung tumors all but disappear. She phoned her son to say that the drug, a pill called crizotinib, might help him.

Dr. Michael Weitz, an emergency room physician from Santa Monica, CA, was diagnosed with lung cancer at age 49. Dr. Michael Weitz, an emergency room physician from Santa Monica, CA, was diagnosed with lung cancer at age 49. (Image courtesy of the Los Angeles Daily News)

Dr. Weitz, an emergency room physician from California who had never smoked cigarettes, needed all the help he could get. Three years earlier, at age 49, the father of three boys had been diagnosed with non-small cell lung cancer (NSCLC), and the disease would eventually invade his bones and his brain. Chemotherapy, surgery, radiation, and erlotinib (Tarceva) had kept him alive, but he never knew when the latest treatment would stop working.

The new drug, however, was a long shot. Fewer than five lung cancers in 100 had the specific genetic change targeted by crizotinib. But because his left lung had been removed, Dr. Weitz had plenty of tumor tissue available for testing. His doctors sent a sample to Massachusetts General Hospital for analysis, and the test came back positive, making him eligible for the treatment.

Dr. Weitz’s tumor cells harbored a fusion of two genes (EML4 and ALK) that appears to drive the disease in some patients. He enrolled in the trial, and 2 months later scans showed a striking reduction in his cancer. By the next round of testing, the tumors had disappeared to the point where doctors described it as “minimal disease.”

“The results were dramatic,” Dr. Weitz said recently. “This was a game-changer.” Compared with his other treatments, he has experienced few, if any, side effects. The beauty of this targeted therapy, he noted, “is that you’re not killing off healthy cells—you’re just going after the bad guys.”

Back to Work

Capsules of the drug crizotinib Patients with a rare genetic change in their lung tumors have responded to treatment with the drug crizotinib.

Although he knows the disease could return at any time, Dr. Weitz has returned to work and is once again exercising. He has also joined the scientific advisory board of the Lung Cancer Foundation of America, an organization dedicated to funding research. In part because of this advocacy work, Dr. Weitz traveled to Chicago earlier this month for the annual meeting of the American Society of Clinical Oncology (ASCO).

He was also there to hear a presentation on the crizotinib trial in which he had been participating. The results were featured in the plenary session, which is unusual for small, early-stage trials. But the results were impressive: 87 percent of the 82 patients in the trial responded and many saw their tumors shrink or their disease stabilize after 8 weeks of therapy, the researchers reported.

“This trial confirms what we have known from the very first patient—that this drug is a great option for these patients,” said Dr. Alice Shaw of the Massachusetts General Hospital Cancer Center and an author of the findings. She cautioned, however, that little is known about the natural history of this particular type of lung cancer and additional research is needed.

More than 100 patients have received crizotinib after testing positive for the EML4/ALK fusion gene. Because most patients are still being treated, the trial does not yet have data on survival, noted Dr. Yung-Jue Bang of Seoul National University College of Medicine in Korea, who presented the findings.

In a discussion of the results at the plenary session, Dr. Martin Edelman of the University of Maryland Greenebaum Cancer Center noted the drug’s “striking activity” and the “durable” responses in patients who had already received multiple therapies. “It’s hard to imagine that these early results will change over time,” he said.

Biological Markers

Dr. Edelman also provided some historical context. Six years ago, when doctors first observed dramatic responses to gefitinib (Iressa) in patients with lung cancer, there were no molecular markers for identifying likely responders. It was only by analyzing patient samples retrospectively that researchers discovered biomarkers of response (mutations in the EGFR gene).

Crizotinib has followed a different path. The EML4/ALK fusion gene, which produces an aberrantly activated ALK protein, is used as a marker to select patients. The drug was initially developed to inhibit a signaling protein called c-Met, but it also proved to be active against the ALK protein, another signaling protein and, like c-Met, a tyrosine kinase.

