Release date: 2017-08-02
summary:
For a long time, cancer has been defined by the tissue from which it begins to grow—lung, colon, and breast, and so on. However, on May 23, 2017, the FDA accelerated the approval of the world's first anti-cancer therapy that does not distinguish tumor tissue, indicating that the testing and use of anticancer drugs has undergone an epoch-making change. The approval of this broad-spectrum indication is for all individuals with specific genetic characteristics, regardless of which tissue the tumor cells are found in. Read on to learn how science and technology and drug development work together to achieve “personalized medicineâ€.
Credit: Yang H. Ku/C&EN/Shutterstock
In early 2013, Adrienne was diagnosed with ampullary cancer, a rare gastrointestinal tumor. For Adrienne, this is not a bad news of the unexpected blue sky. For nearly a decade, she has realized that her own genes are not good for her. Fortunately, she did not know that her genes also helped to point out the direction and method of healing.
Adrienne suffers from Lynch syndrome, a genetic disorder caused by a mismatch repair (MMR) gene that encodes proteins responsible for the discovery and repair of errors during DNA replication. Patients with Lynch syndrome have a 70% risk of developing colon cancer. Women with this deficiency are also at high risk of having endometrial cancer in the early stages.
Adrienne first heard of this syndrome at the end of 2004, when her sister was diagnosed with colon, ovarian and endometrial cancers, which are triads associated with Lynch syndrome. It turns out that Adrienne, her sister and their mother are carriers of the defective MMR gene.
Two types of chemotherapy were received in a year, and Adrienne responded to the onset of chemotherapy and later stopped responding. At this time, her oncologist suggested that she consider taking part in an innovative new drug trial at the Johns Hopkins Kimmel Cancer Center. Clinicians there are testing a drug called Keytruda that is involved in cancer patients with the same genetic defects as her.
Developed by Merck, Inc., Keytruda is a new cancer immunotherapeutic called checkpoint inhibitor that helps the immune system recognize and attack cancer cells.
Despite significant success in treating skin cancer and lung cancer, checkpoint inhibitors did not produce the same effect in colon cancer. Regarding why only a few colon cancer patients benefit, the Hopkins team has a theory: like Adrienne, these patients have defects in the MMR gene. The researchers convinced Merck to provide them with drugs and found a non-profit organization funded to open a clinical study to test their hypothesis.
Every two weeks, Adrienne took a train from her home in Larchmont, New York, to Baltimore, where she was infused with Keytruda.
In less than three months, she underwent a biopsy to assess whether the drug had its own immune system to increase horsepower to attack cancer cells. After the biopsy was completed, the surgeon came in and brought Adrienne an incredible message. Adrienne recalls, the doctor looked at her and widened his eyes and said, "Do you know, if no one tells me that you have ampullary cancer, I don't know at all, because nothing can be detected."
Adrienne is not the only patient who can experience this dramatic response from a doctor. Clinicians later reported that immunotherapy is applicable to a variety of cancers characterized by MMR deficiency or to conditions known as high microsatellite instability.
In clinical trials of 149 patients who did not respond to conventional cancer drugs, approximately 40% of colon cancer patients and 48% of other types of cancer patients had tumor shrinkage.
Luis Alberto Diaz, Jr., MD
“The results are unbelievable!†Luis Diaz, MD, who envisioned this clinical trial at Hopkins, is now the head of the solid oncology department at the Memorial Sloan Kettering Cancer Center. "Things never happen. I mean 80% of the ideas end in failure."
On May 23, 2017, based on Keytruda's strong clinical trial data, the US Food and Drug Administration (FDA) approved for the first time a broad-spectrum cancer therapy for patients with specific molecular characteristics. This “no organization†approval may be the most public example of how to redefine how to treat cancer patients.
Epoch! FDA today accelerates approval of the first anticancer therapy that does not distinguish tumor sources
Cancer treatment has always centered on the organs that the tumor produces - the lungs, breasts, colons, and so on. Even in this era of "personalized medicine", drugs that target genetic aberrations are still approved for specific organs. In addition, new drug development companies still need to conduct separate trials to demonstrate the efficacy of the drug in each organ.
Now, cheaper and faster gene sequencing is constantly updating its iterations, and with these new technologies, researchers are thinking and exploring cancer completely differently than before. With high technology in hand, they can more easily benefit patients with targeted therapy or cancer immunotherapy for patients with specific molecular structures.
A growing number of early and mid-term clinical trials, known as "basket studies," are moving beyond the primary organs and are suitable for anyone with specific genetic traits. Now that the FDA seems to accept a genetics-focused development path, experts predict that the field of cancer will shift significantly from the focus on tumor location.
