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Reality Check: Should People with Cancer Avoid Robotic Surgery?

Source: Memorial Sloan Kettering - On Cancer
Date: 03/08/2019
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On February 28, the US Food and Drug Administration released a statement cautioning about the use of robotic surgery in mastectomy and other cancer surgeries.

In the notice, Terri Cornelison, assistant director for women’s health in the FDA’s Center for Devices and Radiological Health, said that “the use of robotically assisted surgical devices for any cancer-related surgery has not been granted marketing authorization by the agency, and therefore the survival benefits to patients when compared to traditional surgery have not been established.”

Robot-assisted surgery is an extension of laparoscopic surgery, a minimally invasive approach that allows surgeons to perform operations using cameras and instruments inserted through small incisions. The robot adds improved vision and control to laparoscopic procedures. Its enhancements include the ability to see things in high definition and three dimensions as well as robotic arms that can be precisely controlled.

In an interview, Jeffrey Drebin, Chair of Memorial Sloan Kettering’s Department of Surgery, spoke about what this FDA advisory means for patients.

Why do you think this statement was released?

In November 2018, a study published in the New England Journal of Medicine and led by researchers from University of Texas MD Anderson Cancer Center reported that in women treated for early-stage cervical cancer, traditional open surgeries were associated with a lower risk of the cancer coming back compared with minimally invasive surgical procedures. This was true whether the surgeon used a robot or other laparoscopic techniques, so these findings were really not about the robot per se.

Additionally, more and more hospitals are beginning to use surgical robots. This is due in part to the trainings offered by the companies that make them. The FDA may have felt they needed to inform people on what is known about these procedures.

What are the potential benefits of robotic surgery?

For patients, the main benefit of the robot, or of any laparoscopic procedure, is smaller incisions. What comes along with these smaller incisions is the potential for less pain after the operation, less blood loss, a shorter hospital stay, and a quicker recovery.

But cancer surgery is very different from other operations that may be done minimally invasively, like a gallbladder removal or a hip replacement. With a cancer surgery, the size of the incision is not the most important thing for patients. The most important thing is giving patients the best chance of being cured of their cancer.

If that can be done with smaller incisions and less discomfort, then that’s a plus. But if the trade-off is a higher risk that the cancer will come back, that’s not a trade-off I would choose, or that most patients would choose.

What is MSK’s approach to using robotic surgery?

One of the questions the NEJM study didn’t look at was the experience level of the surgeons. It’s very clear that what makes the biggest difference in the outcome of any cancer surgery is the surgeon’s level of experience and training. If one of our surgeons offers a patient the option of robotic surgery, it’s because we have a really good idea that this is going to be better for that individual patient.

For many types of cancer, randomized, controlled trials that have shown that the outcomes for minimally invasive surgery are the same as open surgery in terms of cancer-related death. The trials also found that outcomes such as pain, bleeding, and length of hospital stay are often better. We’ve studied this in prostate cancer, colon cancer, lung cancer, head and neck cancers, and stomach cancer. For uterine cancer, outcomes for robotic hysterectomies are equivalent to open surgeries. We frequently offer robotic surgery to patients with many types of cancer when we believe it’s appropriate.

The FDA statement specifically mentions mastectomies performed with robotic techniques. MSK doesn’t currently offer this procedure, although some members of our team have talked about using it. Whether it ultimately turns out to benefit patients is something that would need to be studied in carefully designed trials over a period of time.

Why should someone choose MSK for cancer surgery?

Experience makes the biggest difference. The robot and other laparoscopic devices are really no different from a scalpel or a pair of forceps. They are all just tools.

The best surgeons use the right tool for the right case for each patient. They don’t simply use the same tool over and over. Surgeons at MSK are able to personalize the best approach for every patient because of the level of training and experience that we have with all of these techniques.

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Some People Who Need a Bone Marrow Transplant Will Never Find a Donor — and What Can Be Done about It

Source: Memorial Sloan Kettering - On Cancer
Date: 03/27/2019
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For many people who have leukemia, lymphoma, or certain other blood disorders, stem cell or bone marrow transplantation (BMT) offers the best chance of a cure. But only about 25% of people who need an allogeneic transplant — the type of transplant in which donor cells are used — have a sibling who is a suitable genetic match. The remaining 75% usually look to registries of unrelated adult volunteers to find a compatible donor.

A study from investigators at Memorial Sloan Kettering reports that for people of certain racial and ethnic backgrounds, finding an unrelated donor match can be difficult if not impossible. This is despite huge growth in the pool of volunteer donors who have joined these donor registries, to tens of millions in recent years.

“Our research demonstrates that many people will never find a matched volunteer donor from any registry because of their racial and ethnic background,” says lead author Juliet Barker, a hematologic oncologist who specializes in BMT. “For this increasingly large group of the US population, funding for research into alternative donor options such as cord blood transplantation is important. These other options can greatly expand access to transplantation for patients without a matched adult donor.”

Cord blood is collected from the umbilical cord and placenta of healthy newborns and donated by the baby’s parents at birth.