When Japanese researchers reported the presence of the fusion gene in lung tumors in August 2007, the drug was already being evaluated in other cancers. Researchers at Massachusetts General Hospital quickly developed a test for the fusion gene. Within months, they had enrolled a patient with lung cancer into the trial, and in less than 3 years, preliminary results from the trial were making news.

“This study demonstrates the power of understanding the biology of cancer,” said Dr. Mark Kris, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, who was not involved in the study. Crizotinib, he continued, is an example of what doctors have always wanted to give their patients—a drug that is tailored to the specific features of a given patient’s disease.

At the ASCO meeting, some lung cancer experts were discussing crizotinib as a model for moving forward in this deadly disease. By discovering genetic alterations underlying subtypes of lung cancer and developing therapies against these changes, the researchers hoped to make progress against this leading cause of cancer death worldwide.

In the case of crizotinib, testing patient tumors was critical for uncovering the drug’s dramatic effects in selected patients. Had the drug been tested in 100 unselected patients with lung cancer, researchers might have concluded that the drug had little or no activity in the disease.

Dr. Edelman stressed the importance of selecting patients in trials of targeted drugs by showing a slide with a long list of disappointing lung cancer trials. “If targeted drugs had been employed in targeted populations, how many of these trials would have been positive?” he asked.

Larger crizotinib trials are planned or underway, including a phase III study called PROFILE 1007. This will compare crizotinib with standard second-line chemotherapy for patients with ALK fusion gene-positive recurrent NSCLC.

A Unique Disease

Last year, Dr. Shaw and her colleagues reported that patients with the EML4/ALK fusion gene had a distinct subtype of NSCLC with identifiable clinical characteristics. These patients, like Dr. Weitz, tend to be much younger than other patients with lung cancer, to be nonsmokers, and to have the adenocarcinoma form of the disease.

The patients also have a high likelihood of responding to ALK-targeted agents, although not all patients with the fusion gene respond to crizotinib. In addition, some patients with the gene fusion have developed resistance to the drug, the researchers said.

Still, many patients are doing well (at least one patient has been on the drug for 20 months). With more than 200,000 new lung cancers diagnosed in the United States each year, an estimated 10,000 patients could be eligible for these agents. “It’s our job as oncologists to find these patients,” said Dr. Kris.

A project launched last fall called the Lung Cancer Mutation Consortium could play a role. Fourteen sites around the country will test patients free of charge for a panel of 10 genetic changes for which there are drugs available, including the EML4/ALK fusion gene. Patients will be referred to the appropriate clinical trials based on their particular tumor types.

The 2-year consortium project, funded with a $5.2 million grant from the American Recovery and Reinvestment Act, aims to determine the frequencies of certain mutations in 1,000 patients with advanced lung adenocarcinomas. Investigators will also collect clinical information to uncover links between specific mutations and clinical features and outcomes.

“The consortium is how we will translate findings from our research on the human genome into medicines for patients,” said Dr. Paul Bunn, former director of the University of Colorado Cancer Center and a project leader. He noted that The Cancer Genome Atlas project, for instance, is characterizing genomic changes in two types of lung cancer and that these results will be used to develop biomarker-driven therapies.

“A Future Again”

In his work advocating for lung cancer research, Dr. Weitz urges patients to have their tumors tested, saying that this can help them develop a strategy for trying to manage the disease in a way that other chronic diseases are managed.

He compares being a patient to playing chess. “You have to think several steps ahead,” he explained. “And you always need several therapies in your back pocket in case the current one doesn’t work out.”

These days, though, he has more than just cancer on his mind. “My friends and family have been so supportive,” he said. “For more than 3 years, there’s been an outpouring of love and affection. I now have energy and can think about planning trips. I have a future again.”

—Edward R. Winstead

See also: Common Cancers May Involve Fused Genes
Trial Makes Push Toward More Individualized Lung Cancer Therapy

A Closer Look

Looking at Older Chemotherapy Drugs through a Biological Lens

More often than not, identifying predictive biomarkers—biological aspects of a tumor that predict whether a drug will prove effective—is now a part of modern cancer drug development. This is because most new drugs are developed to target tumors with a specific molecular trait—a de facto biomarker—such as HER2 overexpression in breast cancer or BRAF mutations in melanoma.