The primary goal of organizing this approach regardless of organization is to make cancer drug development more efficient. Research beyond tumor location offers hope to speed up treatment options for patients such as Adrienne, who may not know they will benefit from the drug.
redefine
Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at the University of California, San Diego-Morgans Cancer Research Center, said: The FDA's approval of Merck's drug disintegration is a "watershed event" in the history of pharmaceutical research and development.
Razelle Kurzrock, MD
Dr. Kurzrock explained that oncology has been using Microscope observations to define cancer cells for many years, leading to today's organ-centric classification. Now, instead of just looking at the surface of the cell, oncologists are more likely to find out what makes it abnormal inside the cell.
“Scientifically, this is very reasonable,†Dr. Kurzrock said. "You are hitting a fundamental change that drives cancer, not the surface appearance of cancer." It is no longer a cure, but a cure.
Despite this, concerns about primary organs still exist, even as pharmaceutical R&D companies turn to drugs to prevent oncogenic genetic mutations found in many tumor types. Roy Baynes, MD, senior vice president of global clinical development at Merck, said: "The concept of precision medicine is actually working, but so far it is mainly limited to the field of cancer. The real hope is this mechanism-based approach. Can be more widely converted."
But the challenges abound. Although oncologists praised Keytruda's approval of the distinction between tumor sources, they also warned against over-rendering genetics as a panacea.
Igor Puzanov, MD, MSCI, FACP
Igor Puzanov, MD, director of early clinical trials at the Roswell Park Cancer Institute, commented: "This is definitely a step forward, but it is not a definitive solution for all cancers."
Dr. Puzanov and other cancer researchers see that the BRAF gene is a myriad of examples of drug development that does not distinguish tumor sources. BRAF mutations are ubiquitous in cancer, most commonly in melanoma, colon and thyroid cancer. When the BRAF inhibitor vemurafenib was discovered, the researchers hope that the molecule will kill any of the three cancer patients.
The result, no! Vimora, which specifically blocks the BRAF V600E mutation, performed very well in skin cancer. Roche received approval for the drug to treat melanoma in 2011, but few colon cancer patients responded to this drug. The researchers spent several years to understand the difference. Even if they put forward a reasonable theory, the inability of BRAF inhibitors to treat both tumors at the same time hinders the advancement of this field.
Dr. Kurzrock of UCSD believes that it is short-sighted to abandon the cancer therapy based on the BRAF “storyâ€. No cancer drugs are omnipotent. Even Wimola, only half of the BRAF mutant melanoma patients have an effect. For the other half of the patient, it is also necessary to block other mutations.
Colon cancer is no different, Dr. Kurzrock said, the key is to find out the other pathways involved so that you can try the right combination therapy. For example, the addition of an EGFR inhibitor to a BRAF inhibitor can cause a response in colon cancer patients.
Changing the perception of cancer in a medical institution means overcoming a mentality that lasts for decades.
“We live in a research world where we sequence 600 genes for each tumor. If you have breast cancer, not lung cancer, you will have a different diagnosis,†Dr. Wendy Winckler, Director of Next Generation Diagnostics, Novartis Institute for Biomedical Research Say. For example, patients with breast cancer usually do not test for EGFR mutations, a mutation usually found in lung cancer.
Wendy Winckler, PhD
In addition, it is easier for drug companies to obtain approval for melanoma patients, with 30-45% of patients having the BRAF V600E mutation, compared with only 1-2% of patients with non-small cell lung cancer. mutation. In order to conduct clinical trials in lung cancer, 100 patients need to be screened to find a patient who can be enrolled. "This has not happened before," Winckler said.
Welcome to the video released during the same period!
Transformation clinical trial
Clinicians hope to make drug development more efficient by changing the way some clinical trials are conducted.
Credit: Yang H. Ku/C&EN/Shutterstock
The availability of extensive screening is changing this paradigm. Dr. Joshua Bilenker, CEO of Loxo Oncology, said: "Historically, the speed of this drug development in the world is limited, mainly due to diagnosis." He pointed out that just five years ago, the cancer molecule driving factor could be tested. A generation of genetic sequencers does not even exist.
Joshua Bilenker, PhD
"The broad test is how to find something you don't even know what you are looking for," Dr. Bilenker said. This is where Loxo's most advanced drug, larotrectinib, targets rare mutations.
Loxo is developing larotinib as a treatment for any cancer patient with TRK gene fusion, and TRK gene fusion occurs when chromosomes divide and recombine in the wrong place. Loxo estimates that 1,500 to 5,000 patients who are newly diagnosed with advanced cancer each year carry TRK gene fusion, meaning that genetic errors occur in less than 1% of all cancers.
