Kratom: What Research Tells Us about This Controversial Supplement for Pain Relief

Source: Memorial Sloan Kettering - On Cancer
Date: 08/08/2018
Link to original
Image of article

In the past few years, a number of companies in the United States have begun selling an herbal product called kratom, mostly online. The product, sold as dried leaves or a powder in capsules, comes from a tropical tree that grows in Southeast Asia.

Proponents of kratom say that it acts as a painkiller and a sedative, among other effects. Some people believe it can treat opioid or alcohol addiction. But none of these benefits have been demonstrated in rigorous clinical trials.

Negative events associated with consuming products that contain kratom have been reported. Many of these cases were caused by long-term abuse. In addition, kratom products have been connected to recent outbreaks of salmonella that sickened about 200 people in several states.

Memorial Sloan Kettering neurologist and pharmacologist Gavril Pasternak is studying the active components of kratom to figure out what the herb does in the body. He’s collaborating on this work with medicinal chemist Susruta Majumdar, who was an assistant attending chemist at MSK and is now an associate professor at the Center for Clinical Pharmacology at the St. Louis College of Pharmacy and the Washington University School of Medicine.

Scientists believe that some of the ingredients naturally found in kratom may hold promise for developing new and better painkillers. These drugs could potentially have fewer side effects than those currently on the market.

How can a natural product become a medicine?

It’s not a crazy notion to think that a new drug could come from a tree. In fact, about half of all drugs sold today originated in living things, including plants, fungi, and bacteria found in the soil. These natural products include the heart drug digoxin, which is isolated from a flower called foxglove; the antibiotic penicillin, which comes from mold; and painkillers like morphine, which is made from poppies. Many cancer drugs are made from natural products too.

Natural products that are developed and sold as drugs may come directly from their source. They may also be created in the lab using chemical synthesis. Chemicals taken from living things may become the starting materials for making similar compounds. Chemists may alter naturally occurring molecules to come up with drugs that are more effective or have fewer side effects.

Can kratom block pain with less risk?

Like most herbal products that come from plants, kratom contains a mixture of many different chemical compounds. In 2016, Dr. Majumdar published a study in collaboration with Columbia University researcher Dalibor Sames showing that among the natural products found in kratom, two compounds activate opioid receptors in human cells — the same receptors activated by drugs like morphine and oxycodone, which are clinically used in the treatment of pain.

Later in the year, in collaboration with Jay McLaughlin of the University of Florida and MSK researchers Ying Xian Pan and Dr. Pasternak, Dr. Majumdar published another study, which reported that two compounds in kratom were more effective than morphine at blocking pain in mice. Their effectiveness was tested using what is called a tail-flick assay. In this assessment, a mouse’s tail is put next to something hot. The efficacy of the pain medication is determined by how many seconds it takes for the mouse to feel pain and flick away its tail.

Further investigations done in cells and mice determined how these molecules provided pain-blocking effects. “We found that these compounds are structurally different from drugs like morphine or fentanyl,” Dr. Majumdar says. “They bind to pain receptors in a different way.” Specifically, they act on the pathways that allow pain to be suppressed without acting on the pathways that suppress breathing. The addictive potential of the natural products found in kratom is presently being investigated and will soon be reported.

“This is a crucial safety issue since respiratory depression is responsible for overdose deaths from opioids,” adds Dr. Pasternak. He and Dr. Majumdar are continuing to work together to design novel drugs based on components in kratom that will be even more effective and safe.

The US Food and Drug Administration and US Drug Enforcement Administration are considering banning kratom. Scientists who study kratom say that such an action would effectively end their research because it would become exceedingly difficult to obtain and work with the compounds. Potentially promising leads for new drugs could be lost.

Can people with cancer take kratom now?

The type of kratom-derived drugs being developed by Drs. Pasternak and Majumdar are at least several years from being evaluated in clinical trials. But the experts in MSK’s Integrative Medicine Service who manage the About Herbs database frequently receive questions from people with cancer — as well as their doctors — about whether kratom as it is now sold is a safe and effective way to manage cancer pain. The database provides information about herbs and other complementary therapies that is based on scientific literature.

