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MSK Program Focuses on Speeding Up Development of New Leukemia Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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On September 3, Memorial Sloan Kettering launched the Center for Drug Development in Leukemia (CDD-L). This new program will focus on creating more phase I clinical trials for most types of leukemia in adults. Its goal is to rapidly bring novel therapies to people being treated at MSK.

We spoke to leukemia experts Eytan Stein, who will lead the new center, and Jae Park about how treatment for acute (fast-growing) leukemia has changed in the past few years. They shared their ideas on how this new center will further accelerate improvements in treating these blood cancers.

Dr. Stein specializes in treating acute myeloid leukemia (AML), one of the most common leukemias in adults. Dr. Park specializes in treating acute lymphocytic leukemia (ALL). This blood cancer is rare in adults but makes up three-quarters of leukemia in children.

How have treatments for leukemia changed over the past few years?

Dr. Park: For ALL in adults, one of the big improvements is the development of new immunotherapies, including blinatumomab (Blincyto®) and inotuzumab (Besponsa®). Blinatumomab is an antibody-based drug that works by linking T cells to leukemia cells. This enhances the T cells’ killing activity. Inotuzumab is an antibody with a drug attached, to allow the selective delivery of chemotherapy to leukemia cells. Both drugs have fewer side effects than chemotherapy. This is important because ALL is often diagnosed in older people, who may not be able to tolerate stronger drugs.

Dr. Stein: For AML, we have moved away from a one-size-fits-all approach, which was common for decades. As with ALL, people with AML tend to be older and therefore not strong enough for intensive chemotherapy. Now we have other options. One is a drug called venetoclax (Venclexta®), which targets a protein on leukemia cells called BCL2. The drug is given with another type of drug, called a hypomethylating agent, which affects cellular function. This combination treatment leads to remission in about 70% of people with AML, and those remissions tend to be long-lasting.

How has personalized medicine improved the treatment of leukemia?

Dr. Park: We’ve learned that about 40% of all cases of ALL have a genetic abnormality called the Philadelphia chromosome. This mutation is also commonly found in chronic myeloid leukemia. We’ve found that drugs that target the mutation also work for ALL, but they need to be combined with other drugs. We are now doing clinical trials to find the best combination for these drugs and are also using MSK-IMPACT™ to look for less-common mutations that can be targeted with different drugs.

Dr. Stein: For the 30% of people who don’t respond to the venetoclax combination or whose disease comes back after treatment, we have many options based on the mutations driving the cancer. For the approximately one-quarter of people who have mutationsin the genes IDH2 and IDH1, the US Food and Drug Administration recently approved the drugs enasidenib (Idhifa®) and ivosidenib (Tibsovo®), respectively. We are looking at adding targeted therapies for other mutations as well. For people with secondary AML, which develops after they have been treated for myelodysplastic syndrome or another cancer, a new drug that is a formulation of two older chemotherapies together seems to be effective.

What are the roles of blood and marrow stem cell transplantation and cell therapies, like chimeric antigen receptor (CAR) T therapy, in treating people with acute leukemia?

Dr. Park: For people with high-risk ALL or those whose disease comes back after chemotherapy, bone marrow transplantation has been the only chance of a cure. More recently, a new and improved form of cell therapy called CAR T has emerged as a promising treatment to achieve a deep and complete remission even in people who have failed all standard therapies, including bone marrow transplantation. This has generated a lot of excitement in the field. MSK is leading the effort to develop effective and safe CAR T cells for people with various blood cancers. What is most exciting about this form of cell therapy is that a single infusion of T cells can result in a long-lasting remission. With continued commitment and research in the field, we are optimistic that we will improve the outcome and quality of life of people with blood cancer.

What are you most enthusiastic about?

Dr. Stein: I’m excited about all of our clinical trials, specifically the phase I trials that the CDD-L is putting forward. We hope to eventually have a trial available for every patient who doesn’t respond to standard treatment. MSK is also a founding member of the Beat AML initiative overseen by the Leukemia and Lymphoma Society. Through these efforts, we want to have a clinical trial available for every individual who doesn’t respond to standard treatment.

Dr. Park: I’m excited about all the new treatment options for all people with ALL. In the next few years, we will focus our efforts on how to best use these therapies to minimize exposure to traditional chemotherapy and shorten the duration of therapies for people with ALL, which currently last several years. We hope to achieve these goals through a series of clinical trials. We’ll use sophisticated tools to detect an extremely low level of leukemia cells, called measurable residual disease, and identify who can benefit from these new therapies.

Beyond the hematologic oncologists, who are the other members of the MSK team that contribute to the care of people with leukemia?

Dr. Stein: Our molecular pathologists and hematopathologists make it possible for us to find the genetic mutations in each patient’s cancer so that we can match them with the right therapy. This kind of testing used to take many weeks, but now they are able to get us results within a few days. It enables us to get patients on trials right away so they can start treatment almost immediately.

Dr. Park: Our nursing staff on the Leukemia Service is phenomenal, and they’re a big reason to come to MSK. They have incredible experience in managing the side effects that may come from the newly approved and experimental therapies. They also understand the emotional and social needs that often come with a diagnosis of leukemia. Because of their expertise and support, we can ensure that most patients will complete their cancer treatments. Effective leukemia treatment requires strong teamwork, and we have an amazing team that I’m proud to work with every day.

Where is the CDD-L located?

Dr. Stein: People who participate in trials through the CDD-L will receive their care in the new David H. Koch Center for Cancer Care. Their treatment is provided within the Developmental Therapeutics Unit, a treatment area with a specialized cadre of nurses who have expertise in the care of people on phase I clinical trials.

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Getting to the Root of Pediatric Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 10/03/2019
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Rihanna was born with a tumor on her upper right arm almost as large as her head. After chemotherapy failed to shrink it, her parents brought her to Memorial Sloan Kettering, hoping for a different outcome. “MSK’s doctors gave me a sense of confidence that they knew what they were doing,” says Rihanna’s mother, Ana.