Finding a Matched Donor

The study, published in Blood Advances, followed 1,312 people treated at MSK between 2005 and 2017 who needed a BMT but did not have a suitably matched brother or sister. The patients were categorized by their racial and ethnic backgrounds based on how they identified themselves and their family history. Thirty-four percent had non-European backgrounds. This included patients of Asian, white Hispanic, African, Middle Eastern, and other mixed non-European descents.

“MSK is an ideal center to do this kind of study because our patient population is so diverse,” Dr. Barker says. “And this study is important as the US population is increasingly becoming more diverse: The problem of finding matched donors will impact more and more transplant centers all over the country.”

The researchers also reported that despite the notion that people of European descent can more easily find donors, many patients of southern European ancestry had diverse markers and therefore were not able to find a match. This includes people from places such as southern Italy and Greece.

The Science of HLA Matching

Stem cell donors and bone marrow transplant recipients must be matched for their tissue type. Specifically, the matching process looks at markers, or proteins, known as human leukocyte antigens (HLAs). HLA markers are inherited and allow the immune system to recognize which cells belong and which are foreign. Over hundreds of generations, humans in different parts of the world have acquired many different HLA genes. Some people, such as those from Africa, have very diverse HLA types.

A close HLA match is critical when transplanting blood and bone marrow–forming stem cells from an adult donor to a patient. This makes it difficult for people of certain races or mixed ancestry to find a match.

By contrast, cord blood transplants do not require a strict HLA match. Another important finding from the study was that cord blood was able to extend transplant access to people from a wide variety of racial and ethnic backgrounds.

Benefits of Cord Blood Transplants

Cord blood is a rich source of blood-forming stem cells. Like stem cells from adult donors, cord blood is obtained through donor registries. Dr. Barker is an expert in this type of transplant and leads MSK’s Cord Blood Transplantation Program.

A major advantage of cord blood is that the immune system of a newborn baby is not yet fully developed. This means that the match that’s required between the cord blood cells and the cells of the person receiving them is less strict.

Dr. Barker explains that for patients in need of a donor transplant who don’t have a matched sibling, MSK doctors can determine very quickly, based on the patients’ HLA markers, whether they are likely to find a match in unrelated volunteer donor registries.

She says this allows doctors to move very efficiently to alternative donor options for the transplant. “Timing is especially important,” she says. “Many patients will be too sick to have any kind of transplant if they wait too long.”

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When a Cancer Therapy Stops Working: Experimental Drug Addresses Resistance

Source: Memorial Sloan Kettering - On Cancer
Date: 04/01/2019
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In November 2018, the US Food and Drug Administration approved the targeted therapy larotrectinib (Vitrakvi®, also called LOXO-101) for cancers caused by a molecular change called a TRK (pronounced “track”) fusion. About 75% of people with this type of mutation initially benefit from the drug. Unfortunately, some of these people eventually stop responding to the drug, and their tumors start to grow again.

On April 1, 2019, at the annual meeting of the American Association for Cancer Research, an international team of researchers led by Memorial Sloan Kettering’s David Hyman presented results from the first phase I clinical trial of a related drug, LOXO-195 (also called BAY 2731954). LOXO-195 was developed specifically to treat people whose tumors have developed resistance to existing TRK inhibitors, like larotrectinib. Nearly half (nine of 20) of the people treated with LOXO-195 who had developed resistance to prior TRK inhibitors because they had acquired new TRK mutations responded. In another six, the tumors didn’t shrink but also didn’t grow.

“Responses to drugs that target TRK fusions, like larotrectinib, can be dramatic. But we know that acquired resistance can develop later, meaning that these patients will need new treatment options,” says Dr. Hyman, Chief of MSK’s Early Drug Development Service.

Blocking Cell Growth Driven by Gene Mutations

TRK fusions occur when a TRK gene and an unrelated gene become abnormally linked together. The result is uncontrolled cell growth. Although TRK fusions are rare, collectively they affect thousands of people who are diagnosed with cancer each year.

Precision oncology is based on the concept that drugs can be designed to target specific gene mutations that drive cancer growth. With this approach, the same drug may work against many tumor types. Larotrectinib was approved for any type of cancer that has a TRK fusion, in both adults and children. LOXO-195 appears to work on many kinds of TRK fusion-positive cancers as well: People with 15 different tumor types were treated in the trial.

LOXO-195 was designed by the company Loxo Oncology based, in part, on research from Dr. Hyman and his colleagues. This prior research found that in people who initially responded to drugs targeting TRK but who later stopped responding, two kinds of changes led to this acquired resistance. For some people, new mutations in the TRK fusion gene had developed, causing these tumors to be insensitive to prior TRK inhibitors. For others, the tumors found a way to grow without the continued need for the TRK fusion. LOXO-195 is designed to work with tumors that develop new mutations in the TRK fusion gene.