“A lot of people are interested in taking kratom for their cancer pain because they’re concerned about the addiction potential of traditional opioid drugs,” says pharmacist K. Simon Yeung, who manages About Herbs. “But right now, we don’t have enough information to know whether it is safe and effective for this purpose.”

“One problem with kratom is that it is a mixture of many different compounds whose levels can vary from preparation to preparation, making it quite difficult to determine what dose should be used,” Dr. Pasternak says. “People with cancer receive more effective and reliable pain relief with established painkillers.”

Dr. Yeung notes that concern about salmonellacontamination makes it even more important to avoid kratom products. “One FDA analysis found that half of all kratom products evaluated were contaminated,” he says. “Because chemotherapy and other cancer treatments can weaken a person’s immune system, getting one of these infections could be very serious.”

MSK doctors stress that people with cancer should not take any herbal substances without first discussing it with their healthcare team.

First Targeted Cancer Drug Approved Based on Mutation Rather than Tumor Type

Source: Memorial Sloan Kettering - On Cancer
Date: 11/26/2018
Link to original
Image of article

The US Food and Drug Administration has approved the drug larotrectinib (Vitrakvi®; LOXO-101) for cancers caused by a genetic mutation called a TRK fusion. This groundbreaking targeted therapy is the first to be developed and approved based solely on its effect on a specific genetic change in a tumor, regardless of where in the body the tumor originated.

The drug was approved for tumors that have spread to other parts of the body or that cannot be surgically removed. It is also approved for patients who have no other treatment options or whose cancers have progressed following other treatments.

“With this drug, we are seeing the true potential of precision oncology come to life,” says David Hyman, Chief of the Early Drug Development Service at Memorial Sloan Kettering. Dr. Hyman is the senior author of a study published in the New England Journal of Medicine (NEJM) in February on the effectiveness of the drug.

A Big Step Forward for Precision Medicine

The idea behind precision oncology is that people can be given drugs that target specific mutations driving their cancer’s growth. In other words, the same drug may work against many tumor types.

Until now, investigators have found that the effectiveness of a particular therapy can vary greatly depending on where the cancer started. This is true even in people whose cancers share the same mutation. Individuals with lung cancer may respond to a targeted treatment that has little effect for those with colorectal cancer, even if the tumors have the same genetic change.

This is what makes larotrectinib so exciting.

“In our research, we have not noticed a meaningful difference in response to larotrectinib with one tumor type versus another,” notes MSK medical oncologist Alexander Drilon, the first author of the NEJM paper. “In addition, it has seemed to work equally well in all age groups.”

The fact that the drug was tested in adults and children at the same time is significant. “Cancers driven by TRK fusion mutations are rare,” says Neerav (Neal) Shukla, who led the pediatric trial at MSK. “But because we sequence the tumor genomes of all of our pediatric patients, we are able to identify everyone who might benefit from this drug.”

A Lasting Response

In the NEJM article, Drs. Hyman and Drilon and their collaborators reported that the overall response rate to larotrectinib was 75%. At one year, 71% of the responses were ongoing, with 55% of people in the study remaining progression free, meaning that their disease had not advanced.

The paper combined three studies that involved 55 people in total. Within the group, there were 17 different types of advanced or metastatic tumors — including colon, lung, pancreatic, thyroid, and salivary cancers as well as melanoma and sarcoma — that had TRK fusion mutations. Patients ranged in age from four months to 76 years.

The most common side effects of the treatment were fatigue, dizziness, anemia, and shortness of breath, and they were not severe. The more serious side effects, which were much less common, included fever, diarrhea, sepsis, abdominal pain, dehydration, skin infections, and vomiting.

TRK fusions occur when one of three genes called the NTRK (pronounced “en-track”) genes becomes mistakenly connected to an unrelated gene. This error can lead to uncontrolled cell growth. Although the fusions are rare within most individual cancers, they do affect thousands of people each year.

Analysis with MSK-IMPACT™ can identify which tumors carry TRK fusions. Other similar tumor analysis tests can find these genetic changes as well.