And the MSK team delivered: They determined that Rihanna’s cancer was caused by a mutation in a gene called NTRK and focused her care plan on attacking the cancer-driving effects of that mutation.

At the time, MSK Kids pediatric oncologist Neerav “Neal” Shukla was leading a clinical trial for larotrectinib (Vitrakvi®), a drug that specifically targets NTRK. Within days of starting Rihanna on larotrectinib, the tumor began to shrink. Five months later, the remaining tumor was removed, allowing Rihanna to have full function of her arm. Now 2, she has shown no sign of the disease. “She is a happy, healthy toddler,” Ana says.

Rihanna’s story illustrates the power of precision medicine. This practice is grounded in uncovering the genetic changes that drive a tumor’s growth and then finding the best drugs to stop them. Over the past two decades, precision medicine has helped many adults with cancer, leading to dozens of more effective, less toxic drugs for cancers of the lung, colon, breast, and more.

But the progress has been slower for children. MSK Kids is changing that: A major effort is underway to fully deliver on the promise of precision medicine for our youngest patients.

Successfully treating one child, like Rihanna, can do a lot to accelerate drug development to help many more kids. The trial she participated in resulted in the simultaneous approval of larotrectinib for both children and adults with NTRK-driven tumors. In the past, children often had to wait until after a drug was approved in adults before pediatric clinical trials were launched.

Making Progress in the Lab

These efforts are guided by MSK’s Pediatric Translational Medicine Program (PTMP), which is led by Dr. Shukla. The PTMP is involved in genomically characterizing patients’ tumors as well as developing new therapies. Through this program, all children cared for at MSK are offered comprehensive tumor testing. Being able to deliver therapies to the right target requires identifying the root cause of each tumor. This interdisciplinary approach is being spearheaded by geneticist Elli Papaemmanuil and her team of data scientists.

“We want to understand the genomic drivers of cancer in children, identify the key targets, and understand which patients will respond to targeted therapies. In this way, we can develop a treatment approach that is patient tailored and data driven,” Dr. Papaemmanuil explains.

Her lab has performed in-depth analyses on tumors from more than 120 children treated at MSK. “Our preliminary data have opened our eyes to the diversity and complexity of pediatric cancers,” she says.

“We have developed and optimized the processes required to deliver tumor analyses quickly enough to benefit patients,” she adds. “We have shown that this is possible.”

How Research Translates to Treatment

Part two of precision medicine is developing drugs that can potentially target the changes driving children’s tumors. Once a tumor has been characterized, members of the PTMP’s clinical research team take over and start working on treatments matched to changes in the cancer genome.

Doctors, molecular pathologists, and data and laboratory scientists work together to make treatment decisions based on what they’ve already learned about the underpinnings of pediatric tumors.

If a child appears to be a good candidate for a treatment matched to a genetic change in their tumor, the next challenge is gaining access to the drug. The best option is to enroll the child in an ongoing clinical trial. This is what happened with Rihanna.

“We aim to have a clinical trial available for every patient, but even common mutations are present in only 1 or 2 percent of pediatric cancers,” says Julia Glade Bender, a pediatric oncologist who is part of the PTMP. “Doing a clinical trial for every genomic abnormality that we find is just not feasible.”

For rarer mutations, a more specialized approach may be needed. “This is when we develop a single-patient use [SPU] treatment plan,” Dr. Glade Bender says. These compassionate-use plans require tremendous resources, including finding a company willing to supply a drug and getting permission from the US Food and Drug Administration to administer it. It can be a lengthy and labor-intensive process.

“We anticipate that many of the drugs we test in individual patients can eventually benefit a greater number of children with cancer,” says Dr. Glade Bender. So far, at least five drugs first given as SPUs at MSK Kids have progressed into pediatric clinical trials.

MSK’s efforts to develop drugs for kids go beyond the doctors and scientists who specialize in pediatrics. For example, clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. (Previously, the age requirement was 18, as it is for most clinical trials.)

“As the largest pediatric oncology program in the world, we are well-positioned to deliver on the promise of precision medicine and to learn from every child who we have the privilege of caring for,” says MSK Kids Chair Andrew Kung.

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Targeting Errors in How Proteins Are Made Is a Promising Approach for Cancer Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 10/09/2019
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Manufacturing proteins is a multistep process that’s hard-coded into how our cells operate. Genes, which are made of DNA, get translated into RNA, which in turn provides instructions on how proteins are made. One key step in this construction process is called RNA splicing. Like the editing of a film, when some pieces may be cut out and discarded, splicing involves removing portions of the RNA and stitching the remaining pieces back together.

New work from Memorial Sloan Kettering is illustrating that when splicing isn’t done properly, it can lead to cancer.

MSK physician-scientist Omar Abdel-Wahab focuses on studying this process in his lab. He recently published two studies looking at the role of specific RNA splicing factors in different cancers. One study focused on acute myeloid leukemia (AML); the other studied melanoma, particularly uveal (eye) melanoma.

“Our earlier research found that splicing factors are mutated at high frequency in a variety of cancer types,” says Dr. Abdel-Wahab, of the Human Oncology and Pathogenesis Program. “What we’re learning is that when these splicing factor proteins are mutated, they’re actually changing the function of the splicing machinery in cells. Importantly, they’re doing it in a way that promotes cancer.”

The research reported in both papers has already suggested possible approaches for targeting these defective splicing factors with drugs.

Combination Approach for Acute Myeloid Leukemia

The first paper, published October 2 in Nature, looked at a splicing factor called SRSF2. The SRSF2 gene is mutated in about one-quarter of AML cases. It turns out that these SRSF2 mutations are more likely to be present when cancer cells also have mutations in the IDH2 gene, which is commonly mutated in AML.

“We were surprised to find that mutations in SRSF2 are particularly frequent in AML that also has IDH mutations,” Dr. Abdel-Wahab says. “We decided to investigate this link.”

