In an extraordinary demonstration of excellence, five Memorial Sloan Kettering physician-scientists were selected to participate in the press program at the 2011 American Society of Clinical Oncology (ASCO) annual meeting, held June 3-7 in Chicago. ASCO is the world's premier oncology professional society, representing nearly 30,000 multidisciplinary medical professionals who treat people with cancer.
The press program highlights clinical cancer research that a panel of ASCO experts considers the most significant of the year and that they determine deserves media attention. This year, out of more than 4,000 abstracts presented or published at the meeting, 24 were selected for the press program. The five Memorial Sloan Kettering studies represented nearly a quarter of all those on the press program.
Memorial Sloan Kettering clinicians on the press program included two melanoma experts who presented their research findings at the Plenary Session. ASCO Plenary Sessions highlight scientific research deemed to have the highest merit and greatest impact on oncology research and practice.
“The success of these drugs is not the end of the story. It's a very exciting and important beginning.”
“This was an incredible year for the Center and for our remarkable clinical staff,” says Memorial Sloan Kettering President Craig B. Thompson. “The number of Memorial Sloan Kettering clinicians chosen to present as part of ASCO's press program shows that Memorial Sloan Kettering produces among the most important practice-changing research in clinical oncology. It is also a special honor that two oncologists from the same institution and the same clinical group were invited to present at the Plenary Session.”
“We are proud not only of the clinicians included in the press program but of all Memorial Sloan Kettering's extraordinary physician-scientists,” concludes Dr. Thompson. “They are passionately committed to their dual roles: as doctors involved in hands-on patient care, and as investigators working to advance the scientific knowledge that leads to new and better treatments for their patients and patients with cancer worldwide.”
What follows are reports of the data presented by the Memorial Sloan Kettering clinicians featured in ASCO's 2011 press program.
“The past decade has brought significant insights into two areas of melanoma that have now led to drug development,” says medical oncologist Jedd D. Wolchok. “The first is a better understanding of what genetic errors are contained inside a melanoma cell. This has allowed for the development of drugs that target those errors. The second is a better understanding of how the body's immune system can recognize cancers like melanoma. From this, we have learned how to activate a vigorous immune response against the disease.”
Medical oncologists Paul Chapman and Jedd Wolchok describe two studies of promising new therapies for advanced melanoma.
”We now have two new drugs — one that has been approved by the Food and Drug Administration for the treatment of metastatic melanoma and a second that is on its way,” medical oncologist Paul B. Chapman elaborates. “This is the fruition of years of hard work in both the laboratory and the clinical research environment here at Memorial Sloan Kettering and with our colleagues around the world.”
At the ASCO Plenary Session, Dr. Chapman presented findings about one of the new drugs, a targeted therapy called vemurafenib. “We know that about half of melanomas have a mutation in a gene called BRAF,” Dr. Chapman says. “Vemurafenib targets and inhibits BRAF.” The study — a multicenter phase III clinical trial led by Dr. Chapman — showed that in previously untreated patients with metastatic melanoma, vemurafenib caused striking regressions of tumors that had the mutation in the BRAF gene. In addition, the tumors that shrank stayed smaller longer and patients lived longer than patients who received standard chemotherapy.
Dr. Wolchok presented data at the Plenary Session about ipilimumab (Yervoy™), the drug approved by the FDA in March for the treatment of patients with metastatic melanoma. (Learn more about the the FDA approval of ipilimumab.) It is the first agent ever shown to improve overall survival for patients with advanced melanoma. “This is a significant achievement in a disease that has been resistant to standard therapies,” says Dr. Wolchok.
Using a novel approach known as immunotherapy, ipilimumab exploits the body's immune system to fight cancer. Originally known as anti-CTLA-4, it was developed in 1996 by James P. Allison, Chair of the Sloan Kettering Institute's Immunology Program. Memorial Sloal-Kettering researchers have been deeply involved in preclinical and clinical studies of the drug.