Longer-Lasting Results for Some People

In addition to the 20 people who were treated as part of the trial, another 11 received the drug through the FDA’s Expanded Access Program, which allows people who don’t have other treatment options and who cannot participate in clinical trials to receive experimental drugs. In total, 24 adults and seven children received the drug.

None of the people who had developed resistance to a prior TRK inhibitor and who didn’t have the additional mutations in the TRK fusion gene that LOXO-195 targets responded. “These findings were generally consistent with what we expected based on our biological understanding of how the drug works,” Dr. Hyman says. “While it is too early to say for sure whether LOXO-195 could be a meaningful treatment option for patients whose tumors don’t develop these new TRK mutations, these very early data suggest that more research is needed to determine the optimal treatment approach for these people.”

The most common side effects observed in the trial were dizziness, nausea, anemia, muscle and abdominal pain, fatigue, and a reduced number of lymphocytes (a type of white blood cell). Most side effects seemed to vary with the amount of drug given, with LOXO-195 being very well tolerated at lower to moderate doses. The side effects were reversible.

“This research shows the value of continuing to focus on precision oncology,” Dr. Hyman adds. “By studying patients after they develop resistance, we’ve been able to quickly develop additional drugs to extend the total benefit of this approach.”

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An Old Protein Gets a New Look: Researchers Target TGF-ß to Make Immunotherapy More Effective

Source: Memorial Sloan Kettering - On Cancer
Date: 04/05/2019
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The immunotherapy drugs called checkpoint inhibitors have transformed treatment for some people with cancer. Currently, a major focus in cancer research is looking for ways to make these drugs effective for a greater number of people and more types of cancer.

One of the many approaches that scientists are now studying is combining immunotherapies with drugs that block the actions of a molecule called transforming growth factor-beta (TGF-ß). The importance of TGF-ß was uncovered more than 30 years ago by Sloan Kettering Institute Director Joan Massagué.

“There has been tremendous interest in this new avenue of treatment,” Dr. Massagué says. “Right now, we have a serious opportunity to leverage the robust knowledge that we’ve built about TGF-ß and use it to make immunotherapy more effective. TGF-ß is actually a hormone that is released by cells. This means it is quite accessible to drugs that can block its activity.”

A Fundamental Molecule with Many Roles

TGF-ß is critical for regulating how cells function. It works by sending signals from a cell’s membrane to its nucleus, telling it which genes to make into proteins. Among the most important jobs of TGF-ß are directing embryonic development and regulating the immune system. It also plays a role in whether cancer spreads.

It is the effect of TGF-ß on the immune system that many researchers are now most interested in studying.

A study published in February 2018 in Nature reported that, in people being treated with the immunotherapy drug atezolizumab (Tecentriq®), levels of TGF-ß in tumors correlated with how well people responded. In short, the more TGF-ß that tumors had, the less likely it was that atezolizumab worked. This is because TGF-ß can prevent the immune cells called T cells from infiltrating and attacking tumors. Checkpoint inhibitors boost the activity of T cells, but if the immune cells can’t get into the tumor, they will not be effective.

Another study in the same issue of Nature reported that combining a TGF-ß-blocker called galunisertib with immunotherapy allowed the immune system in mouse models of colon cancer to attack tumors that it had previously not been able to go after.

“This research showed that TGF-ß prevents the incoming T cells from penetrating and infiltrating the tumor,” Dr. Massagué says. “If you block TGF-ß, however, T cells infiltrate and kill the tumor cells.”

Combining Approaches in the Clinic for Many Cancer Types

Several clinical trials now under way are looking at how to combine immunotherapy with drugs that block TGF-ß. MSK medical oncologist Anna Varghese is the co-principal investigator of one such trial for pancreatic cancer.

“Immunotherapy alone is not effective against pancreatic cancer for most patients,” Dr. Varghese explains. “This is because pancreatic tumors have an immunosuppressive microenvironment.” That means the cells and tissue around the tumor prevent immune cells from getting in and attacking the cancer.

Dr. Varghese’s trial combines the immunotherapy drug durvalumab (Imfinzi®) with galunisertib. The study is still ongoing, and it’s too early to know how effective the combination will be or what side effects it will have, but Dr. Varghese hopes to report preliminary findings soon.

Research on TGF-ß blockers goes beyond immunotherapy to look at their effectiveness when combined with other kinds of drugs. Recently, MSK medical oncologist James Harding was an investigator in a trial that looked at galunisertib, either alone or in combination with other drugs, for the treatment of liver cancer.

Early analysis of the study showed that when galunisertib was combined with the targeted therapy sorafenib (Nexavar®), people had more favorable outcomes compared with other treatments. However, Dr. Harding comments that “the design of this early study makes it difficult to say how impactful this combination strategy will ultimately be for liver cancer.

“Furthermore,” he adds, “with the advent of effective immunotherapy, the focus of the investigation has shifted to pairing galunisertib and other TGF-ß blockers with immune checkpoint inhibitors.”

Clinical trials focusing on TGF-ß blockers are ongoing at other cancer centers as well as at MSK.