Two IDH genes — IDH1 and IDH2 — are commonly mutated in AML. Together, these mutations also are found in about one-quarter of AML cases. In the past few years, the US Food and Drug Administration has approved two drugs designed to target these mutations: enasidenib (Idhifa®) for IDH1 and ivosidenib (Tibsovo®) for IDH2.

“IDH mutations have been very clearly shown to drive leukemia development,” Dr. Abdel-Wahab explains. “What we showed in this paper is that the splicing errors caused by SRSF2 mutations are also part of this process. The interplay between these two types of mutations is very important.”

Dr. Abdel-Wahab’s lab is focused on developing drugs to target mutant splicing factors, including SRSF2. He is already conducting an early-stage clinical trial with one of these drugs, and more studies are planned.

“Now we’re really interested in trying to develop ways to target forms of AML that have both mutations,” he says. “The idea is that we could use these drugs together, so that we’re targeting the cancer from two sides.”We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.

Targeting Melanoma with a New Kind of Therapy

In the second paper, published October 9 in Nature, Dr. Abdel-Wahab and his colleagues looked at another splicing factor, called SF3B1. Mutations in the SF3B1 gene are found in many types of cancer, including some types of leukemia and many solid tumors. They are most commonly found in uveal melanoma, a rare but aggressive eye cancer.

In this study, a collaboration with researchers at the Fred Hutchinson Cancer Research Center in Seattle, the investigators studied RNA sequencing data from people with several forms of cancer.

“We wanted to see if we could find a link to what the mutation is doing in these diseases,” Dr. Abdel-Wahab says. “We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.”

As part of the study, the researchers were able to develop a way to block the altered RNA splicing caused by the mutated splicing factor. Instead of using a drug, they used a small piece of DNA called an antisense oligonucleotide. Oligonucleotide therapy is a relatively new form of treatment: A handful of oligonucleotide-based drugs have been FDA approved, mostly for genetic neurologic diseases.

Dr. Abdel-Wahab and his colleagues tested the antisense oligonucleotide in cultures of cells with SF3B1 mutations and found that it blocked the growth of cancer cells. They then tested the therapy in mice that were implanted with material from patient samples of uveal melanoma. The treatment reduced the size of the tumors in the mice.

“We would like to work to develop this antisense oligonucleotide as a treatment, so that we can eventually start a clinical trial,” Dr. Abdel-Wahab says. “It’s a challenging undertaking because of the way these oligonucleotides behave in the body. But we think it’s a promising approach.”

The October 2 Nature paper was funded by the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Leukemia and Lymphoma Society, a Japan Society for the Promotion of Science Overseas Research Fellowship, a Bloodwise Clinician Scientist Fellowship, the Oglesby Charitable Trust, National Institutes of Health grants (K99 CA218896 and R01 HL128239), an American Society of Hematology Scholar Award, Cancer Research UK, the Cancer Prevention and Research Institute of Texas, the Welch Foundation, a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-16-1-0059), the Starr Foundation, the Henry and Marilyn Taub Foundation, the Edward P. Evans Foundation, the Josie Robertson Investigators Program, and the Pershing Square Sohn Cancer Research Alliance.

The October 9 Nature paper was funded by the Leukemia and Lymphoma Society, the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Conquer Cancer Foundation, an American Society of Clinical Oncology Young Investigator Award, an American Association for Cancer Research Lymphoma Research Fellowship, a Mahan Fellowship from the Fred Hutchinson Cancer Research Center, the Pershing Square Sohn Cancer Research Alliance, the Henry and Marilyn Taub Foundation, the Starr Cancer Consortium, National Institutes of Health grants (R01 DK103854 and R01 HL128239), the Evans MDS initiative, and the Department of Defense Bone Marrow Failure Research Program.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People

Source: Memorial Sloan Kettering - On Cancer
Date: 11/07/2019
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Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they don’t work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

“Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs,” says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. “It’s important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.”

Looking to Evolution and Population Diversity for Answers

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

“The classic battle between pathogens and the human immune system plays out in the HLA genes,” Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the body’s ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chan’s co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chan’s lab and graduate student Federica Pierini from Dr. Lenz’s lab were the co-first authors.

Recognizing Tumors as Foreign

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasn’t seen before.

“For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign,” Dr. Chan says. “High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.”

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. “These are the yin and yang of T cell–based immune checkpoint treatment,” Dr. Chan says. “High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.”

Finding New Ways to Measure Genetic Diversity

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. “But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out what’s going on,” he says. “It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation that’s seen in the role of TMB in immunotherapy trials.”

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chan’s team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

This research was funded by National Institutes of Health grants (R35 CA232097, RO1 CA205426, and P30 CA008748), the PaineWebber Chair in Cancer Genetics at MSK, and a German Research Foundation grant.

Dr. Chan has filed for a patent related to HED. Additionally, he is an inventor on a patent application filed by MSK relating to the use of TMB in cancer immunotherapy. MSK and the inventors may receive a share of revenue from license agreements relating to these patent applications. Dr. Chan is also a co-founder of Gritstone Oncology and holds equity. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as an adviser for Bristol-Myers Squibb, Illumina, Eisai, and An2H.

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Three Scientists Are Named Winners of the Paul Marks Prize for Cancer Research

Source: Memorial Sloan Kettering - On Cancer
Date: 11/08/2019
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Memorial Sloan Kettering has named three investigators as the recipients of this year’s Paul Marks Prize for Cancer Research. The award recognizes promising scientists for their accomplishments in the area of cancer research. 

The winners for the 2019 Paul Marks Prize for Cancer Research are Nathanael Gray of the Dana-Farber Cancer Institute and Harvard Medical School, Joshua Mendell of the University of Texas Southwestern Medical Center, and Christopher Vakoc of Cold Spring Harbor Laboratory.

“The body of research represented by this year’s winners touches on three different but equally important areas of cancer research,” says Craig B. Thompson, President and CEO. “Each of the recipients is conducting investigations that will have a major impact on cancer care in the years to come.”