“The data I presented looks at patients who did not receive prior treatment for metastatic melanoma,” says Dr. Wolchok. “They were divided into two groups. One group received standard chemotherapy. The other group received the same chemotherapy along with ipilimumab. The results showed that the patients who received ipilimumab lived significantly longer than those receiving chemotherapy alone.”
Both physicians are enthusiastic about what these results mean for patients. “The conversations we can have with men and women with advanced melanoma are very different from what they were even a few months ago,” says Dr. Wolchok. “We now have at least two medicines that make a real impact on this disease and we can have much more hopeful discussions.”
“However we are still intently focused on the need to conduct clinical research,” Dr. Chapman adds. “The success of these drugs is not the end of the story. It's a very exciting and important beginning.”
Dr. Chapman's and Dr. Wolchok's studies were published in a special online issue of the New England Journal of Medicine (NEJM), timed to coincide with their ASCO presentations.
Ovarian cancer is most often diagnosed when the disease is in its more advanced stages. Standard therapy involves surgery and chemotherapy, and while the majority of women respond to this initial treatment, approximately 80 percent will experience disease recurrence.
Carol Aghajanian presented a study in ovarian cancer.
Carol Aghajanian, Chief of the Gynecologic Medical Oncology Service, presented results of a randomized, double-blinded phase III trial in 484 women whose cancer had recurred after initial treatment. Two groups were randomly assigned to receive either the standard regimen with a placebo (an inert substance), or the standard regimen along with a drug called bevacizumab (Avastin®). Bevacizumab is a therapy designed to inhibit angiogenesis, the process by which new blood vessels develop and carry nutrients to a tumor.
“The results showed a statistically significant and clinically relevant benefit to adding bevacizumab to a standard chemotherapy regimen in recurrent ovarian cancer,” says Dr. Aghajanian. There was a 52 percent improvement noted in progression-free survival (a period of time during which there is no progression in a patient's disease). In addition, 79 percent of women treated with bevacizumab in combination with chemotherapy had significant tumor shrinkage as compared with 57 percent of women treated with chemotherapy alone. Tumor shrinkage also lasted longer. To maximize its benefit to patients, bevacizumab was continued after the completion of chemotherapy until the disease progressed.
“The study points to an important role for bevacizumab, in combination with platinum-based chemotherapy, for recurrent ovarian cancer,” Dr. Aghajanian says. “This is great news for women with ovarian cancer because we are dealing with a chronic disease: Women face having to receive chemotherapy multiple times in order to keep the disease under control. This regimen affords them a better response to chemotherapy and allows them a longer time until their cancer grows and they need treatment again. Extending the time between treatment cycles may not only make chemotherapy work better — because patients are less likely to develop resistance to the drugs — but it gives patients a period of time without chemotherapy and an opportunity to return to the activities of daily life.”
An international study of the new drug abiraterone (Zytiga™) — recently approved by the FDA — found an even greater median survival benefit than previously reported, and has established a new class of treatment for men with metastatic castration-resistant prostate cancer (disease that progresses despite treatment to lower testosterone). In addition, researchers began the process of exploring a potential biomarker — circulating tumor cells (CTCs) — that could be used to hasten drug approvals. The results were presented by Howard I. Scher, Chief of the Genitourinary Oncology Service.
Medical oncologist Howard Scher answers questions about an important new drug for metastatic prostate cancer called abiraterone (Zytiga).
”In addition to the demonstration that abiraterone prolongslives, the drug offers men with metastatic castration-resistantdisease who have received prior chemotherapy containing docetaxel anew option at a point in the illness where hormonal agents aretypically not considered,” says Dr. Scher. (Abiraterone works byinhibiting the androgen [hormone] production that fuels a prostatecancer's growth.) “The survival benefit seen in the trial showed that these tumors are not uniformly resistant to a hormonal agent,”Dr. Scher continues. “Noteworthy as well is that we have a potentialnew biomarker for measuring a drug's effectiveness in prostatecancer.”
