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Immunotherapy Combination Is Better than Chemotherapy for Non-Small Cell Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2018
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A treatment that combines two specific immunotherapy drugs has already had success in some people with advanced melanoma and kidney cancer. A phase III study has now shown that the same combination was also effective for people with lung cancer. The international research team that conducted the trial was led by Memorial Sloan Kettering medical oncologist Matthew Hellmann. The findings are being presented at the 2018 American Association for Cancer Research (AACR) annual meeting. They are being published online in the New England Journal of Medicine as well.

The clinical trial was called CheckMate -227. It looked at combining nivolumab (Opdivo®) and ipilimumab (Yervoy®) to treat people with advanced non-small cell lung cancer, the most common type of lung cancer. The analysis being presented focused on people with a molecular marker indicating that there were many mutations in their tumors. Previous studies from MSK have suggested that tumors with many mutations are likely to respond to immunotherapy. After a minimum follow-up of nearly a year, those whose tumors had many mutations who received the immunotherapy combination were 42% less likely to have their cancer progress compared with those in the control group, who got standard-of-care chemotherapy.

“This trial had two important findings,” says Dr. Hellmann, who is a member of the Parker Institute for Cancer Immunotherapy at MSK. “First, it showed us that the combination of these immunotherapies together control lung cancer better than chemotherapy. Second, it showed that molecular markers are effective in helping to predict which people will benefit from immunotherapy.

“The results of this study highlight the importance of molecular profiling to identify the best treatment options for each patient,” he adds. “We are already doing this type of testing routinely for people with lung cancer, for example, with MSK-IMPACT™.”

Leading the Way in Clinical Trials

Ipilimumab and nivolumab are both in the class of drugs called immune checkpoint inhibitors. These drugs help control cancer by taking the brakes off the immune system. This allows the white blood cells called T cells to attack tumors. MSK physician-scientist Jedd Wolchok led the clinical research that resulted in the approval of ipilimumab in 2011 by the US Food and Drug Administration for the treatment of advanced melanoma.

Dr. Wolchok also led the pivotal clinical trial that resulted in FDA approval for the combination of ipilimumab and nivolumab in melanoma in 2015. Because that combination has worked well for melanoma, researchers decided to evaluate it for other cancers as well, including non-small cell lung cancer. Nivolumab on its own is already approved for this type of lung cancer, as well as for a number of other cancers.

Importance of Mutational Burden

Despite the striking success of checkpoint inhibitors at stopping cancer growth and even eliminating tumors in some people, these drugs don’t work for everyone. Research at MSK has focused on why that’s the case and looked for ways to predict beforehand who is most likely to benefit.

One important discovery that’s been made in many types of cancer is that tumors with a greater number of mutations tend to respond better to checkpoint inhibitor drugs than those with fewer mutations. This characteristic is called a high tumor mutation burden (TMB). In a related study, published online April 12, 2018, in the journal Cancer Cell, Dr. Hellmann and colleagues at MSK and elsewhere focused on the role of TMB in people with non-small cell lung cancer who were treated with nivolumab plus ipilimumab. The goal of study was to examine was to link the molecular features of the tumors to the patients’ outcomes after treatment with nivolumab plus ipilimumab in a phase I trial called CheckMate-012.

Based on their analysis, the researchers found that a high TMB was a good way to predict the effectiveness of combination immunotherapy in people with non-small cell lung cancer. The findings were used to guide the testing that was later done in the CheckMate -227 trial. TMB is already part of the results obtained from the MSK-IMPACT test.

A New Treatment Option for Non-Small Cell Lung Cancer

In CheckMate -227, among people whose tumors had a high TMB, the response rate was much better for those who got immunotherapy rather than chemotherapy. After getting the combination, 45% had their tumors shrink compared with 27% of those who got chemotherapy. And responses were distinctly durable with immunotherapy, where 68% were still responding to the immunotherapy combination one year after treatment started compared with only one-quarter of those who got chemotherapy.

The researchers say that immunotherapy is an important addition to the roster of treatment options for people with advanced non-small cell lung cancer. “This drug combination shows that some people can be spared treatment with chemotherapy,” Dr. Hellmann says. “And if a person stops responding to immunotherapy, they can still be given chemotherapy for additional benefit.”

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Findings from Two Patients Shed New Light on Drug Resistance in AML

Source: Memorial Sloan Kettering - On Cancer
Date: 06/27/2018
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Last summer, the US Food and Drug Administration approved enasidenib (Idhifa®) for the treatment of acute myeloid leukemia (AML). Enasidenib works differently than most cancer drugs. Rather than killing leukemia cells, it turns them into normal blood cells. Memorial Sloan Kettering hematologist-oncologist Eytan Stein led the pivotal clinical trial that resulted in the drug’s approval.

Now, a collaborative team of researchers is reporting that people who take enasidenib can develop resistance to it — and in a way never seen before. The findings are being reported in Nature.

“Everyone who studies precision medicine spends a lot of time thinking about why some people respond to certain drugs and why some stop responding or never respond at all,” says physician-scientist Ross Levine, who was one of the paper’s senior authors, along with Dr. Stein. “MSK has been one of the leaders in figuring this out.”

The discovery was made by a team of doctors, laboratory researchers, and pharmaceutical company scientists. They used cells from people who were being treated with enasidenib to uncover why the drug sometimes stops working. 

Targeting a Mutation Found in Several Different Cancer Types

Enasidenib is approved for people with AML that is driven by a mutation in a gene called IDH2. About 15% of people with AML have this mutation. IDH2 mutations and mutations in the related gene IDH1 are found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile-duct cancer.

