FDA Announces First Approval of Targeted Therapy Based on Basket Study

Precision medicine clinical trial leads to approval of first treatment for Erdheim-Chester disease

The US Food and Drug Administration (FDA) has announced that it has approved the drug vemurafenib for the treatment of patients with BRAF V600-mutant Erdheim-Chester disease (ECD). This is the first approval of a targeted therapy based on a basket study and the first-ever drug approved for ECD, a rare blood disorder.

This landmark approval came as a direct result of research at Memorial Sloan Kettering Cancer Center (MSK). MSK researchers, led by Physician-in-Chief José Baselga, MD, PhD, pioneered the concept of a basket study, which harnesses the power of precision medicine by assigning treatments to patients based on the genetic alterations driving their cancers rather than where their tumors originated in the body. This approval is based off of the data of 22 ECD patients enrolled in the phase II VE-BASKET study. 

ECD is one of an extremely rare form of blood cancers known collectively as histiocytoses that can lead to life-threatening complications, including damage to the heart, lungs, and kidneys. It’s estimated that there are fewer than 300 cases of ECD in the United States. More than 50 percent of people with ECD have BRAF V600-mutant disease, indicating that they would benefit from this drug. Previous treatments for ECD have included off-label use of chemotherapy, radiation, steroids, and the immunotherapy drug interferon, but all of these have limited efficacy based on anecdotal reports and potentially severe side effects.

Based on the work of MSK medical oncologist Paul Chapman, MD, vemurafenib was previously approved for the treatment of advanced melanoma that carries the BRAF V600E mutation. Dr. Chapman led the phase III trial for vemurafenib that led to the drug’s approval for that disease in 2011. In August 2017, vemurafenib was granted FDA Priority Review and Breakthrough Therapy Designation for the treatment of BRAF V600-mutant ECD.

About the Study

This approval is based on data from the phase II VE-BASKET study, a nonrandomized, histology-independent evaluation of the efficacy of vemurafenib, an inhibitor of BRAF V600 kinase, in non-melanoma cancers, including ECD. This first-in-kind study enrolled participants across multiple diseases, based predominantly on genetic profile rather than where the cancer originated. Initial study results were published in the New England Journal of Medicine in August 2015.

Final results for the 22 people with ECD showed a best overall response rate of 54.4 percent by RECIST v1.1. Importantly, responses and disease control were extremely durable. The median duration of response was not estimable at a median follow-up time of 26.6 months. At two years, 83 percent of patients remained progression free. The safety of vemurafenib in ECD patients was similar to that previously reported in patients with melanoma. The most common adverse events were joint pain, rash, hair loss, fatigue, change in heart rhythm and skin tags. 

Precision Medicine at MSK

Experts at MSK have taken the lead in developing clinical trials for a number of promising treatments that are based on tumors’ mutational profiles. Since August 2015, when MSK experts published initial results of the first basket study, histology-agnostic clinical trials have emerged as one important means of systematically testing a targeted therapy across a variety of tumor types. This innovative clinical trial design helps collect data faster and may accelerate the development of medicines for diseases with high unmet need. Basket studies can include many more people than disease-specific trials, allowing researchers to evaluate multiple diseases simultaneously. This is particularly important for diseases such as ECD that are extremely rare, making it difficult to fully enroll a disease or tumor-specific trial.

MSK leadership saw the promise of precision oncology early on and committed to realizing its ability to create better treatment options for all people with cancer. In 2014, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) was established to improve cancer care and research through genomic analysis and MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets) was launched. This powerful diagnostic test provides detailed genetic information about a patient’s cancer that can guide treatment and identify clinical trial opportunities. To date, more than 20,000 MSK patients with advanced cancer have had their tumors sequenced through MSK-IMPACT. Most recently, Dr. Baselga and colleagues published a roadmap to precision oncology in the form of a seminal review paper in Cell.  

Scripps Florida Scientists Create Innovative Drug Design Strategy To Improve Breast Cancer Treatment

While there have been advances in the treatment of hormone-driven breast cancer, resistance to these therapies remains a significant problem. Side effects, including an increased risk of uterine cancer among postmenopausal women, also severely curtail their use for prevention.

However, a new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) offers a novel structure-based drug design strategy aimed at altering the basic landscape of this type of breast cancer treatment.
The findings show that the current approach is not the only, or even the best way, to block the estrogen receptor.

“We have created a different approach that gives us a mechanism to produce new types of therapeutic molecules,” said TSRI Associate Professor Kendall Nettles. “There are a lot of ways to avoid resistance and other cancer risks, and this gives us a tool box full of alternative approaches that could limit or eliminate those effects.”

“With the standard method, no one understands the structural basis,” he continued. “With our approach we know exactly how we did it. If you can see the shape of the receptor protein and see how the drug works on it, that makes the development process that much faster.”

The findings were published November 21, 2016, by the journal Nature Chemical Biology.