A Milestone in Pediatric Cancer Care

Some of the rare cancers treated with larotrectinib in the study included pediatric diseases, such as infantile fibrosarcoma (a soft tissue tumor found in babies) and secretory breast carcinoma (a type of breast cancer sometimes found in children).

Developing more clinical trials for childhood cancers is the focus of MSK’s Pediatric Translational Medicine Program. This effort aims to build a wealth of early-stage trials focused on taking discoveries made in the lab and bringing them to patients. Working closely with the Early Drug Development Service, the experts in MSK’s Department of Pediatrics are seeking to take full advantage of the latest discoveries in molecular oncology.

“For decades, our pediatric patients have had access to the best care anywhere,” Dr. Shukla says. “Now, with the advances in genetic sequencing, we are coming into an age where we are finding similarities across different kinds of pediatric cancers. For example, we may find that the same mutation is driving both a leukemia and a brain tumor. In addition, because we treat all cancers in all age groups, we are poised to take advantage of these discoveries made in both adults and children.”

MSK’s Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) has also allowed MSK to take a leadership role in developing trials for pediatric cancers. The goal of POETIC, led by hematologic oncologist Tanya Trippett, is to promote the early clinical development of promising therapies for the treatment of children, adolescents, and young adults with cancer and related disorders. This includes basket trials for new targeted agents as well as new drug combinations.

New Opportunities for People with Rare Cancers

The development of larotrectinib was based on the concept of basket trials. These studies test therapies that act against tumors based on their mutations, regardless of where they develop. In addition to having a benefit for many people with common cancers, these kinds of studies also provide an important opportunity to test therapies for rare cancers, which are often underrepresented in clinical trials.

Although many of the studies’ participants had long-lasting responses to larotrectinib, a few became resistant over time when their tumors developed another mutation. The company that makes the drug, Loxo Oncology, has already designed a second drug called LOXO-195 to target this additional alteration. The company is working with investigators at MSK and other institutions to test this drug in people who have stopped responding to larotrectinib. A clinical trial is now open at MSK and is being co-led by Drs. Drilon and Hyman for adult patients. A trial for pediatric patients is being led by Dr. Shukla.

“As we develop more precisely targeted drugs, a large and diverse clinical trials program such as ours, with an integrated effort to characterize patients’ tumors in advance, is key. It allows us to identify an often small group of people for whom a striking benefit may be seen, as in the larotrectinib story,” says Paul Sabbatini, MSK’s Deputy Physician-in-Chief for Clinical Research.

Personalized Medicine 2.0: MSK Leads the Way in the Study of Drug Resistance in Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2018
Link to original
Image of article

Lung cancer was one of the first cancers that could be targeted by drugs aimed at specific mutations in tumors. Advances in genomic medicine and the molecular analysis of tumors can largely take the credit for this early progress. Unfortunately, that also means that people with lung cancer who were treated with these drugs were among the first to develop resistance. When a treatment that initially works stops working, it is called acquired resistance. Overcoming acquired resistance is one of the most critical challenges in cancer research today.

Memorial Sloan Kettering investigators are at the forefront of studying this problem. They are looking for ways to address acquired resistance. The methods they are considering include combination therapies that attack cancer on multiple fronts at the same time.

“We’re taking personalized medicine to the next level — version 2.0,” says MSK medical oncologist Helena Yu. “It’s not enough anymore to just look for a mutation and give everyone who has the mutation the exact same treatment. Many factors influence how people respond to therapy, and we’re trying to direct treatment in a much more specialized way.”

Is Treatment Resistance Inevitable?

About 20% of lung adenocarcinomas, the most common lung cancer in the United States, are driven by mutations in a gene called EGFR. This type of cancer is often found in people who have never smoked. The first targeted therapy to treat EGFR-driven cancer, called gefitinib (Iressa®), was approved by the US Food and Drug Administration in 2003. Since then, these drugs have become a conventional treatment. As a result, testing for EGFR mutations has become a standard part of diagnosis for advanced lung cancer.

Most people who take these drugs benefit greatly from them. Their tumors shrink measurably, leading to an improvement in some cancer symptoms, such as pain and shortness of breath. In addition, EGFR inhibitors are taken at home as pills and have few side effects compared with chemotherapy.