Taking a New Look at a Familiar Target

“For a long time, drug companies have been interested in harnessing the power of TGF-ß blockers, not only for cancer but for other diseases as well,” Dr. Massagué says. “Until now, there’s been concern about doing that because we know that TGF-ß has so many different functions in cells.” Long-term use of these drugs, he explains, would have too many harmful side effects.

“However, combining a TGF-ß blocker with checkpoint immunotherapy and using it as temporary way to boost the effectiveness of these other drugs may be possible,” he concludes.

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How MSK Is Reducing Inequality in Cancer Care in Harlem and Beyond

Source: Memorial Sloan Kettering - On Cancer
Date: 04/17/2019
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On April 1, 2019, the Ralph Lauren Center for Cancer Care (RLC) officially became part of Memorial Sloan Kettering. Opened in 2003 as a partnership between MSK, the Polo Ralph Lauren Foundation, and the former North General Hospital, the RLC has served as a model for quality and equity in healthcare for residents of Harlem and surrounding neighborhoods.

We recently spoke with Lewis Kampel, an MSK medical oncologist and Medical Director of the RLC, about the center’s mission and his goals for its future.MSK Ralph Lauren Center.

Why was the RLC originally established, and what was MSK’s role?

The intellectual spark for the center came from Harold Freeman, a prominent African American cancer surgeon. He had begun noticing disparities in cancer incidence and outcomes in Harlem and the surrounding community. He was one of the first to bring this important topic to the public’s attention.

Dr. Freeman connected with fashion designer Ralph Lauren. At that time, through his foundation, Mr. Lauren was developing an interest in cancer research and access to care. The two of them joined up with Harold Varmus, who was then President and CEO of MSK. Dr. Varmus also felt strongly about reducing disparities in cancer care.

So MSK has been a vital part of the Ralph Lauren Center from the very beginning.

What changed this month?

Until now, the RLC has operated as a separate corporation, even though it was owned and controlled by MSK. Now that we have received approvals from the New York State Department of Health and other state agencies, it will operate more like MSK’s other outpatient facilities.

Could you talk more about the mission of the RLC?

The mission of the Ralph Lauren Center is to reduce disparities in cancer incidence and outcomes in the communities we serve. We do this by providing high-quality prevention, screening, and treatment services to those who might otherwise face challenges in getting them. The communities we care for may be underserved for a number of reasons. These include financial barriers and a variety of others.

It is important to emphasize that the mission and culture of the Ralph Lauren Center will not change. We will continue to provide high-quality care in a community-friendly atmosphere. As part of MSK, we will be able to tap into the expertise, experience, and technology available at a world-class cancer center.

What services are offered at the RLC?

When possible, we try to prevent cancer from developing in the first place. For example, we know that obesity is a risk factor for many cancers. So we offer nutrition counseling focused on healthy eating and weight reduction.

We also offer vaccinations for the human papillomavirus (HPV). This virus is associated with several cancers, including cervical cancer, anal cancer, and head and neck cancers. HPV vaccination can lower that risk. And of course, tobacco is another huge risk factor. We will be resuming a tobacco cessation program later this year.

If we can’t prevent cancer, we try to detect it early, when it’s more likely to be cured. Currently, we offer screenings for breast, cervical, lung, and prostate cancers, as well as periodic screening for skin and head and neck cancers. Eventually, we will offer screening for colorectal cancers as well. Later this year, the Breast Examination Center of Harlem will be moving into our space, which will help streamline the screening process.

For those diagnosed with cancer or certain blood diseases, we offer chemotherapy and other systemic therapies. We also have a breast surgeon on staff who can evaluate people with breast lesions. We refer those who require surgery or radiation therapy to MSK or other hospitals, depending on the patient’s choice.

Eventually, we hope to offer clinical trials to patients getting their treatment here. These studies are designed to determine the best treatment for a given cancer. Historically, people of African American descent have been underrepresented in clinical trials. Because of that, the conclusions of those studies may not apply to them.

What’s offered at the RLC that’s different from what people might get at other MSK outpatient locations?

We have several patient navigators, and they are key members of our team. Before patients even come for their first appointment, the navigators reach out to them to make sure that we have all the information we need from the referring doctor. Navigators can arrange things like transportation and child care, and help with financial and insurance issues.

We know that for breast cancer as well as other cancers, reducing the length of time between the initial diagnosis and the beginning of treatment can make a big difference in outcomes. So our navigators make sure that patients are seen here as quickly as possible after they receive a diagnosis and start treatment in a timely manner.

Good nutritional status is important for getting through cancer treatment, so our nutritionist provides advice on healthy eating. Many of our patients may not have access to healthy food, so our food pantry can provide food packages

Who are the patients treated at the RLC?

Our patients come from all over New York City, especially upper Manhattan, Harlem, and the Bronx, as well as Brooklyn and Queens. They also come from southern Westchester County and even parts of New Jersey. Many of them find it convenient to get their care here.

Roughly 40% of our patients are African American and 40% are Hispanic. Many of them speak Spanish. We’re also starting to see patients of West African descent who speak French. Our patients tend to be lower on the income scale and have other medical problems in addition to cancer.

