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Cancer care enters a new, exciting phase, experts say.
New ways to win the war on cancer include novel methods of diagnosing and treating it. Here’s a look at some developments in the pipeline as well as ones that recently got FDA’s stamp of approval.
Comprehensive genomic profiling (CGP) tests analyze tumor tissue or blood samples for molecular changes in genes. Using next-generation sequencing technology to analyze DNA mutations, CGP can help match patients to available targeted therapies, immunotherapies, or clinical trial options.
CGP can be used to manage all types of advanced cancer, says Brian Alexander, MD, MPH, chief medical officer of Foundation Medicine, and associate professor of radiation oncology at Harvard Medical School, both based in Cambridge, Massachusetts.
Unlike single-marker assays that only test for a few cancer driving mutations, CGP can simultaneously test for mutations in hundreds of genes. Foundation Medicine’s FoundationOne CDx test, for example, can screen for changes in more than 300 genes and can match patients to potential targeted therapies, immunotherapies, or clinical trial options based on genomic insights for each individual’s cancer. “Using a single CGP test conserves tissue by avoiding sequential testing and reduces the need to take additional tissue biopsies,” Alexander says.
FoundationOne CDx incorporates multiple FDA-approved companion diagnostics in a single platform to guide personalized treatment decisions. Published studies demonstrate that advanced cancer patients have better outcomes on matched therapies.
Ezra is a novel artificial intelligence (AI) technology that can aid radiologists in detecting lesions or tumors on the prostate. “It is designed to help radiologists detect prostate cancer with additional accuracy, as well as streamline their workload,” says Azra Raza, MD, professor of medicine, and director of Myelodysplastic Syndrome Center, Columbia University Medical Center, and New York Presbyterian Hospital, both in New York City. “We plan to build additional AI for other organs, and ultimately create technology that can perform a full-body MRI scan.”
Ezra’s engineers created an AI algorithm to detect prostate cancer using MRI images from 346 patients obtained from a cancer imaging archive data portal. The AI uses advanced neural network architecture to learn from a radiologist’s assessment of prostate lesions on MRIs. “The AI can predict lesion locations that could be clinically significant cancers on images that it has not previously seen,” says Raza, who is on the board of medical advisors at Ezra and uses the technology.
In April 2019, a studypublished in the International Journal for Computer Assisted Radiology & Surgery showed that Ezra could detect lesions with 93% accuracy.
Arfolitixorin is a drug candidate being tested in a phase 3 clinical study across 80 sites in the United States and Europe as part of a first-line treatment regimen for metastatic colorectal cancer.
Arfolitixorin is the first pure form of a molecule called MTHF, an active ingredient that can improve standard chemotherapy’s effectiveness. MTHF helps prevent cancer cell growth by working with other chemotherapy agents to block DNA replication that’s needed to produce new cancer cells, says Karin GanlÃ¶v, MD, chief medical officer, Isofol Medical, a health system in Gothenburg, Sweden. Unlike existing chemotherapy additives, which are only effective in a small percentage of patients, MTHF can benefit almost everyone with advanced colorectal cancer who receives chemotherapy.
GanlÃ¶v says arfolitixorin is the first major innovation to the first-line metastatic colorectal cancer treatment regimen in decades. “For years researchers have unsuccessfully tried to produce pure MTHF, knowing that this molecule is necessary to improve chemotherapy’s effectiveness,” she says.
As the first treatment that someone with metastatic colorectal cancer would receive, the drug could potentially benefit a large number of people, GanlÃ¶v says. Arfolitixorin could also be used in other cancer types like gastric, pancreas, and head and neck cancers. In a previous study, patients had a greater than 30% reduction in tumor size from baseline when taking the drug.
KEYNOTE-671 is a phase 3 clinical study evaluating the role of adding immunotherapy to standard chemotherapy in high-risk patients with early stage lung cancer, prior to having surgery. Immunotherapy activates the patient’s immune system to allow it to successfully fight cancer. “Cancer cells have a cloak that allows them to hide from a patient’s own immune system,” says Dan Costin, MD, FACP, director, White Plains Hospital, Center for Cancer Care, White Plains, New York, which is a member of the Montefiore Health System. “Modern immunotherapy targets both cancer and immune cells, removes the cloak protecting the cancer cells, and exposes cancer cells to the immune system. This allows a patient’s own immune cells to eradicate the now vulnerable cancer cells.”
Preliminary data prior to starting the study suggested that treating these high-risk patients prior to surgery with both immunotherapy and chemotherapy resulted in the eradication of more than 90% of the cancer in the vast majority of patients treated. “This is an astonishing outcome, which is rarely seen in modern oncology,” Costin says.
“If these findings are confirmed in larger phase 3 studies, including KEYNOTE-671, then the landscape of cancer therapy may forever be changed,” Costin says. “Patients will require less aggressive surgical procedures, less toxic treatment protocols, and will have dramatically improved survival compared to historical expectations.” Similar phase III studies using comparable approaches to treatment are now ongoing in patients with triple negative breast cancer, kidney cancer, and head and neck cancer.