But the effectiveness of EGFR inhibitors is not long lasting. Although some people respond for years, the average time until the drugs stop working is 12 to 18 months. In some people, the drugs work for only a few months or not at all.

“Not all of the cells within a tumor are the same,” Dr. Yu says. “Even if 99% of the cells respond to an EGFR inhibitor and die off, the ones that don’t die will eventually become dominant and start to take over. Also, because cancer is a living thing, it has the ability to evolve and adapt while being exposed to treatment.”

Finding Genetic Markers for Resistance to Targeted Drugs

When people with lung cancer stop responding to an EGFR inhibitor, their MSK doctors are ready with an arsenal of other treatments. Many patients have a second biopsy. The resistant tumor is then analyzed with MSK-IMPACT, a test that looks for more than 400 mutations that are known to play a role in cancer.

“Sometimes we find a mutation that wasn’t there the first time we analyzed the tumor. That may suggest that there are other targeted drugs to try,” Dr. Yu says. But other acquired changes, such as changes that don’t affect genes’ sequences, are not detected with MSK-IMPACT.

“Genomic sequencing of tumor tissue is part of the story, but not the whole story,” she adds. “We’re working on additional tests that can detect other kinds of molecular changes.”

MSK investigators are also developing liquid biopsies. These tests could allow doctors to analyze the molecular changes in a tumor with a blood test rather than having to take samples of the tumor from the lung.

Combining Targeted Therapies for a One-Two Punch

MSK already has clinical trials underway to address some of the acquired mutations commonly seen in lung cancer. One clinical trial combines a newerEGFR inhibitor called osimertinib (Tagrisso®) with an experimental drug called AZD6094. This second drug targets a mutation in the gene Met. About 20% of people treated with osimertinib eventually develop a Met mutation.

Another trial is looking at the combination of osimertinib and bevacizumab (Avastin®). Bevacizumab blocks the growth of a tumor’s blood vessels. Earlier research suggested that it is sometimes effective in combination with EGFR inhibitors.

Researchers have found thatEGFR inhibitors can drive some adenocarcinomas to transform into small cell lung cancer, a type of lung cancer that is treated with different drugs. And so another trial is testing osimertinib in combination with the chemotherapy drugs typically used to treat small cell lung cancer. This trial is open to people whose tumors carry genetic mutations that make their cancer more likely to transform. “We’re always trying to stay ahead of the curve,” Dr. Yu says.

Most people with EGFR mutations don’t initially respond to immunotherapy, but they may respond if the cancer develops additional mutations.

Dr. Yu emphasizes that combination treatments have more side effects than using EGFR inhibitors on their own. That is why it is important to carefully identify who is likely to benefit from these more aggressive drugs.

“Unfortunately, we can’t cure stage IV lung cancer as of yet, but the longer we can maintain people on treatments that are effective and have minimal side effects, the better,” she concludes. “We want to be able to stretch out the benefit for each treatment as long as possible while, at the same time, always having more options in our back pocket when we need them.”

Kirt’s Story: How a Clinical Trial for a Rare Tumor Gave Me a New Lease on Life

Source: Memorial Sloan Kettering - On Cancer
Date: 12/20/2018
Link to original
Image of article

When Kirt Robinson, now age 43, started feeling pain in his neck about three years ago, he thought that he’d pulled a muscle while working out. After three months of increasingly severe pain, he noticed a large bump near his collarbone and finally decided to see his doctor.

“I’m very stubborn. It took me a while to admit how bad it had gotten,” says the longtime Brooklyn resident and native of Guyana. “I couldn’t raise my arm over my head to put on a T-shirt. I couldn’t turn my neck. The pain was sometimes excruciating.”

His doctor ordered a needle biopsy of the tumor. When the results were inconclusive, Kirt was referred to a head and neck specialist for a surgical biopsy. His tumor sample was then sent to pathologists at Memorial Sloan Kettering for analysis.