Some of our patients don’t have insurance, and others are underinsured. We make every possible effort to treat anyone who needs our care.

How did you get involved in the center, and when did you become medical director?

I grew up in Newark, New Jersey, and at a very early age I became aware of how the experiences of poor people within the healthcare system were very different from the experiences of those who were not poor. I also came of age in the 1960s and was strongly influenced by the social justice movement.

When I joined MSK in 1993, I began focusing on prostate cancer. I soon became aware that men of African descent — African American men and Caribbean men — have a much higher risk of prostate cancer than men who are white. Their disease also tends to be more aggressive. About ten years ago, I began working with the consul general of Jamaica and members of the Jamaican community in New York to study these issues. Genetics play a role, but there may be other factors as well.

At about the same time, I was Chair of the Quality Assessment Committee at Memorial Hospital. Through that work, I became interested in the issues surrounding equity in care. Being able to offer high-quality care doesn’t mean much if that care isn’t available to everybody.

When the opportunity to lead the Ralph Lauren Center as medical director presented itself three years ago, I jumped at it. It is the perfect role for me. It allows the convergence of several issues I am passionate about.

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One Patient’s Exceptional Response Leads to a Surprising Discovery about Immunotherapy

Source: Memorial Sloan Kettering - On Cancer
Date: 04/30/2019
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Findings from a single person with cancer can kick-start a major scientific breakthrough. When one person benefits from treatment in an uncommon way, doctors call it an exceptional response. In this era of personalized medicine, exceptional responses offer clues about how a drug or class of drugs works.

In a study published online on April 22 by Nature Medicine, a group of Memorial Sloan Kettering doctors and scientists describes one such exceptional response. The research suggests that in some cancers, genetic changes called gene fusions can occasionally send signals that the immune system can recognize. These signals can boost the effectiveness of immunotherapy drugs called checkpoint inhibitors. Checkpoint inhibitors take the brakes off the immune system and allow it to attack tumor cells.

“This is a great reminder that despite what we know about how immunotherapy and other cancer drugs work, we’re far from understanding all the rules,” says physician-scientist Timothy Chan, one of the paper’s two senior authors.

“What we’ve learned from this one patient has opened a new door,” adds surgeon-scientist Luc Morris, the paper’s other senior author. “Our findings suggest a new way that the immune system can recognize and attack certain types of tumors. But we’re really just at the beginning of knowing how to apply this discovery and target these alterations. We are working on the next steps in the laboratory.”

An Unexpected Outcome

The exceptional response described in the paper was in a teenage girl with a head and neck cancer that had spread to her lungs. She initially saw Dr. Morris, a head and neck cancer surgeon, who began tests to genetically profile the tumor, saving samples in the hopes of learning more about her cancer in the future. She was then treated by MSK pediatric oncologist Leonard Wexler with chemotherapy, which kept the disease stable. When the cancer started growing again, Dr. Wexler decided to try the immunotherapy drug pembrolizumab (Keytruda®).

“Further chemotherapy was unappealing because of the side effects and the limited chance that it would be effective,” Dr. Wexler says. “We also knew that the tumor had some unusual features for a head and neck cancer. We decided to think outside the box about how to treat the patient.”

Only about 12 to 15% of head and neck cancers respond to drugs like pembrolizumab. An initial analysis of this patient’s tumor suggested that she was not likely to be one of them.

There were two reasons for this belief. For one, her tumor had very few mutations. It’s known that the more mutations a tumor has, the more likely it is to respond to checkpoint inhibitors. That’s because having a lot of mutations means a tumor is more likely to produce proteins called neoantigens, which the immune system recognizes as foreign. This discovery was first reported in 2014 by Dr. Chan and his colleagues.

Additionally, her tumor was “cold,” meaning it had little immune activity around the tumor cells. By contrast, tumors described as “hot” — with many immune cells interspersed among the tumor cells — are more susceptible to checkpoint inhibitors. Immune cells can more easily find and attack a cancer when they’re already in the vicinity.

Despite these factors, the girl’s cancer had begun to shrink within five months. After three more months, it had completely disappeared. The MSK team decided to take a deeper dive, studying the tumor in greater detail to figure out why.

A Focus on Neoantigens

After sequencing the entire genome of the patient’s tumor, the MSK team discovered it had a kind of alteration called a gene fusion. Gene fusions occur when a gene from one chromosome breaks off during cell division and attaches to a gene on another chromosome. This new combined gene can make a protein that drives cancer growth.

“The fusion that this patient had was totally unheard of, something that has not been seen before,” Dr. Morris says. “But this gene fusion is probably what caused her cancer.”

The researchers discovered that the protein created by the gene was a neoantigen. “Neoantigens are seen as foreign by the immune system. They’re something that doesn’t belong in the body,” says Dr. Chan, who is Director of MSK’s Immunogenomics and Precision Oncology Platform. “In this case, the neoantigen resulting from the gene fusion made the patient’s cancer susceptible to immunotherapy.”