In practice, the effects of treatment are monitored by measuringthe level of prostate-specific antigen (PSA), a protein produced bycells of the prostate gland, in the blood. However, there are nostandards to assess disease activity in bone, the most common siteof spread; and while PSA levels are used to guide patientmanagement, there are situations in which a patient may bebenefiting from treatment when levels are rising, and not benefitingwhen they are going down.
Circulating tumor cells represent approximately one cell in abillion of those found in the blood stream. Interest in CTCs islongstanding and has increased with the availability of assays anddevices to detect, count, and characterize these cells. Counting CTCs was of particular interest to investigators because it is not PSA based “and, as such, would not be affected solely by the changein testosterone levels that occurs after treatment with drugs like abiraterone,” explains Dr. Scher.
“Noteworthy as well is that we have a potential new biomarker for measuring a drug's effectiveness in prostate cancer.”
In this study, Dr. Scher and his team began examining the question of a surrogate endpoint in clinical trials. Surrogate endpoints are biomarkers that can be substituted — or used in place of — a clinical endpoint such as survival.
“A critical goal of our research,” says Dr. Scher, “is to identify a biomarker endpoint measured shortly after a treatment is started that can serve as a surrogate for survival in a clinical trial” [meaning that physicians would not have to wait for an outcome such as the death of a patient to know whether a drug is working]. “Such a surrogate, if FDA approved, could be used in New Drug Applications, and enable drugs to be approved more rapidly.” (A New Drug Application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States.)
Dr. Scher cautions that researchers must continue testing the biomarker identified in the current trial in future clinical trials of a similar design. “The process is similar to the sequence of trials required to get a drug approved,” he concludes. “One trial does not establish surrogacy.”
Dr. Scher's study was also published in the special online issue of the NEJM.
In 2009, Memorial Sloan Kettering's lung cancer disease management team initiated the Lung Cancer Mutation Analysis Project (LC-MAP) in which Memorial Sloan Kettering pathologists look for all known mutations in tumors of patients diagnosed with lung adenocarcinoma, or non-small cell lung cancer, the most common form of the disease. “In the last decade, due in large part to work done here at Memorial Sloan Kettering, it has been established that the key to treating lung cancer effectively has to do with finding the specific mutation in the tumor cells of each individual's cancer,” says Mark G. Kris, Chief of the Thoracic Oncology Service.
Today, when a patient with non-small cell lung cancer comes to Memorial Sloan Kettering for treatment, a sample of his or her tumor is analyzed for mutations in ten genes known to be so-called driver mutations. “In the laboratory, if you take a normal cell and insert a mutation into that normal cell, it assumes control of the cell and it takes on the characteristics of a cancer cell, or becomes cancerous,” explains Dr. Kris. “If you then turn the mutation 'off,' experimentally, the cell dies and normal cells can take over. That's why we call them driver mutations. Right now, we are able to find these mutations in 60 percent of patients with non-small cell lung cancer. We then use this information to guide treatment.”
Mark Kris presented findings from an ongoing study from the NCI’s Lung Cancer Mutation Consortium.
At ASCO, Dr. Kris — a member of the executive committee of the National Cancer Institute's Lung Cancer Mutation Consortium (LCMC) — presented an ongoing study from that group. LCMC member institutions (Memorial Sloan Kettering Cancer Center and 13 other centers) are prospectively enrolling 1,000 patients with lung adenocarcinomas to test their tumors for the ten known driver mutations. “The goal is to make the information obtained available to patients and their physicians so it can be used to guide care,” Dr. Kris says. “Where a targeted drug is available, a patient receives that drug. Where no medicines that target a specific mutation are available, patients are referred to clinical trials that are investigating new targeted therapies.”
“The next step is to expand the concept to all stages and types of lung cancer,” concludes Dr. Kris. “Whenever a new mutation is found we will add it to the panel of mutations for which our pathologists test tumors.” He adds that the process investigators have created can work to help guide treatment for any form of cancer. “Our panel already includes important mutations in colorectal cancer and melanoma, and members of Memorial Sloan Kettering's Department of Pathology are developing a group of tests that will ultimately be done on virtually every cancer.”