Since it was first presented in 2001, the biennial Paul Marks Prize for Cancer Research has recognized 31 scientists and awarded more than $1 million in prize money. The award was created to honor Dr. Marks, President Emeritus of MSK, for his contributions as a scientist, teacher, and leader during the 19 years he headed the institution.

The prize winners were selected by a committee made up of prominent members of the cancer research community. Each recipient will receive a medal and an award of $50,000 and will speak about their research at a scientific symposium at MSK on December 5.Paul Marks Prize for Cancer Research

The Paul Marks Prize for Cancer Research is intended to encourage young investigators who have a unique opportunity to help shape the future of cancer research. Named for the late Paul A. Marks, who served as President of Memorial Sloan Kettering for nearly two decades, the prize is awarded to up to three investigators every other year.

Nathanael Gray

Dr. Gray is the Nancy Lurie Marks Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and the Dana-Farber Cancer Institute. He also leads the Dana-Farber chemical biology program.

Dr. Gray’s research centers on drug development and medicinal chemistry related to targeted therapies for cancer. Most traditional targeted therapies block the activity of cancer-causing proteins. Dr. Gray’s lab is taking a different approach: finding ways to degrade these proteins.

“The analogy used with conventional targeted therapies is that the drug is a key and the protein is a door that can be unlocked,” he says. “But what happens when you have a door with no keyhole and no combination? The only way you can get rid of the door is to blow it up. That’s the degradation approach.”

Most medicinal chemists work either at a drug company or in a chemistry department, but Dr. Gray sees great value in working at a cancer center. “This is the most valuable environment I could be in,” he says. “I’m collaborating with basic cancer scientists as well as physicians. All of us are focused on the problem of cancer. My job is to figure out which problems are tractable and then figure out an approach for solving them.”

Four drugs that Dr. Gray has had a hand in developing have already been approved by the US Food and Drug Administration or are currently in clinical trials. “We plan to continue working on targets that were once considered ‘undruggable’ by using this protein-degradation approach,” he says.

Joshua Mendell

Dr. Mendell is a professor and the Vice Chair of the Molecular Biology Department at UT Southwestern Medical Center. He is also a Howard Hughes Medical Institute Investigator.

His lab studies noncoding RNAs, which lack the instructions for making proteins. Much of his research focuses on a class of very small noncoding RNAs called microRNAs. “MicroRNAs regulate messenger RNA molecules, which do encode proteins,” Dr. Mendell says. “Over the years, my lab has investigated how these small noncoding RNAs contribute to tumor formation and how they become dramatically reprogrammed in cancer cells.”

One particularly important contribution from his lab was the discovery that MYC, a gene that’s overactive in many human cancers, promotes cancer in part by reprogramming microRNAs to favor tumor growth.

Not all microRNAs in cancer cells have the same function. Some act as oncogenes, meaning that they drive the formation of tumors. Others are tumor suppressors. This means that when levels of the microRNAs go down, tumors are able to form.

“We’re interested in finding therapies that change the activity of these microRNAs,” he explains. “For those that act as oncogenes, it could be beneficial to inhibit their activity. On the other hand, for those that act as tumor suppressors, we are working to restore their activity or increase their levels in cancer cells.”

Research in Dr. Mendell’s lab has expanded to include the study of other types of noncoding RNAs. “Other classes of noncoding RNAs are much more mysterious, and their mechanisms are more diverse compared to microRNAs,” he says. “We want to understand why our genome is producing so many RNAs that do not encode proteins and what role they may have in diseases, including cancer.”

Christopher Vakoc

Dr. Vakoc is a professor at Cold Spring Harbor Laboratory. His research is focused on gene regulation. Specifically, he is determining how certain genes drive cancer growth and looking for ways to disable those genes. “The objective of our research is to figure out how we can use drugs to turn off cancer-promoting genes as a way to eliminate tumors,” he says.

In his lab, Dr. Vakoc performs genetic screening with the gene-editing technique CRISPR to figure out which genes and proteins are most important for cancer. “We systematically subtract each one to learn which of them are vital for sustaining cell growth,” he says. “The idea is that if we find a protein that cancer cells are addicted to, we can look for a way to block them.”

Among his most important discoveries was identifying the protein ZFP64 as an essential factor in the growth of certain types of leukemia. His findings helped illustrate how this protein drives cancer growth and suggested new treatments.

Dr. Vakoc’s lab is currently studying cancer growth in several other kinds of cancer, including pancreatic cancer, lung cancer, and sarcoma. “A lot of our methods are universally applicable,” he says. “It’s been very illuminating for me to compare and contrast how solid tumors behave differently from blood cancers with respect to gene regulation. We’re using a variety of different approaches to develop methods for targeting these genes.”

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Machine Learning May Help Classify Cancers of Unknown Primary

Source: Memorial Sloan Kettering - On Cancer
Date: 11/14/2019
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Experts estimate that between 2 and 5% of all cancers are classified as cancer of unknown primary (CUP), also called occult primary cancer. This means that the place in the body where the cancer began cannot be determined. Despite many advances in diagnostic technologies, the original site of some cancers will never be found. However, characteristic patterns of genetic changes occur in cancers of each primary site, and these patterns can be used to infer the origin of individual cases of CUP.

In a study published November 14, a team from Memorial Sloan Kettering reports that they have harnessed data from MSK-IMPACT™ to develop a machine-learning algorithm to help determine where a tumor originates. MSK-IMPACT is a test to detect mutations and other critical changes in the genes of tumors. When combined with other pathology tests, the algorithm may be a valuable addition to the tool kit used to make more-accurate diagnoses. The findings were reported in JAMA Oncology.

“This tool will provide additional support for our pathologists to diagnose tumor types,” says geneticist Michael Berger, one of the senior authors of the new study. “We’ve learned through clinical experience that it’s still important to identify a tumor’s origin, even when conducting basket trials involving therapies targeting genes that are mutated across many cancers.”