Looking for Potential Benefit in More Cancer Types

Although this patient’s particular gene fusion was rare, other fusions are more common in certain cancer types. The investigators analyzed tumors from other people treated at MSK for a type of head and neck cancer with common fusions. They found that immune cells in these people were able to recognize tumor cells with these gene fusions.

“One of the things that our team is doing now is systematically going through every single gene fusion across human cancers and predicting which ones may result in neoantigens that can be seen by the immune system,” Dr. Chan says. “We expect these findings are going to apply broadly to many different types of cancer.”

The original patient completed treatment with pembrolizumab and has remained free of cancer. It has been more than 30 months from when she started immunotherapy.

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What Can Be Learned from a Negative Clinical Trial? Findings from a Sarcoma Study at ASCO 2019

Source: Memorial Sloan Kettering - On Cancer
Date: 06/02/2019
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At this year’s American Society of Clinical Oncology (ASCO) annual meeting, researchers from around the world have gathered to learn about the latest advances in cancer treatment. Much of the research being discussed highlights meaningful improvements in cancer care. At least one study, however, is attracting a lot of attention despite disappointing results.

That study, for advanced soft-tissue sarcoma, was called the ANNOUNCE trial. ANNOUNCE was a randomized study that compared a combination treatment of the chemotherapy drug doxorubicin and the targeted drug olaratumab (Lartruvo®) to doxorubicin on its own. The trial found that adding olaratumab to chemotherapy did not increase survival.

Based on an earlier report from this phase III study, Eli Lilly, the company that makes olaratumab, announced in April 2019 that it is withdrawing the drug from the market.

Memorial Sloan Kettering sarcoma expert William Tap led the ANNOUNCE trial as well as earlier studies on olaratumab. In an interview, he talked about why the findings from the study were disappointing and what’s next for sarcoma treatment.

What was MSK’s role in the research that led to olaratumab’s approval?

We led the phase II trial, which was published in June 2016. That study included 133 people with many subtypes of sarcoma. The participants were randomized to receive either olaratumab and doxorubicin or doxorubicin alone. All of the participants had advanced disease that had spread beyond the original tumor.

The average survival of people who got the combination was 26.5 months, compared with 14.7 months for those who got standard treatment, which was doxorubicin alone. Sarcoma is very hard to treat, and there are few good options once it has spread and can no longer be eliminated with surgery. The findings that olaratumab extended life for nearly a year were remarkable. We felt very hopeful based on those results.

The drug was given accelerated approval from the US Food and Drug Administration in October 2016 based on that study’s impressive results and the unmet need for sarcoma treatments. It also received conditional approval in Europe.

What are you presenting at ASCO this year?

These are the results from the follow-up phase III trial. The FDA required this study to confirm the benefit seen in the earlier trial. Unlike the earlier study, this one unfortunately was negative. Overall survival, which is how long someone lives after starting treatment, was not statistically higher in the group that got olaratumab.

Nearly three-quarters of new cancer drugs fail in phase III trials. But it’s much more unusual for a drug to fail a phase III trial after receiving accelerated or conditional approval.

Those of us in the sarcoma research community are still trying to understand why we saw such different results between the two trials. There are a lot of possibilities. It may be differences in the way the two studies were designed. It could also be the types of patients who were enrolled in the studies and the specific subtypes of disease that they had.

One thing that’s important to mention is that olaratumab didn’t add any serious side effects, compared with chemotherapy alone.

What did you learn from this study?

Sarcoma is a rare disease, and anytime you’re able to collect this much data on a rare disease, it’s going to be useful. There are not many large, multicenter studies on sarcoma. What we’ve learned will be helpful in our overall understanding of this disease. It will also help us design other clinical trials in the future.

One remarkable outcome was that the survival in the control group, those who got only doxorubicin, was higher than what we’ve ever seen in any other phase III clinical trial. Many of these patients did quite well, even without receiving any benefit from olaratumab. This is the third time in the past five years where a negative phase III study has shown such measurable improvements in the control arm compared with historical outcomes.

There are likely several reasons that these patients did so much better than expected. We think it’s because of overall advances in the way this disease is treated — including progress in surgery, radiation, and supportive care. There have also been improvements in treating particular subtypes as we increase our understanding of what drives them.

I can’t overstate the exceptional effort from everyone who worked on the phase II and phase III trials. For this trial, we were able to enroll and care for 509 participants at 110 hospitals in 25 countries.

Eli Lilly announced in April that it was removing olaratumab from the market. What will happen to people who are already taking the drug?

At MSK, we are not recommending that anyone start taking the drug. For those who are already taking it, we are phasing out that treatment.

There are some patients who perceive that the drug is helping them. It’s possible it is, since sarcoma is a heterogeneous disease and not all tumors behave the same way. But we don’t yet have enough insight to know which subtypes or disease characteristics may respond to olaratumab.

The drug company is working with people who have been taking the drug and, in some circumstances, will continue to provide it. The details are still being determined.

What else should people know about this research?