Diagnosed with a Rare Tumor

The experts at MSK determined that Kirt had a desmoid tumor. Desmoid tumors, also called aggressive fibromatosis, are rare growths that usually occur in the arms, legs, or torso. Fewer than 1,000 cases are diagnosed every year in the United States. Most people who are diagnosed with a desmoid tumor are in their teens, 20s, or 30s, and the tumor is more common in women than in men, although experts don’t know why.

Desmoid tumors are a type of soft tissue sarcoma. Unlike most forms of sarcoma, they are not considered cancerous, as they don’t spread to other parts of the body like the lungs, liver, and other organs. They can, however, cause severe pain and other symptoms and may be life-threatening depending on their location.

When surgically removed, desmoid tumors often come back. If surgery is not possible or requires something drastic, like an amputation, a variety of treatments are used. These include hormonal therapies and traditional chemotherapies. Because desmoid tumors are so hard to treat, MSK researchers have focused on new approaches, such as targeted therapies.

After the diagnosis, Kirt first saw a surgeon at MSK. He learned that his tumor was not operable because of its location next to critical areas, like nerves and blood vessels in his neck. His surgeon told him that he might be eligible for a clinical trial. After that, Kirt went to see MSK medical oncologist Mrinal Gounder. Dr. Gounder is an expert in desmoid tumors and other types of soft tissue sarcoma.

The Opportunity to Participate in a Groundbreaking Trial

Kirt was concerned about having chemotherapy, so he was happy to learn that Dr. Gounder was leading a clinical trial for a different kind of drug. The trial was the first to evaluate the use of a pill called sorafenib (Nexavar®) to treat desmoid tumors. Sorafenib is a targeted therapy that was originally developed to treat kidney cancer, but it is also known to block proteins that frequently drive the growth of desmoid tumors. Targeted therapies tend to have fewer side effects than chemotherapy because their activities in cells are more specific.

Kirt was one of 87 people to participate in the trial, the results of which are now being published in the New England Journal of Medicine. The phase III study reported that there was a benefit of more than seven-fold in people who took sorafenib compared with those who didn’t. The drug helped stop tumor growth for an average of nearly two years. Many of the patients had their tumors shrink significantly, including Kirt. People who didn’t get the drug in the first part of the trial were able to later receive it, and many of them benefited as well.

“Until now there hasn’t been a standard way to treat people with desmoid tumors, and there haven’t been many studies on them because it’s such a rare disease,” Dr. Gounder says. “As it’s become increasingly clear that surgery is not the best way to treat these tumors, the need to find different approaches has become more apparent.”

Dr. Gounder’s trial came about in an unconventional way. After he published a paper in 2011 describing a few patients with desmoid tumors who had been given access to sorafenib under a compassionate use program, he was contacted by the Desmoid Tumor Research Foundation, a patient advocacy group. The group’s leaders encouraged him to conduct a phase III trial and assisted with recruiting participants. The trial ultimately included people treated at nearly 25 hospitals in the United States and Canada.

Dr. Gounder says it is now up to Bayer, the company that makes sorafenib, to decide whether to apply to the US Food and Drug Administration to get the drug officially approved for desmoid tumors. Since its approval for kidney cancer, the drug has also been approved for liver and thyroid cancers.

A Return to Normal Life

Kirt is feeling much better since going on the drug, which he still takes. He needs some physical therapy to regain full mobility of his arm and hand, but he no longer has pain and is able to get restful sleep again.

The side effects from the drug have been minor and manageable. They include occasional rashes, high blood pressure, and diarrhea, all of which affected many other people in the trial. He has also experienced tingling in his hands and feet and changes in skin pigmentation.

He has returned to many of his regular activities, including participating in New York City’s annual West Indian Day Parade, of which he has been an active participant for many years. He’s even grateful to be able to do mundane chores again, like cleaning his bathroom.

“It’s by the grace of God that I found MSK and Dr. Gounder,” Kirt says. “It was really by happenstance that I stumbled upon the opportunity to participate in this trial, which has impacted me in such a positive way.”

Patient-Reported Side Effects: A Crucial Part of Cancer Clinical Trials

Source: Memorial Sloan Kettering - On Cancer
Date: 02/26/2019
Link to original
Image of article

Memorial Sloan Kettering researchers oversee hundreds of clinical trials every year. Some of the most exciting and potentially revolutionary studies look at brand-new drugs that are being given to people with cancer for the very first time.