Basket trials are designed to take advantage of targeted treatments by assigning drugs to people based on the mutations found in their tumors rather than where in the body the cancer originated. Yet doctors who prescribe these treatments have learned that, in many cases, the tissue or organ in which the tumor started is still an important factor in how well targeted therapies work. Vemurafenib (Zelboraf®) is one drug where this is the case. It is effective at treating melanoma with a certain mutation but doesn’t provide the same benefit in colon cancer, even when it’s driven by the same mutation.Cancer of Unknown Primary Origin

If it is unclear where in the body a cancer started, it is called cancer of unknown primary (CUP) or occult primary cancer.

Harnessing Valuable Data

Since MSK-IMPACT launched in 2014, more than 40,000 people have had their tumors tested. The test is now offered to all people treated for advanced cancer at MSK.

In addition to providing detailed information about thousands of patients’ tumors, the test has led to a wealth of genomic data about cancers. It has become a major research tool for learning more about cancer’s origins.

The primary way that pathologists diagnose tumors is to look through a microscope at tissue samples. They also examine the specific proteins expressed by cancers, which can help predict a cancer’s origin. But these tests do not always allow a definitive conclusion.

“However, there are occasionally cases where we think we know the diagnosis based on the conventional pathology analysis, but the molecular pattern we observe with MSK-IMPACT suggests that the tumor is something different,” Dr. Berger explains. “This new tool is a way to computationally formalize the process that our molecular pathologists have been performing based on their experience and knowledge of genomics. Going forward, it can help them confirm these diagnoses.”

“Because cancers that have spread usually retain the same pattern of genetic alterations as the primary tumor, we can leverage the specific genetic changes to suggest a cancer site that was not apparent by imaging or conventional pathologic testing,” says co-author David Klimstra, Chair of MSK’s Department of Pathology.

“Usually the first question from patients and doctors alike is: ‘Where did this cancer start?’ ” says study co-author Anna Varghese, a medical oncologist who treats many people with CUP. “Although even with MSK-IMPACT we can’t always determine where the cancer originated, the MSK-IMPACT results can point us in a certain direction with respect to further diagnostic tests to conduct or targeted therapies or immunotherapies to use.”

Collecting Data on Common Cancers

In the current study, the investigators used data from nearly 7,800 tumors representing 22 cancer types to train the algorithm. The researchers excluded rare cancers, for which not enough data were available at the time. But all the most common types are represented, including lung cancer, breast cancer, prostate cancer, and colorectal cancer.

The analysis incorporated not only individual gene mutations but more complex genomic changes. These included chromosomal gains and losses, changes in gene copy numbers, structural rearrangements, and broader mutational signatures.

“The type of machine learning we use in this study requires a lot of data to train it to perform accurately,” says computational oncologist Barry Taylor, the study’s other senior author. “It would not have been possible without the large data set that we have already generated and continue to generate with MSK-IMPACT.”

Both Drs. Berger and Taylor emphasize that this is still early research that will need to be validated with further studies. In addition, since the method was developed specifically using test results from MSK-IMPACT, it may not be as accurate for genomic tests made by companies or other institutions.

Improving Diagnosis for Cancer of Unknown Primary

MSK’s pathologists and other experts hope this tool will be particularly valuable in diagnosing tumors in people who have CUP. Up to 50,000 people in the United States are diagnosed with CUP every year. If validated for this purpose, MSK-IMPACT could make it easier to select the best therapies and to enroll people in clinical trials.

“This study emphasizes that the diagnosis and treatment of cancer is truly a multidisciplinary effort,” Dr. Taylor says. “We want to get all the data we can from each patient’s tumor so we can inform the diagnosis and select the best therapy for each person.”

This work was funded in part by Illumina, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Cycle for Survival, National Institutes of Health grants (P30-CA008748, R01 CA204749, and R01 CA227534), an American Cancer Society grant (RSG-15-067-01-TBG), the Sontag Foundation, the Prostate Cancer Foundation, and the Robertson Foundation.

Dr. Varghese has received institutional research support from Eli Lilly and Company, Bristol-Myers Squibb, Verastem Oncology, BioMed Valley Discoveries, and Silenseed. Dr. Klimstra reports equity in Paige.AI, consulting activities with Paige.AI and Merck, and publication royalties from UpToDate and the American Registry of Pathology. Dr. Berger reports research funding from Illumina and advisory board activities with Roche. All stated activities were outside of the work described in this study.

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Study in Mice Suggests Lactose in the Diet Feeds Dangerous Gut Bacteria When the Immune System Is Compromised

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2019
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Infections with the Enterococcus bacterium are a major threat in healthcare settings. They can lead to inflammation of the colon and serious illnesses such as bacteremia and sepsis, as well as other complications.

Enterococcus infections are particularly risky for people having stem cell and bone marrow transplants (BMTs) to treat blood cancer. Studies have suggested that high levels of Enterococcus increase the incidence of graft-versus-host disease (GVHD), a potentially fatal condition in which immune cells from the donor’s stem cells attack the recipient’s organs.

Now, an international team led by scientists from Memorial Sloan Kettering has shown for the first time that foods containing lactose, a sugar that’s naturally found in milk and dairy products, help Enterococcus thrive in the gut, at least in mice. They also studied changes in the bodies of people having BMTs. The study was published November 29 in Science.

“These findings hint at a possible new way to reduce the risk of GVHD as well as dangerous infections,” says MSK physician-scientist and GVHD expert Jonathan Peled. “But they are still preliminary, and it’s too early to suggest cutting out lactose in the diets of people undergoing BMTs or other hospitalized patients who are at risk from Enterococcus.”

Focusing on the Microbiota

For several years, Dr. Peled and Marcel van den Brink, head of MSK’s Division of Hematologic Malignancies, have been studying the relationship between GVHD and microbiota — the community of microorganisms that inhabit the body. The two of them are co-senior authors of the new study.

Their previous research has shown that when harmless strains of microbes are wiped out, often due to treatment with antibiotics, Enterococcus and other harmful types of bacteria can take over due to lack of competition. As part of the new study, which included analysis of microbiota samples from more than 1,300 adults having BMTs, the team confirmed the link between Enterococcus and GVHD.