This shows the complexity of researching a disease like sarcoma, which is actually not one cancer but about 50 or 60 diseases. Each sarcoma has its own biology. It’s important for us to continue studying all these different types so that we can develop more-effective, personalized therapies.

I’m worried that what happened with olaratumab will negatively impact the development of other sarcoma drugs. Because sarcoma is less common than many other cancers, it’s already hard to get funding for it. Treatment is getting better, as our results for patients in the control group showed, but there is still a great need to find better drugs.

This is just the nature of science sometimes. There is no reason to give up hope.

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Ro Versus Musashi: How One Molecule Can Turn Cancer Cells Back to Normal

Source: Memorial Sloan Kettering - On Cancer
Date: 06/19/2019
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Since 2012, Memorial Sloan Kettering cancer biologist Michael Kharas has focused on studying a family of proteins called Musashi. These proteins play a role in acute myeloid leukemia (AML) as well as in many solid tumors, including colorectal, breast, lung, and pancreatic cancers. Musashi proteins function by binding to messenger RNAs. These molecules serve as a template for making proteins.

On June 19, 2019, in Nature Communications, Dr. Kharas’s team reported that they have identified a molecule that appears to block the function of Musashi-2. This protein plays a role in making cancer grow and spread. The compound appears to eliminate tumor cells in human cancer cell lines and in mice.

“This research provides a strategy for how to develop inhibitors for RNA-binding proteins,” says Dr. Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. “Historically, it’s been difficult to develop inhibitors to proteins that bind to RNA because of their challenging structural properties.

“We don’t think this particular compound will ultimately make it into clinical trials,” he adds, “but we now have a road map to guide us in future drug development.”

Turning Cancer Cells Back to Normal

This latest work builds on earlier research from Dr. Kharas’s lab, in which the investigators started with more than 150,000 molecules that could potentially block Musashi-2. They then developed a number of tests that could rapidly look for effective molecules in an automated way. Eventually, they settled on a molecule called Ro 08-2750, or just Ro for short.

In the current study, the team used structural biology to look at where Ro binds to Musashi-2. “Based on this research, we have an idea of where to start in designing additional molecules that could be used as drugs,” Dr. Kharas says. “We know the binding region and how the drug fits.”

Researchers know that Musashi-2 plays a role in how aggressive cancer is. The protein is present in more than 70% of people with AML. Solid tumors that contain a high level of the protein are more likely to grow, spread, and resist treatment. It appears that Musashi-2 allows cancer cells to continue growing and resist signals to die.

“Musashi-2 is required for cancer stem cells to survive,” Dr. Kharas explains. Cancer stem cells are cancer cells that have the ability to give rise to all types of cells within a tumor. “When Ro was added to AML cells in a dish, the cells became normal. They stopped growing and died.” The same effects were observed in mice that had AML

A Cooperative Effort among Several Labs

This research was possible due to collaboration among many different experts at MSK. The project was overseen by Gerard Minuesa, a postdoctoral researcher in Dr. Kharas’s lab.

SKI computational chemist John Chodera, SKI structural biologist Dinshaw Patel, and Yehuda Goldgur, Head of MSK’s X-Ray Crystallography Core Facility, helped determine the structure of the Musashi-2 protein and how Ro binds to it. SKI computational biologist Christina Leslie helped with the gene expression data generated from this research.

“Thanks to this study, we’ve shown that it’s possible to develop drugs for these difficult targets,” Dr. Kharas concludes. “It provides a path forward for future work, so we can eventually develop drugs that can be tested in clinical trials in people with cancer.”

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Research Clarifies How IDH Mutations Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/01/2019
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A family of genes called IDH are associated with cancer. These genes make enzymes called isocitrate dehydrogenases. The enzymes help break down nutrients and generate energy for cells. Mutations in IDH genes prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become.

When cells can’t differentiate properly, they may begin to grow out of control. Scientists are still learning about what controls this process.

Now a team of researchers working in the lab of Memorial Sloan Kettering President and CEO Craig Thompson have made discoveries about how this malfunction occurs, at least in test tubes. Although the work is still in an early stage, they hope their findings will eventually contribute to new approaches for developing cancer drugs.

“Although IDH mutations are not very common overall, there are some diseases where these genetic changes contribute to a significant portion of cases,” says Juan-Manuel Schvartzman, a postdoctoral fellow in the Thompson lab, an instructor in the Gastrointestinal Oncology Service, and the first author of a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). “For these subtypes of cancer, better targeted therapies are needed.”

IDH mutations are found in about one-quarter of people with acute myeloid leukemia (AML), the most common type of leukemia in adults. They may also be found in a type of bile duct cancer called cholangiocarcinoma, a bone cancer called chondrosarcoma, low-grade glioma, and some kinds of lymphoma. The mutations occur much less frequently in more common cancers, such as colon cancer, breast cancer, and lung cancer.