But as the research community’s knowledge of the genetic underpinnings of cancer grows, it has become apparent that the efficacy of some older chemotherapy drugs also depends on the genetic makeup of tumors. Identifying biomarkers to help predict which patients will actually benefit from these older drugs would improve treatment planning by sparing patients the toxicity of drugs that would provide no therapeutic benefit.

When you have a drug that’s already in widespread use, it can be very difficult to go back and start doing randomized trials where that drug is withheld.

—Dr. Richard Simon

The ideal study of any predictive biomarker is a randomized trial in which some patients get the drug in question and some don’t and in which the candidate predictive biomarker is measured and defined in advance. Such a trial would allow researchers to understand whether there is any difference in the effectiveness of a treatment depending on the presence or absence of the biomarker. However, “when you have a drug that’s already in widespread use, it can be very difficult to go back and start doing randomized trials where that drug is withheld,” said Dr. Richard Simon, chief of NCI’s Biometric Research Branch in the Division of Cancer Treatment and Diagnosis (DCTD).

Looking Prospectively at Past Trials

To circumvent the near-impossibility of performing a randomized trial in which an accepted drug is withheld, some researchers have turned to a type of study that is sometimes called a “prospective-retrospective” analysis to explore whether specific biomarkers can predict the efficacy of anticancer drugs. In these studies, stored biospecimens from participants in past randomized trials are analyzed for a specific biomarker chosen based on independent experiments before the prospective-retrospective analysis is done.

Importantly, prospective-retrospective studies should not be “fishing expeditions,” in which samples are compared for differences in biomarkers without a prespecified hypothesis, explained Dr. Simon who, along with colleagues Dr. Soonmyung Paik and Dr. Daniel Hayes, recently published recommendations on this subject. Such studies often lead to false-positive results that do not stand up to replication. “You have to do a focused analysis,” said Dr. Simon.

Well-designed prospective-retrospective studies recently showed that patients with colorectal cancer who have mutations in a gene called KRAS will not be helped by drugs such as cetuximab (Erbitux) and panitumumab (Vectibix) that target the protein product of another gene, EGFR.

This type of study design is also being used to take a closer look at older chemotherapy drugs. Last month, Dr. Daniel Sargent, professor of biostatistics and oncology at the Mayo Clinic, and his colleagues published a study looking at a potential predictive biomarker for response to fluorouracil (5-FU), a drug that has served as the backbone of chemotherapy for colorectal cancer for decades.

Their research group had previously used a prospective-retrospective analysis to find evidence that patients with stage II or III colorectal cancer whose tumors have defective DNA mismatch repair (dMMR) mechanisms do not benefit from treatment with 5-FU. Researchers already knew that patients with dMMR have better prognoses than patients with tumors of the same stage and normal mismatch repair mechanisms.

“We had a finding supported by preclinical data that was potentially very important in terms of identifying a cohort of colorectal cancer patients who would not benefit from further treatment after surgery,” said Dr. Sargent. “Because the standard option after surgery for patients at high risk of relapse is 5-FU-based chemotherapy, we felt that we had to generate as much evidence as possible—and the best quality of evidence—to provide a very thorough recommendation in that regard.”

Toward a Molecular Definition of Risk

The researchers established an international collaboration to obtain archived biospecimens from five phase III clinical trials that had compared chemotherapy with 5-FU and either levamisole or leucovorin after surgery with surgery alone for patients with stage II or stage III colorectal cancer. The status of mismatch repair could be determined in 457 patients, 70 of whom had dMMR.

Overall, as in their earlier study, they found no benefit from such chemotherapy in preventing disease recurrence for patients with dMMR, whereas 5-FU-based treatment did benefit patients with normal DNA repair mechanisms. This finding also held for patients with stage II or stage III disease considered separately when the researchers pooled the data from the new analysis with the data from their previous analysis.