Latrotinib, which inhibits gene fusion, became a dazzling focus at the annual meeting of the American Society of Clinical Oncology held in Chicago last month. The researchers presented the results of a clinical study of 50 children and adults with TRK fusions with 17 cancer types, ranging from rare tumors to common colon and lung cancers. Surprisingly, 76% of patients had tumor shrinkage and the drug was still effective for a responsive patient after one year.
Dr. Bilenker said: "The real tumor-independent activity we have seen is a bit surprising for us. Loxo plans to apply for FDA approval for all patients with TRK fusion in early 2018."
Heavy: NTRK small molecule kinase inhibitor Larotrectinib data is gratifying, is expected to become the first "target basket"
Last month, the biotech company also began experimenting with the next-generation TRK inhibitor LOXO-195. Although many patients have demonstrated a sustained response to larotinib, cancer cells inevitably develop resistance to targeted drugs. LOXO-195 aims to overcome the resistance by locking the conformation of the TRK into a large loop.
Another company, Ignyta Inc., will also seek approval for TRK fusion drugs next year.
Ignyta uses a slightly different approach to its main compound, entrectinib, which blocks the fusion of TRK, ROS1 and ALK. It plans to gain approval for new drug approvals for TRK fusion and new drug approval for ROS1 mutant lung cancer patients by 2018.
Looking for signals
The development path of the organization chosen by Loxo and Ignyta is still a niche. Although several other large basket trials are underway, most are designed to find some signs of efficacy before the company enters a specific organ or tissue test. Of course, the researchers hope that some of these studies will reveal drugs with broad efficacy.
The National Cancer Institute (NCI) recently announced that it has sequenced 6,000 tumors as part of the Molecular Analysis for Therapy Choice (NCI-MATCH). The study began recruiting patients in August 2015 with the goal of matching any patient with a specific molecular characteristic of the tumor to one of 21 drugs or combinations of drugs.
Barbara A. Conley, MD
Barbara Conley, MD, associate director of the NCI Cancer Diagnostics Program, oversees the NCI-MATCH study. She said that so far, about 19% of the patients recruited have found a matching drug or combination of drugs, more than half of which have rare cancers.
The purpose of the trial was to find a signal that determines if the targeted therapy is effective. It remains to be seen that these signals are indicative of the widespread use in patients with co-mutations or the efficacy in specific organs. Dr. Conley said: "There will be some drivers that are so powerful that they can respond to a variety of tumors and benefit patients," but she expects a response to individual organs that may be more prevalent.
At the same time, Novartis has been running its so-called Signature trials for the past few years, similarly matching patients to one of the targeted therapies.
Richard Woodman, director of North American oncology clinical research at Novartis, said that since the launch of the signature trial in 2013, Novartis has studied more than 600 patients with 15 cancers and received a series of experimental compounds.
Next wave
Looking ahead, the researchers saw several opportunities for organizing drug approvals. Everyone points out that a high tumor mutation burden, a measure of the number of gene mutations in cancer cells, is believed to be associated with a positive reaction to checkpoint inhibitors such as Keytruda.
Researchers are also interested in exploring PARP inhibitors, which block enzymes that help repair tumor DNA, have been approved for the treatment of BRCA mutant ovarian cancer, and are widely and effectively resistant to all BRCA-mutated cancers. Ongoing trials to investigate whether breast cancer therapy targeting HER2 can be effective against other HER2 mutant tumors.
Dr. Bilenker of Loxo said: "In the future, extensive sequencing analysis will be used in almost all conventional cancer treatments to find any information that can help find the right treatment options."
The FDA seems to be paving the way for new ways to develop drugs based on genetics. Chief Executive Scott Gottlieb, MD, testified to the Senate Subcommittee last month that the agency will introduce a new policy this year, "will address the issue of targeted drugs and how to simplify drug development for rare diseases caused by genetic variation. These diseases all have similar genetic fingerprints, even if the clinical manifestations are slightly different."
Regardless of what happens next, patients with rare mutations such as Adrienne are grateful for the recent advances in pharmaceutical research and development. Adrienne stopped using Keytruda in April 2016 and has no tumor recurrence for more than a year. Given her genetic makeup, she knows that her cancer may be "returning." However, she is reassured that she can get help from approved drugs regardless of the disease.
This reassurance is not just about her own future. Adrienne has four daughters, three of whom have been tested positive for Lynch syndrome. She said: "I can face almost certain deaths, I have done it, and I will tell you that I am ready. But the fact that my child is in danger is the worst. Now, this is bad. The facts make drug trials and fabulous results more meaningful to me."
Reference material
Cancer, redefined (Author: Lisa M. Jarvis, Published: July 3, 2017)
Image source: original, company official website, etc.
Source: Medicine Age (Micro Signal DrugSNS)
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