Deciphering Underlying Changes

To learn more about how IDH mutations block differentiation, the investigators studied them in the context of a well-characterized model: cells called fibroblasts that can be coaxed to become muscle cells. By figuring out how the mutations prevent muscle cells from forming properly, the team aimed to get at the underlying defects in cells that these mutations cause.

Earlier research showed that IDH mutations influence cells through epigenetic changes. Epigenetics involves changes in gene expression that do not cause changes in the DNA sequence. Many of these have to do with the way DNA is packaged in the nucleus of a cell. The strands are wrapped around spool-like proteins called histones. Small chemical groups attached to DNA and histones — including fragments called methyl groups — can affect how DNA is spooled. Ultimately, this can influence how and when genes get made into proteins.

Specifically, IDH mutations lead to the formation of a molecule called 2-hydroxyglutarate (2HG). This molecule, in turn, can block the removal of methyl groups.

In the PNAS paper, the investigators dove deeper into the specific epigenetic changes caused by IDH mutations. “What we found was that they didn’t have much to do with DNA methylation, which is what we previously thought,” Dr. Schvartzman says. “Instead, they were related to methylation on histones.”

This change affects how the DNA strands are wrapped around histones. When they are tightly wrapped, it can prevent certain regions of DNA from being accessible. This can affect which genes get made into proteins.

Expanding the Development of Drugs

There already are drugs that are approved to work in AML caused by IDH mutations. Ivosidenib (Tibsovo®) targets IDH1, and enasidenib (Idhifa®) targets IDH2. Both of these drugs prod cancer cells into differentiating normally. But investigators say that there are many more avenues to be explored for new drugs that work against IDH-mutant cancers.

“I’m very interested in looking not just at tumors that are IDH mutant but more broadly at how these cellular changes affect the ability of those cells to differentiate,” Dr. Schvartzman says. “In addition to the buildup of 2HG, there are other changes in the cell that may prevent methyl groups from being removed from histones. We want to study those as well.

“It’s a little early to talk about how this could be applied to new drugs,” he concludes. “But one thing that’s exciting is the ability to understand more about how cells are wired and how different cellular changes affect levels of methylation. There are many enzymes we can start to explore that could be interesting for new cancer drugs.”

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FDA Approves Pexidartinib, a Targeted Therapy for a Tumor of the Joints

Source: Memorial Sloan Kettering - On Cancer
Date: 08/05/2019
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On August 2, the US Food and Drug Administration announced that it had approved pexidartinib (TuralioTM) for certain people with tenosynovial giant cell tumor (TGCT). It is the first drug approved specifically to treat this rare tumor of the joints.

Memorial Sloan Kettering medical oncologist and sarcoma expert William Tap led the clinical trials for this drug. The results of a phase III study were published in June 2019 in The Lancet.

“For the right patient, this is a drug that can really help,” Dr. Tap says. “However, because of the potentially serious side effects, it’s important to consult with doctors who understand this disease and this drug.”

A Valuable Drug for a Debilitating Condition

TGCT, also called pigmented villonodular synovitis (PVNS), is not considered a cancer because it doesn’t spread to other parts of the body. But it is a condition that can be painful and debilitating. It most often affects the knees. The disease is most often treated with surgery. If it continues to come back, people with the condition may run out of treatment options.Tenosynovial giant cell tumor (TGCT) is also called pigmented villonodular synovitis (PVNS).

In the phase III study, which enrolled patients in the United States, Europe, and Australia, 120 people were randomized to receive either the drug or a placebo. After nearly six months, 39% of people who got the drug had a measurable response, meaning that their tumors got smaller. Many of those who responded to the drug had noticeable improvements in range of motion and a reduction in pain in the affected joint. No one who received a placebo had any measurable response.

The drug is a targeted therapy that works by blocking a protein called colony-stimulating factor 1 kinase. This protein drives the development and growth of these tumors.

Pexidartinib is approved for people who can no longer have surgery for their tumor, or who are trying to avoid amputation. Because the drug can cause liver damage, the FDA did not approve pexidartinib for people who can be treated surgically or if the tumor is not seriously affecting a person’s quality of life.For the right patient, this is a drug that can really help.William D. TapMedical oncologist

“Unfortunately, this drug can cause a specific type of liver toxicity called cholestatic hepatotoxicity,” Dr. Tap explains. “It’s exceedingly rare, but when it occurs, it can be very dangerous. It’s important that people who get the drug are treated somewhere where they can be closely monitored for liver problems.” He explains that for this reason, only certain pharmacies will be able to dispense the drug, and doctors will have to go through a certification process before they can prescribe it.Back to top 

Meaningful Improvements for a Neglected Condition

Despite the warnings, Dr. Tap says the approval of pexidartinib is an important breakthrough that can lead to meaningful improvements in many people’s lives.

“TGCT has been neglected by much of the medical community and the pharmaceutical industry for a long period of time,” he notes. “Even though it’s rare, it has a relatively high prevalence. This is because it tends to first affect people when they are in their 20s and 30s. If it can’t be successfully treated with surgery, they have to live with it for the rest of their lives. So there are a lot of people out there who are coping with this disease.”