The proteins made from mutated IDH genes can drive cells to become cancerous. MSK President and CEO Craig Thompson conducted much of the fundamental research on IDH mutations and their relationship to cancer. He is one of the co-authors of the Nature paper.

Researchers had previously shown that only one of the two copies of the IDH2 gene needs to be mutated to drive cancer. The other one is usually normal. In the new paper, the investigators report that when cells developed resistance to enasidenib, the additional mutations that allowed the cells to resist the drug occurred on the normal copy of IDH2.

This stands in contrast to how resistance develops against most targeted cancer therapies. In those cases, an already mutated gene develops an additional mutation that allows the cancer cell to fend off the drug’s effects. “The finding about IDH2 suggests that genetic resistance is more complicated than we thought,” says Dr. Levine, who is a member of MSK’s Human Oncology and Pathogenesis Program (HOPP).

Just two patients were in the study, but the investigators learned a great deal. Experiments with laboratory models allowed them to study how the mutations work. The findings suggest that some people may develop resistance to IDH inhibitors due to a mutation on the same copy of the gene that carries the cancer-causing mutation.

Dr. Levine says that this prediction was confirmed when the researchers identified a third patient being treated with a similar drug that targets a mutation in IDH1. The IDH inhibitor stopped working in this person when a resistance mutation appeared on the copy of the IDH1 gene with the cancer-causing mutation. This suggests that the process may be universal to all IDH-blocking drugs. “It’s a small number of people, but we’re quite confident that we’ll see this same mechanism in others moving forward,” he adds.

Targeting IDH mutations is a growing area of cancer drug development. Earlier this month, Dr. Stein was a co-first author of a paper published in the New England Journal of Medicinethat looked at another drug that targets the IDH1 mutation in people with AML. The multicenter phase I trial reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with the drug, ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected in people with this stage of AML and severe side effects were rare. The researchers plan to continue studying the drug in larger, placebo-controlled trials.

A New Biomarker for Drug Resistance

After the people in the study developed resistance, their tumors started growing again. Doctors were able to switch them to other drugs that worked in a different way, however, so they were not affected by the additional mutation. There are a number of other treatment options for people with AML. These include both FDA-approved therapies and experimental drugs being tested in clinical trials. Many people with AML ultimately receive stem cell or bone marrow transplants, which offer the opportunity for a cure. However, many people are not able to undergo transplants, which makes developing new drugs an important focus.

“Now that we know resistance to enasidenib can develop, we can start to monitor people for it by conducting blood tests,” says first author Andrew Intlekofer, who is also a physician-scientist in HOPP. “Over the course of therapy, we can use the protein as a biomarker for the formation of resistance. Then we’ll know we need to offer a different treatment.”

Far-Reaching Implications for Other Cancers

Understanding how resistance to enasidenib develops could lead to the development of additional drugs. Although, Dr. Intlekofer adds, more research is needed before new drugs can be identified. He also notes that the new discoveries about enasidenib could apply to other drugs that work in a similar way. Treatment of other cancers that are characterized by IDH1 and IDH2 mutations could be affected as well.

Dr. Levine highlights the importance of collaboration when conducting this kind of research. Working closely with scientists from Agios, the company that makes enasidenib, was of particular importance, he says. “To do this kind of work, it requires a great team. Everyone who worked on this study made important contributions. This work was one of the most satisfying research experiences I’ve ever had.”

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FDA Approves Ivosidenib (Tibsovo®), a Targeted Drug, for Acute Myeloid Leukemia

Source: Memorial Sloan Kettering - On Cancer
Date: 07/26/2018
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The US Food and Drug Administration has approved the drug ivosidenib (Tibsovo®) for the treatment of certain people with acute myeloid leukemia (AML) that has stopped responding to other therapies. Memorial Sloan Kettering hematologist-oncologist Eytan Stein was a co-leader of the study that led to the drug’s approval. The results of the trial were published last month in the New England Journal of Medicine (NEJM), and the drug was approved on July 20, 2018.

Ivosidenib is the first drug in a class called IDH1 inhibitors to receive FDA approval. It works in a similar way as enasidenib (Idhifa®), a drug approved in 2017 to treat AML that’s driven by a mutation in a related gene, IDH2. Both drugs represent a “new approach to treating cancer,” says Dr. Stein.

“Instead of killing cancer cells, like other leukemia drugs, it reprograms them and transforms them into normal, healthy, functioning cells,” he says.

About 10% of people with AML have mutations in the IDH1 gene, and another 15% have IDH2 mutations. These mutations are also found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile duct cancer. Targeting these mutations is a growing area of cancer drug development.

MSK President and CEO Craig Thompson led the basic science research that explains how IDH1 mutations drive AML, in collaboration with MSK physician-scientists Ross Levine and Omar Abdel-Wahab. The Peter and Susan Solomon Family Foundation supported that research, which was first reported in 2010. The investigators found that the mutations produce a cancer-causing enzyme called hydroxyglutarate (2HG). This enzyme stops the development of the blood cells called myeloid cells when they are in an immature form, which leads to leukemia.

Ivosidenib brings down the level of 2HG, so the blood cells can begin to develop normally again.

The NEJM study was a multicenter phase I trial that reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected for people with this stage of AML, and severe side effects were rare.

MSK Leukemia Service Chief Martin Tallman also participated in the study.

Ivosidenib and enasidenib are both made by Agios Pharmaceuticals.

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

Source: Memorial Sloan Kettering - On Cancer
Date: 08/08/2018
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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.

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

Source: Memorial Sloan Kettering - On Cancer
Date: 11/26/2018
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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.

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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
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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.”

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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
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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.”

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

Source: Memorial Sloan Kettering - On Cancer
Date: 02/26/2019
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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.”

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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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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
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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.