The investigators conducted further Enterococcus research in cell cultures and in mice. “Mouse models are very helpful for understanding the mechanisms in the gut that lead to GVHD,” says Dr. van den Brink, who is also Co-Director of the Parker Institute for Cancer Immunotherapy at MSK and leads a lab in the Sloan Kettering Institute’s Immunology Program. “We studied mice that had been given BMTs and found that the cells lining their intestines, called enterocytes, were no longer able to make lactase, the enzyme that breaks down lactose. The high levels of undigested lactose in turn led to a total domination of Enterococcus. It was shocking to see how one type of bacteria completely takes over.”

Dr. van den Brink adds that on top of the defective enterocytes, the loss of competing healthy strains of bacteria caused by antibiotic treatment makes problems in the gut even worse. “It’s a double whammy,” he says.

A Trip to the Pharmacy Leads to a Surprising Discovery

To study whether higher lactose levels were boosting the growth of Enterococcus, or whether the connection was only a coincidence, visiting researcher and first author Christoph Stein-Thoeringer went to the pharmacy to buy Lactaid®. These lactase-containing pills break down lactose, helping people who are lactose intolerant to eat dairy products without side effects.

The researchers discovered that when lactase was added to lab cultures of Enterococcus, the bacterial growth was blocked. So, they began to feed lactose-free chow to lab mice that had been given BMTs and found that mice on the special diet were protected against Enterococcus domination.

“We’re not suggesting this is a cure for GVHD,” Dr. van den Brink says. “But it appears to be an important modulator.”

The investigators have not yet tested the new findings in humans, but existing data suggests that the same connection between lactose and Enterococcus seen in the mice may be at play in people who have had BMTs. “We know which gene variants are associated with being lactose intolerant,” Dr. Peled notes. “We looked at our records and found that people who had these gene variants tended to have a harder time clearing Enterococcus from their guts than others did.”

He adds that many BMT recipients become temporarily lactose intolerant, likely due to the loss of enterocytes caused by chemotherapy. “We are considering doing a trial in which people eat a lactose-free diet or take Lactaid during their cancer treatment to see if the growth of Enterococcus is blocked,” Dr. Peled says.

A Global Effort

Another important aspect of the new study is that it didn’t just look at people treated at MSK. It also included patient samples from Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Researchers from those three institutions also contributed to the Science paper.

“Researchers who study the microbiome know that the environment in which a person lives is a major factor,” Dr. van den Brink says. “We’ve made a major effort to collect samples from all over the world, so we know that when we find common features, they are likely to hold up worldwide.”

This work was supported by the German Research Foundation, a Young Investigator-Award from the American Society of Bone Marrow Transplantation, the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSK, the Sawiris Foundation, the Society of MSK, an MSK Cancer Systems Immunology Pilot Grant, the Empire Clinical Research Investigator Program, Seres Therapeutics, the Japan Society for the Promotion of Science, the Center of Innovation Program from Japan Science and Technology, a Conquer Cancer Foundation Young Investigator Award/Gilead Sciences, and more than a dozen National Institutes of Health grants (R01-CA228358, R01-CA228308, P30 CA008748, P01-CA023766, R01-HL125571, R01-HL123340, P01-AG052359, U01 AI124275, R01 AI032135, AI095706, U01 AI124275, KL2 TR001115-03, 2P30AG028716-11, R01CA203950-01, 1R01HL124112-01A, R01 CA203950-01).

Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. Dr. van den Brink has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Magenta Therapeutics, WindMIL Therapeutics, Merck & Co. Inc., Acute Leukemia Forum (ALF), and DKMS Medical Council (Board). He also has IP licensing with Seres Therapeutics and Juno Therapeutics and stock options from Smart Immune.

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Largest Study of Its Kind Reveals New Targetable Genetic Causes of the Rare Blood Disorder Histiocytosis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/04/2019
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Histiocytoses are a group of blood diseases that are diagnosed in only a few hundred people in the United States every year. Despite that rarity, researchers at Memorial Sloan Kettering have extensive experience with histiocytosis. MSK doctors care for more adults with histiocytosis than doctors at any other hospital in the country.

In recent years, MSK investigators have led a number of studies on the specific gene mutations that cause different types of histiocytoses (also called histiocytic neoplasms). On November 25, in Nature Medicine, an international team led by MSK reported findings from the largest study of its kind. They identified mutations for nearly all of the 270 people included in the study.

“We’ve known for some time that most cases of this disease are driven by a single mutation,” says MSK neurologist and histiocytosis expert Eli Diamond, one of the paper’s two senior authors. “In the past, we’ve been able to define those mutations for about 70% of patients.”

“Through the more extensive sequencing that we’ve done in this study, we can now define the mutations driving the disease in close to 100% of patients,” adds MSK physician-scientist Omar Abdel-Wahab, the paper’s other senior author. “For most of these mutations, we already have drugs to target them.”

Previous Success with Targeted Therapies

Histiocytosis occurs when the body makes an unusually large amount of abnormal white blood cells, referred to as histiocytes. These cells can build up and form tumors, which can grow in any part of the body. The bones and skin are most commonly affected.

The most common types of histiocytoses are Erdheim-Chester disease, which occurs mostly in adults; Langerhans cell histiocytosis and Rosai-Dorfman disease, which can affect both children and adults; and juvenile xanthogranuloma, which is found almost exclusively in children. All of these types were included in the study, as well as some other, rarer forms of the disease.

Thanks to earlier research done at MSK and elsewhere, experts already knew about the mutations driving many of these subtypes. That understanding has led to targeted therapies that are effective in treating them.

In 2017, vemurafenib (Zelboraf®) was the first drug approved for people with Erdheim-Chester disease. Vemurafenib targets mutations in a gene called BRAF. In October 2019, the US Food and Drug Administration announced that it had granted a Breakthrough Therapy Designation for the drug cobimetinib (Cotellic®) to treat histiocytosis with mutations in the genes MEK1 and MEK2. This designation indicates that the agency believes the drug is particularly promising. The clinical trials for both of these drugs were led by investigators at MSK.