Clinical application of these results for patients with stage III disease is somewhat confounded, explained Dr. Sargent, by the fact that current regimens for stage III colorectal cancer, such as FOLFOX, include the drug oxaliplatin. “It’s possible that the addition of oxaliplatin to 5-FU could overcome the resistance that patients with defective mismatch repair have to 5-FU,” he explained.

But for patients with stage II disease, for whom oxaliplatin has not been shown to be beneficial, given the generally excellent prognosis of patients who have defective mismatch repair, “the lack of benefit from 5-FU-based chemotherapy in patients with dMMR tumors indicates that such patients should not receive 5-FU-based adjuvant chemotherapy,” the authors concluded.

“The prognostic importance of dMMR has been demonstrated convincingly in two additional large studies. Coupling this with the current observation of an apparent lack of treatment efficacy in the dMMR stage II patients, it would be reasonable to concur with Sargent et al. and suggest that the absolute benefits of chemotherapy are so marginally small in this good prognostic group that adjuvant chemotherapy should not be considered,” agreed Drs. David Kerr and Rachel Midgley from the University of Oxford in an accompanying editorial.

“For now, dMMR will likely be one of many factors patients and their physicians consider when determining whether to initiate adjuvant chemotherapy for stage II colorectal cancer,” said Dr. Jack Welch, head of Gastrointestinal and Neuroendocrine Cancers Therapeutics in DCTD. “Both assessment of biological risk factors and informed patient decision-making have a place in today’s treatment of stage II colorectal cancer,” said Dr. Welch. “I think eventually we’ll evolve a completely molecular definition of risk in stage II disease, and it might be that there are drugs besides 5-FU that would have some acceptable toxicity and give a reasonable boost to well-defined populations at relatively lower risk,” he concluded.

—Sharon Reynolds

Featured Clinical Trial

Optimizing Adjuvant Therapy for Resected Pancreatic Cancer

Name of the Trial
Phase III Randomized Study of Adjuvant Gemcitabine Hydrochloride with Versus without Erlotinib Hydrochloride Followed by the Same Chemotherapy Regimen with Versus without Chemoradiotherapy with Either Capecitabine or Fluorouracil in Patients with Resected Head of Pancreas Adenocarcinoma (RTOG-0848). See the protocol summary.

Dr. Ross Abrams Dr. Ross Abrams

Principal Investigator
Dr. Ross Abrams, Radiation Therapy Oncology Group

Why This Trial Is Important
Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. It develops in the lining of ducts in the pancreas that deliver digestive juices to the small intestine through the main pancreatic duct. The majority of pancreatic adenocarcinomas occur in the head of the pancreas, the part of the organ that is closest to the small intestine.

The only potentially curative treatment for pancreatic adenocarcinoma is a complex surgical procedure called the Whipple procedure. However, most patients are not eligible for this treatment because the cancer has spread beyond the pancreas by the time it is diagnosed. Furthermore, about 80 percent of those who have the Whipple procedure relapse and die within 5 years due to the presence of microscopic deposits of tumor cells that remain behind after surgery. Consequently, doctors often use adjuvant therapies to try to destroy the remaining cancer cells.

Chemoradiotherapy that includes a radiosensitizing agent, such as 5-fluorouracil (5-FU), is often used as adjuvant treatment for surgically resected pancreatic cancer. More recently, adjuvant chemotherapy with the drug gemcitabine has been shown to delay recurrence and modestly improve survival. Doctors are now investigating whether combining these adjuvant therapies can further increase survival after surgery. Additionally, they want to know if adding a second drug to gemcitabine will improve survival compared with gemcitabine alone. In patients with advanced, inoperable pancreatic cancer, the drug erlotinib has shown the ability to prolong survival when combined with gemcitabine. Therefore, doctors are hopeful it will also help patients who have had surgery.