Clinical trials investigate both the safety and efficacy of new treatments. One component of safety relates to side effects that impact the quality of life of the person getting the treatment. Symptom-based side effects — like fatigue, insomnia, and pain — often can’t be measured with a scan or a blood test yet are still significant.

Patient-reported outcomes are unfiltered reports directly from patients. They reflect the symptoms and experiences of people enrolled in clinical trials, and are considered the gold standard for documenting these side effects. Increasingly, the experiences of people in trials are helping shape how a new treatment is used and even whether it ultimately gets approved by the US Food and Drug Administration.

“People who participate in clinical trials are truly our partners in cancer research,” says Thomas Atkinson, of MSK’s Patient-Reported Outcomes, Community-Engagement, and Language Core. “It’s our duty to allow them to provide input into clinical decision-making processes.”

Collecting data on patient-reported side effects is a key part of clinical trials, explains clinical trials nurse Asia McCoy, who helps oversee the studies at MSK related to bladder cancer. “We stress to patients who are participating in clinical trials that they need to contact us if they’re experiencing any new symptoms, even if they seem insignificant or unrelated,” she says.

An Increased Focus on Patient-Reported Symptoms

Dr. Atkinson was part of a team funded by the National Cancer Institute (NCI) that developed a new system to make it easier for patients to report their treatment-related symptoms during clinical trials. In 2014, the team released an electronic platform called the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). It collects information about these symptomatic experiences. PRO-CTCAE is now used in the majority of NCI-funded trials.

“There’s been a shift toward capturing information about side effects directly from patients,” he explains. “It’s no longer considered acceptable for a clinician to assess how a patient is feeling without including input from the patient.”

Dr. Atkinson says the increased emphasis on survivorship is a big reason for this change. The primary focus of cancer treatment was once treating the disease almost at any cost, he notes. But as people are living longer with cancer and many are being cured of their disease, the short- and long-term side effects of therapy have become ever more important.

With Side Effects, Expect the Unexpected

With the boom in the development of cancer therapies, including newer treatments like immunotherapy and targeted therapy, the number of clinical trials conducted every year has grown. Every clinical trial must be approved and monitored by a hospital’s Institutional Review Board. This team of experts is responsible for protecting the rights and welfare of trial participants.

Until a new drug is given to a patient for the first time, however, researchers can’t always anticipate every side effect. Some symptoms may not be predictable even when researchers know which kinds of cells and tissues will be affected by the drug. Other side effects are not easy to measure in animal studies.

“The first time I meet with a patient, I review all of the possible side effects that we already know about,” says Lauren Kaplanis, a clinical trials nurse who helps manage many of the trials conducted by MSK’s Early Drug Development Service. “When it’s a new drug, we’re honest about the fact that we don’t always know what all the side effects will be.”

“Data about symptoms is important information for us to have,” Ms. McCoy adds. “It can propel a drug into the next stages of development, or it can shut down a protocol.”

An Emphasis on Open Communication in Cancer Trials

Dr. Atkinson, Ms. McCoy, and Ms. Kaplanis all worry that people enrolled in trials may be afraid to report side effects.

“They’re concerned they may have to make an extra trip to come see us,” Ms. McCoy says. “Or they think we’ll view them as complaining too much.”

Fear of being removed from a study may also be a factor, especially if the patient considers it their last chance for successful treatment.

“It’s human nature to worry that if you’re constantly reporting things like severe pain or nausea, you may get taken off a trial,” Dr. Atkinson says. “But trial participants need to understand that they have to report these things. If the drug eventually gets FDA approved, the doctors who are prescribing it need to know which side effects may occur, so they can help future patients.”

If a patient is experiencing a lot of symptoms when receiving a new drug, they may be able to continue receiving it, at a lower dose, for example, or they may take a temporary break, Ms. Kaplanis explains. “We want people to know about these opportunities for treatment, and we stress the idea of having an open dialogue,” she says. “We’re all on the same team.”