“Another thing that’s important to note is that unlike treatment with most targeted therapies, where the tumors eventually become resistant to the drugs, when histiocytosis is treated with these therapies, patients’ responses tend to be long-lasting,” Dr. Diamond says. “Many people have remained on these drugs for years with durable benefits and few side effects.”

The new study opens up opportunities for even more people to be treated with targeted therapies. The researchers uncovered mutations in the RET, ALK, and NTRK genes. All of these mutations can be targeted with drugs that are already approved or are in clinical trials for other types of cancer with these mutations.

The study also reported for the first time that the gene CSF1R is implicated in certain cases of histiocytosis. CSF1R was already known to be important in the formation of a type of white blood cell called a macrophage.

“One of the strengths of this study is that it included all subtypes of histiocytosis. We have enough data to make these correlations between specific gene mutations and specific forms of histiocytosis,” says Dr. Abdel-Wahab, who leads a lab in MSK’s Human Oncology and Pathogenesis Program.

New Details about the Causes of Histiocytosis

The study revealed valuable information about the underlying origins of these diseases as well.

For example, doctors observed twins with histiocytosis. The investigators found that the common mutation driving the disease came not from the twins’ parents but from a mutation in the very early embryo that affected how their blood cells developed. These findings have implications for understanding how histiocytosis forms in many people.

Many of the patients whose data were included in the study were treated at MSK, but people treated at hospitals in Europe and other parts of the United States were included, too. Investigators from several other institutions were co-authors on the paper.

One way that the team was able to collect so many samples is through Make-an-IMPACT. This MSK initiative provides individuals with rare cancers the opportunity to receive genomic testing of their tumors at no cost. Histiocytosis is one of the cancer types included in this program.

“It’s very important that everyone who has histiocytosis gets their tumor sequenced,” Dr. Abdel-Wahab says. “It not only can help them but can also make important contributions to research.”

This work was supported by grants from the Histiocytosis Association, the Erdheim-Chester Disease Global Alliance, the American Society of Hematology, the Leukemia and Lymphoma Society, the Pershing Square Sohn Cancer Research Alliance, the Functional Genomics Initiative at MSK, The Society of Memorial Sloan Kettering, a Translational and Integrative Medicine Award from Memorial Sloan Kettering, the Geoffrey Beene Cancer Research Center at MSK, the Frame Family Fund, the Joy Family West Foundation, the Nonna’s Garden foundation, the Flanders Institute for Biotechnology in Belgium, and the National Institutes of Health (K08CA218901, UL1TR001857, P30CA008748, and 1R01CA201247).

This work was also supported by Cycle for Survival, MSK’s rare cancer fundraising program. Make-an-IMPACT is also funded by Cycle for Survival.

Dr. Abdel-Wahab has received grants from H3 Biomedicine and personal fees from H3 Biomedicine, Foundation Medicine, Merck, and Jansen unrelated to this manuscript.

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MSK Experts Report New Findings about Multiple Myeloma at the 2019 ASH Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 12/09/2019
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Multiple myeloma is a cancer that arises from the type of white blood cells called plasma cells. When normal plasma cells in the bone marrow develop certain genetic mutations, they may turn into myeloma cells.

At the annual meeting of the American Society of Hematology (ASH), held December 7 through 10 in Orlando, Florida, Memorial Sloan Kettering researchers reported on some of the latest advances in detecting and treating multiple myeloma.

A New Combination Therapy

One of those studies, led by MSK hematologic oncologist Ola Landgren, Chair of the Myeloma Service, is a phase II clinical trial looking at a new combination of drugs for those recently diagnosed with multiple myeloma.

In this trial, the participants had a targeted antibody drug called daratumumab (Darzalex®) added to a standard chemotherapy combination, called KRD, which is comprised of three drugs: carfilzomib (Kyprolis®), lenalidomide (Revlimid®), and dexamethasone (Ozurdex®).

“After someone completes treatment for multiple myeloma, the measure of how effective that treatment was is called minimal residual disease, or MRD,” Dr. Landgren explains. “MSK uses two very sensitive tests that can detect a single cancer cell in 100,000 or more plasma cells. If we can’t find any cancer, we feel quite confident the treatment has been successful.”

Among the 30 people who got the KRD-daratumumab combination, 77% of them were MRD negative after eight cycles of treatment. Based on cross-study comparison, the average level of MRD negativity seen with other therapies is 54% for those who get KRD alone, 58% for those who get KRD followed by an autologous stem cell transplant, and 59% for those who get a different chemotherapy combination called VRD-daratumumab followed by a transplant.

Daratumumab is currently approved by the US Food and Drug Administration for use in people who are unable to have transplants because of age or other health problems. Dr. Landgren says that based on these findings and other emerging studies, he thinks daratumumab could be used more widely.

Along with the biotech company Amgen, Dr. Landgren is working with the FDA to develop a large, randomized, multicenter clinical trial designed to evaluate KRD-daratumumab in comparison to the drug combinations that are currently considered the standard of care. He says that if the new combination is shown to be effective in a head-to-head comparison with current standard treatments, it could lead to wider approval of the drug.

“It’s too early to say that the addition of daratumumab to KRD, as a consequence of the high rate of MRD negativity, will result in an increasing proportion of newly diagnosed multiple myeloma patients opting for delaying their transplants, but it’s possible that may be the case,” he says. “Transplants are effective, but they are also associated with significant short-term as well as long-term toxicities, whereas side effects from daratumumab are quite minimal. The current phase II study is limited by small numbers and short follow-up, but the early results showing 77% of patients with no MRD are very exciting.”If we can

Learning How Multiple Myeloma Develops

Another important study looked at the early development of multiple myeloma. The disease is diagnosed in about 32,000 people in the United States every year, but experts estimate that by age 60 many more people — from 3% to 5% of the population — will have cells detectable in their blood that show signs of pre-myeloma.