In this clinical trial, patients with resected adenocarcinoma of the head of the pancreas will be randomly assigned to receive either gemcitabine for five treatment cycles or gemcitabine and erlotinib for five cycles. Patients who do not experience disease progression (recurrence or growth of residual tumor tissue) will then be randomly assigned to undergo an additional cycle of the same chemotherapy regimen with or without subsequent chemoradiation using either intravenous 5-FU or a similar oral drug called capecitabine. Doctors will follow the patients’ survival, compare the toxicity of these treatments, and try to determine whether certain biological characteristics of the patients are associated with outcomes.

“This trial is basically asking two questions,” said Dr. Abrams. “The first question is, do patients treated with gemcitabine and erlotinib do better than those treated with gemcitabine alone? The second question is, for those patients who finish chemotherapy without evidence of recurrence or progression, does the addition of radiation to the area where the tumor was removed, along with 5-FU or capecitabine, accomplish something above and beyond the chemotherapy?”

For More Information
See the lists of entry criteria and trial contact information or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/ft-all-featured-trials.

FDA Update

FDA-ASCO Educational Module Expands Access to Investigational Drugs

Screenshot of Expanded Access to Investigational Drugs Web page

When a patient has a serious or life-threatening disease and no satisfactory alternative therapies, what options does a physician have in providing care for the patient?
 
Depending on the patient’s clinical course and situation, he or she may be eligible to receive an investigational drug to treat the disease or condition. Treatment use of an investigational drug, referred to as expanded access, has occurred since the 1970s. However, this mechanism was not widely known or used by physicians. Expanded access to an investigational drug provides a patient with access to drugs that have not been approved by the FDA. One of the requirements is that the patient has a serious or life-threatening disease and no satisfactory alternative therapy. The goal of providing this type of access is to treat patients.

Because many physicians were unaware of the expanded access mechanism and the process for requesting expanded access, the FDA published a new rule on expanded access in August 2009. The new rule clarified existing regulations on providing treatment use of investigational drugs and also outlined criteria, submission requirements, and safeguards for expanded access programs.

To familiarize oncologists with expanded access and its processes, the FDA and the American Society of Clinical Oncology (ASCO) have developed an educational module that explains expanded access, the process for requesting an expanded access program for an individual-patient Investigational New Drug (IND) application, other options for patients who have no satisfactory alternative therapies, and investigator responsibilities in sponsoring an expanded access program.

The module is available on the ASCO University Web site and is available for members and nonmembers free of charge. The module also includes a glossary of regulatory terms often used when requesting expanded access, an expanded access checklist, and helpful templates often submitted with an expanded access IND application.

Dr. Richard Pazdur
Director, FDA Office of Oncology Drug Products

Dr. Tamy Kim
Acting Associate Director for Regulatory Affairs, FDA Office of Oncology Drug Products

NCI’s Efforts to Provide Patients with Access to Investigational Drugs

NCI’s Cancer Therapy Evaluation Program (CTEP) has a long-standing program designed to provide patients access to investigational anticancer agents. The Treatment Referral Center (TRC), managed by CTEP's Pharmaceutical Management Branch (PMB), is the point of contact for clinical investigators seeking investigational treatments for their patients. TRC staff can research and provide information on relevant on-going clinical trials. If a patient is not eligible to participate in a clinical trial, TRC staff have mechanisms to provide expanded access to Investigational New Drugs (IND), the most often used being a “special exception” mechanism.

For agents where CTEP holds an IND Application, and where there is company collaborator concurrence, CTEP provides single-patient access to investigational agents that have both a demonstrated safety profile and demonstrated activity in the specific disease. These agents are available to all CTEP-registered investigators. Since 1988, CTEP has treated over 19,000 patients through the special exception program.