Seeing Is Believing

The current method of creating this class of drugs, which includes tamoxifen, involves attaching a bulky cluster of atoms with a chainlike structure (called, appropriately, a side chain) to molecules that disrupt the estrogen receptor binding site.

The team’s strategy taps a technique called x-ray crystallography to visualize the drug candidate as it binds to the receptor. This image is used to guide the production of estrogen receptor degraders that also lack the side chain, helping to reduce the risk of resistance and the development of other cancers.

“Our structure-trapping approach to X-ray crystallography provides a molecular snapshot of how subtle changes to a compound series generate a range of graded activity profiles,” said Research Associate Jerome C. Nwachukwu, who was co-first author with Research Associate Sathish Srinivasan. “This structurally distinct mechanism, acting indirectly rather than involvement of the typical side chain, provides a new way to design biologically distinct molecules for breast cancer prevention and treatment.”

The new method also makes it possible to identify structural rules for how the molecules interact.

“This is the first example of a structure-based design strategy targeting the estrogen receptor where there is a clear correlation between the chemistry, crystal structure and activity, which is another big advance that will be of broad interest to the cancer community,” Srinivasan said. “We show that indirect antagonism can result in inhibition of proliferation in a predictive fashion.”

Antibody-Based Drug Helps “Bridge” Leukemia Patients to Curative Treatment

In a randomized Phase III study of the drug inotuzumab ozogamicin, a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.

Inotuzumab ozogamicin, also known as CMC-544, links an antibody that targets CD22, a protein found on the surface of more than 90 percent of ALL cells. Once the drug connects to CD22, the ALL cell draws it inside and dies.

The study, which revealed complete remission rates of nearly 81 percent and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine.

“Forty-one percent of ALL patients in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11 percent we have seen qualify through standard chemotherapy,” said Hagop Kantarjian, M.D., chair of Leukemia. “Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging.”

Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.

Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90 percent. However, many of those patients will relapse and only about 30 to 50 percent will achieve long-term, disease-free survival lasting more than three years.

“Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier, and just 18 to 25 percent in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58 percent, higher than previously reported, possibly due to patients being treated later in the disease course.”

The study reported moderate side effects, the most common being cytopenia, a disorder that reduces blood cell production, and liver toxicity. Funding was provided by Pfizer, Inc.

Precision Prevention of Colorectal Cancer

Precision medicine’s public face is that of disease — and better treatments for that disease through targeted therapies.

But precision medicine has an unsung partner that could affect the lives of many more people: Precision prevention — a reflection of the growing realization that preventing cancer and other diseases may not be one-size-fits-all.

“Precision medicine has been kind of a buzzword recently, but often when people think about precision medicine, they think about treatment,” said Fred Hutchinson Cancer Research Center biostatistician Dr. Li Hsu, who focuses on precision prevention for colorectal cancer. “I think it’s just as important if not more important to prevent disease.”

In work presented Monday at the American Association for Cancer Research’s annual meeting in New Orleans, Hsu and other researchers from Fred Hutch, the University of Michigan and other research groups debuted their latest progress in precision prevention — an in-the-works method to predict risk of colorectal cancer that integrates genetic, lifestyle and environmental risk factors.

This research is not yet ready to move into clinical practice, said Fred Hutch epidemiologist Dr. Ulrike “Riki” Peters, one of the study authors. But it’s the first attempt at combining so many different areas of colorectal cancer risk into one convenient risk predictor.

Current risk stratification methods for colorectal cancer screening recommendations are relatively crude, based on age and family history alone. No family history of the disease? Start colonoscopies at age 50. Have an immediate relative who had colorectal cancer? Screen at age 40.

But these methods are likely missing many at risk, Peters said. Eighty percent of those with colorectal cancer have no known family history. And, unlike some, it’s a cancer where screening and prevention are tightly linked — colonoscopies can catch premalignant lesions and if those lesions are removed, the patient is spared from ever developing cancer.

“That is a very unique aspect of colorectal cancer,” Peters said.

Even though the disease is highly preventable if caught in the precancerous stages, colorectal cancer is the second leading cause of cancer-related deaths (for men and women combined) in the U.S., topped only by lung cancer. So along with encouraging people to get the recommended colonoscopies, a better sieve to catch those at higher risk of the disease could have an impact both on cancer prevention and on sparing those at low risk of the disease unnecessary procedures.

“At the end, what we want to do is prevent disease given limited resources,” said Dr. Jihyoun Jeon, a biostatistician at the University of Michigan who presented the risk prediction model in a poster at the AACR meeting. “We want to save resources but also prevent as much [disease] as possible.”

The improved risk prediction method was developed using data from more than 18,000 people, approximately 8,400 of whom had colorectal cancer. These data come from two large colorectal cancer studies that Peters leads, known as the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Transdisciplinary study (CORECT).

The model incorporates 19 known environmental and lifestyle risk factors for the disease, as well as 64 common genetic risk factors.