When a Cancer Therapy Stops Working: Experimental Drug Addresses Resistance

Source: Memorial Sloan Kettering - On Cancer
Date: 04/01/2019
Link to original
Image of article

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.”

Why Do Germs Become Resistant to Antibiotics? An MSK Program Is Focused on Avoiding this Problem

Source: Memorial Sloan Kettering - On Cancer
Date: 05/22/2019
Link to original
Image of article

The rapid emergence of drug-resistant microorganisms is “a global crisis that threatens a century of progress in health and achievement,” according to a recent report from the World Health Organization. Increasingly, experts have been sounding the alarm about the evolution of drug resistance. As a result, many common infectious diseases may become untreatable.

The best way to prevent microorganisms from developing resistance is ensuring that antimicrobial drugs are used properly. Memorial Sloan Kettering was one of the first hospitals in New York City to recognize and address this problem. In 2001, MSK established a program to oversee the use of antibiotics and other antimicrobial drugs. It has since served as a model for other cancer centers.

In an interview, Susan Seo, an infectious disease doctor who leads MSK’s Antibiotic Management Program, talks about how MSK is leading the way in ensuring that these drugs are used responsibly.

Why is a cancer hospital focused on antibiotic use?

Infections are a major complication of cancer treatment. We know that preventing and treating them improves patients’ overall health and outcomes.

People with cancer may be more prone to infections because of the underlying disease itself. They may also have weakened immune systems as a result of the therapy they’re receiving to treat the cancer. Subsequently, most people with cancer receive antibiotics at some point during their treatment.

Why is it important to ensure that antibiotics are used properly?

If people take antibiotics when they don’t need them, they may end up with bacteria that can resist those antibiotics. People who have infections due to antibiotic-resistant bacteria can have longer and more serious infections. They may have limited treatment options. And they can die from antibiotic-resistant infections. In addition, people who take a lot of antibiotics can develop side effects. These might include a rash or antibiotic-related diarrhea caused by the bacterium Clostridium difficile. So it’s important that antibiotics are prescribed to people only when they are truly needed.

I think of antibiotics as a precious resource. If we run out of effective antibiotics to treat or prevent infections for people with cancer, then giving chemotherapy or doing surgery becomes very high risk.

What is the role of the Antibiotic Management Program at MSK?

Antibiotic stewardship is a commitment to using antibiotics optimally and safely. My team includes infectious disease–trained clinical pharmacists. Together, we assist doctors and nurses at our hospital in ensuring that antibiotics are prescribed with the appropriate drug, dose, and duration. This allows the drugs to wipe out infections that have been diagnosed and prevent others from occurring. We want to ensure that antibiotics are stopped if there is no evidence of infection.

Members of the program are engaged in teaching our colleagues about antibiotic stewardship because it’s everybody’s responsibility to use antibiotics wisely. In this way, we can preserve them not just for today but for all the generations that come after us.

Can you give an example of how this program has made a difference in patient care?

The problem of antibiotic resistance is due to misuse or overuse of antibiotics. A common example is taking an antibiotic for a viral infection, such as the common cold.  

We recently did a collaborative study with our colleagues on the Lymphoma Service. We wanted to see how many of the people who had cold symptoms were getting antibiotics.

We then developed guidelines that describe the features of common upper respiratory tract infections, the diagnostic workup, and how to manage them. We used the Centers for Disease Control and Prevention’s recommendations for treating upper respiratory tract infections.

We educated doctors and nurses about this issue. The guidelines were posted in the workroom pods. We then looked to see if this made a difference. Happily, we found that the rate of antibiotic prescriptions for upper respiratory tract infections dropped. We recently presented this work at MSK’s Quality Improvement Fair.

My team is now pondering how to build on this work. One focus is keeping this effort going in lymphoma care. We are also thinking about adapting this approach for other outpatient clinics at MSK.

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
Link to original
Image of article

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 surgeryradiation, 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.

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

Source: Memorial Sloan Kettering - On Cancer
Date: 06/19/2019
Link to original
Image of article

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 colorectalbreastlung, 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.”

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

Source: Memorial Sloan Kettering - On Cancer
Date: 08/05/2019
Link to original
Image of article

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.”