Notes

NCRR and Yale Host Third Annual Clinical Research Management Workshop

The Yale Center for Clinical Investigation and the National Center for Research Resources (NCRR) will host the Third Annual Clinical Research Management Workshop June 21–22 at the Bethesda North Marriott Hotel and Conference Center in Bethesda, MD. This year’s workshop will provide a venue for collaboration among representatives from the NIH community, Clinical and Translational Science Award (CTSA) sites, clinical research organizations, private industry, health advocacy organizations, academia, government, and others to explore clinical research management topics ranging from recruitment and retention strategies to grants and contract management.

Participants will discuss challenges to the clinical research management process and share strategies and tools for process improvement with a focus on clinical oncology trials. Dr. George Weiner, director of Holden Comprehensive Cancer Center at the University of Iowa, will discuss budgeting resources and prioritization. Dr. James Doroshow, director of NCI’s Division of Cancer Treatment and Diagnosis, will speak on “Expectations for Academic Health Centers in Clinical Research Management of NIH-Sponsored Trials.” Other speakers will discuss the prospective use of metrics, performance analysis, recruitment and retention, and industry’s evolving perspective on management.

A poster session on June 21 will highlight best practices in process control, institutional review boards, contracts management, metrics, registration, and electronic protocol management.

Call 203-785-3482 to register in advance or register onsite.

NCAB Convenes Meeting Next Week

The National Cancer Advisory Board (NCAB) will meet June 22–23 in Building 31 on the NIH main campus in Bethesda, MD. The agenda is now available, and the meeting will be broadcast online.

Third Telephone Workshop for Cancer Survivors Slated for June 22

The third of four telephone workshops in NCI’s annual “Living With, Through, and Beyond Cancer” series will be held June 22 from 1:30 to 2:30 p.m. EDT. Part III of the series is titled “Survivorship and Workplace Transitions.”

The free series offers cancer survivors, their families, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends. The workshops are presented by CancerCare, in collaboration with NCI, LIVESTRONG, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Speakers for the June 22 workshop include Peter Daly, a patient advocate from the University of Wisconsin; Martha Gaines, director of the Center for Patient Partnerships at the University of Wisconsin; and Dr. Cathy Bradley, professor and chair of the Department of Healthcare Policy and Research at the Massey Cancer Center.

Part IV, “Survivors Too: Communicating With and Among Family, Friends, and Loved Ones,” will take place on July 13.

These workshops are free; no phone charges apply. To register, visit the CancerCare Web site.

If you missed parts I or II of the series, recordings are available online via podcast.

Administrative Supplements to Increase Awareness of Pediatric Cancers

NCI has announced the availability of administrative supplements to NCI-funded research grants that address and/or are relevant to public awareness of cancers in children, adolescents, and young adults. The Caroline Pryce Walker Conquer Childhood Cancer Act of 2008 gave the secretary of the Department of Health and Human Services the authority to award grants to increase public awareness of pediatric cancers and available treatments and research.

NCI will commit approximately $1 million in FY 2010 to fund four to seven administrative supplements in response to this initiative. The application submission deadline is July 16, 2010. September 1, 2010, is the earliest anticipated start date for supplement awards.

For additional information, see NOT-CA-10-026. General inquiries concerning program and review matters should be directed to Stacey Vandor or Dr. Lenora Johnson.

caBIG Annual Meeting Slated for September

2010 caBIG Annual Meeting banner

The 2010 cancer Biomedical Informatics Grid (caBIG) annual meeting, “Building a Collaborative Biomedical Network,” will take place September 13–15 at the Marriott Wardman Park Hotel in Washington, DC.

caBIG is an information network led by NCI’s Center for Biomedical Informatics and Information Technology that enables cancer researchers, physicians, and patients to share data and knowledge. The components of caBIG are widely applicable beyond cancer as well. The caBIG mission is to develop a collaborative information network that accelerates the discovery of new approaches for the detection, diagnosis, treatment, and prevention of cancer, ultimately improving patient outcomes.

Registration and abstract submissions are now being accepted. Admission is free and open to the public. Registration, however, is required and available online along with more information.