These myeloma precursors can develop years or even decades before symptoms of the disease begin to develop. The symptoms include bone pain and frequent infections. Since the discovery of these early changes was made about ten years ago, the challenge has been determining who is most likely to develop the disease — and therefore should consider closer observation or possibly treatment — and those who don’t need to worry.

In the new research, an international group of investigators led by MSK hematologic oncologist Francesco Maura, a member of Dr. Landgren’s lab, developed a computational algorithm to understand when the first genetic driver of these pre-myeloma cells is acquired. Using genetic information from samples collected through two large, public databases, the researchers were able to reconstruct the life history of these blood cells long before the myeloma developed.

“We were quite surprised to find that many of the key changes associated with myeloma are acquired when people are in their 20s and 30s, even though the average age of disease onset is 63,” Dr. Maura says. “In this study, we developed a way to find the tumor cells’ mutation rate by looking at when the key drivers are accumulated and the degree to which they contribute to the formation of cancer.”

One of the main goals of this research is to understand who has a high risk of ultimately developing cancer so that it can be treated before symptoms start. “We also know that as it progresses, multiple myeloma develops additional mutations that make it more aggressive and harder to treat,” Dr. Maura says. “Ideally, we would want to eradicate the cancer when it is less complex.”

Dr. Landgren has received funding from the Leukemia and Lymphoma Society, the Rising Tide Foundation, the National Institutes of Health, the US Food and Drug Administration, the Multiple Myeloma Research Foundation, the International Myeloma Foundation, the Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm. He has received honoraria from and/or served on the advisory boards of Adaptive, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer.

In addition to the funding he receives as a member of Dr. Landgren’s lab, Dr. Maura also has received funding support from The Society of Memorial Sloan Kettering.

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Targeted Drug Shows Promise Against HER2-Positive Breast Cancer That Stops Responding to Other Drugs

Source: Memorial Sloan Kettering - On Cancer
Date: 12/11/2019
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About 15 to 20% of breast cancer that has spread (metastatic cancer) is driven by a protein called HER2. Drugs that target HER2 are a critical tool for bringing this form of the disease under control. Unfortunately, most cancers eventually stop responding to HER2 drugs and begin growing again. Because of this, many breast cancer experts are focused on developing new ways to target HER2.

At this year’s San Antonio Breast Cancer Symposium, which is being held December 10 to 14, Memorial Sloan Kettering medical oncologist Shanu Modi was part of a multicenter group that presented findings from a phase II clinical trial of an experimental drug targeted at HER2-positive metastatic breast cancer. Dr. Modi is also the lead author of a paper detailing the results from the trial, which was published December 11 in the New England Journal of Medicine. The drug is called trastuzumab deruxtecan or DS-8201a.

“There are already two great options for treating HER2-positive metastatic breast cancer, and these existing drugs can provide people with months or years of controlled disease,” Dr. Modi explains. “But once they stop working, there is no standard approach. Therefore, there is a lot of excitement around new HER2-targeting drugs.”

Delivering a Potent Dose of Chemotherapy

DS-8201a is a type of medication called an antibody-drug conjugate. It consists of two parts: an antibody called trastuzumab attached to chemotherapy. The trastuzumab antibody is designed to seek out the HER2 protein. When it finds it, it delivers its payload of chemotherapy directly to the tumor, sparing healthy tissue.

DS-8201a is not the first antibody drug-conjugate developed for breast cancer. A drug called ado-trastuzumab emtansine (Kadcyla®) works in the same way but carries a different chemotherapy drug. That drug was approved by the US Food and Drug Administration for metastatic breast cancer in 2013. Antibody drug-conjugates are used to treat other types of cancer as well, especially blood cancers.

“DS-8201a appears to work in people who have stopped responding to ado-trastuzumab emtansine,” Dr. Modi says. “One reason why is that DS-8201a has twice as many molecules of chemotherapy linked to each antibody. Additionally, the chemotherapy that’s attached has some unique properties that make it very effective.”

Another Approach for a Challenging Disease

In the phase II study, called the DESTINY01 trial, 184 patients received DS-8201a by IV every three weeks. The participants had previously received trastuzumab and ado-trastuzumab emtansine but had stopped responding to them. More than 60% of the patients responded to DS-8201a. That means their tumors either shrank or stopped growing.

The average time from when patients received the drug until the tumors started growing again was about 16 months. Although there was no direct comparison to other therapies in this trial, these results are much better than the responses seen with other treatments given at this stage of treatment, usually chemotherapy, Dr. Modi explains.

The common side effects from the drug were nausea and lowered blood counts, and these were easily managed with medication. However, a small number of people in the trial had a severe response: They developed a condition called interstitial lung disease, which means their lungs developed scarring, leading to difficulty breathing. This risk was first noted in the phase I trial.There is a lot of excitement around new HER2-targeting drugs.Shanu Modimedical oncologist

In this phase II study, because the doctors knew that this could occur, patients were monitored very carefully. Anyone who developed lung problems or other severe side effects was taken off the drug. However, four people in the phase II trial died from interstitial lung disease.

Based on the findings from this trial, three large, multicenter phase III trials are already underway. Two of them are open at MSK, including one trial for people with lower levels of HER2. Dr. Modi expects MSK to be one of the main hospitals to recruit people for the trial.

“This disease is so challenging to treat, and the responses we’ve seen so far are amazing,” she concludes. “I felt good every time I was able to enroll one of my patients in this trial.”

This study was funded by Daiichi Sankyo, the company that developed DS-8201a. Daiichi Sankyo and AstraZeneca were collaborators on the study.

Dr. Modi has consulted for or served on the advisory boards of Genentech, Carrick Therapeutics, MacroGenics, Puma, GlaxoSmithKline, Novartis, AstraZeneca, Seattle Genetics, and Eli Lilly. She has served on the Genentech Speakers Bureau. She has also received compensation from Daiichi Sankyo for advisory services.