Non-Hodgkin lymphomas (NHLs) are divided into more than 80 subtypes. Diffuse large B-cell lymphoma (DLBCL) comprises nearly 30% of NHLs. Front-line therapy with a chemotherapy regimen called RCHOP can effectively cure about two-thirds of DLBCL patients, however the remaining patients either don’t respond or relapse soon after receiving it.
Polatuzumab is a novel targeted antibody-drug conjugate that has had impressive results in relapsed and refractory patients (R/R) with DLBCL who have failed to respond to standard chemotherapy. In a phase 2 study in R/R DLBCL patients with aggressive lymphomas, polatuzumab was combined with rituximab (an antibody therapy) and a less intensive chemotherapy called bendamustine. “The combination was well tolerated and showed tremendous response and survival rates,” says Manali Kamdar, MD, MBBS, assistant professor and clinical director of lymphoma services, University of Colorado, Anschutz Cancer Center, Denver, Colorado. Given this, the FDA granted accelerated approval of polatuzumab vedotin-piiq (POLIVY, manufactured by Genentech, Inc.) in June 2019.
Polatuzumab targets a protein called CD79b, which is expressed on most B cell NHLs such as DLBCL. Polatuzumab targets this protein, gets internalized, and releases a chemotherapy toxin which causes death of lymphoma cells. “The idea is to target cancer cells alone and spare normal fast-growing cells, thus decreasing toxicity without decreasing efficacy,” Kamdar says.
Spectrum Health in Grand Rapids, Michigan, is also having success treating R/R diffuse large B-cell lymphoma. Stephanie Williams, MD, division chief, Adult Blood and Marrow Transplant program, says CAR T-cell therapy, a type of immunotherapy, uses a patient’s own white blood cells to combat cancer cells. “Results have been so positive, that the FDA rapidly approved its use for adults with advanced lymphomas and children with acute lymphoblastic leukemia,” she says. CAR T-cell therapy is the first cellular immunotherapy approved by the FDA.
Specifically, T-cells are removed from a patient’s bloodstream and are genetically engineered with the Chimeric Antigen Receptor (CAR) gene to become “killer cells” directed toward the patient’s lymphoma. The engineered cells are infused into the patient in order to seek and destroy cancer cells.
Patients who undergo CAR T-cell therapy have tried other treatments that were unsuccessful. More than half of the patients treated with this therapy enter remission and retain it beyond 18 months. “With this type of lymphoma, no other therapy gives these types of results,” Williams says.
Researchers are investigating whether CAR T-cell therapy can be effective in treating other forms of cancer, such as multiple myeloma, and solid tumors of the lung, brain, breast, and colon.
In January 2019, FDA approved ibrutinib in combination with the drug obinutuzumab as a first-line therapy for newly diagnosed chronic lymphocytic leukemia (CLL) patients, making it the first non-chemotherapy combination for CLL. “This marks another advancement in the growing trend toward chemo-free cancer regimens,” says Lee Greenberger, MD, chief scientific officer for The Leukemia & Lymphoma Society.
Ibrutinib is the first of a category of drugs that target the BTK proteins found in several types of blood cancers including CLL, mantle-cell lymphoma, and Waldenstrom’s macroglobulinemia, a type of non-Hodgkin lymphoma. When they mutate, these proteins cause an overgrowth of cancer cells. These drugs suppress the activity of the mutated BTK protein and stop the signal for the cancer cells to grow.
These drugs are targeted therapies that attack cancer cells directly while sparing healthy cells from harm and they have fewer side effects. “For patients, this eases the physical and financial strains that are often tied to chemotherapy,” Greenberger says. “Patients can take a pill purchased at their local pharmacy and don’t have to visit a clinic to receive treatment.”
What the future holds
Cancer care has entered a new, exciting, and constantly-improving phase. “Decades of clinical research have finally begun to bear fruit, ushering in a surge in effective medications such as targeted antibodies, immunotherapy, and non-chemotherapy pills,” Kamdar says. “The eventual goal is to cure cancer.”
In order to do that, clinical investigators are trying to figure out mechanisms of tumor destruction which not only increase tumor killing, but do so without inducing undue toxicities to patients. “Themes gaining momentum and showing great promise in clinical trials are combining anti-cancer drugs, which are synergistic, effective as single drugs, and don’t have overlapping toxicities when used in combinations,” Kamdar says.
Cancer research is also focused on early diagnosis and detection of relapse. The concept of molecular detection of cancer is gaining traction in the form of minimal residual disease (MRD) monitoring in blood. MRD analysis at diagnosis, and tracking the tumor cell population during therapy and post completion of therapy to detect relapse, is being tested in several clinical trials. “This has great potential in managing some types of cancers like lymphomas,” Kamdar says.
Impact of large data sets
On another front, the availability of large amounts of real-world data and analytics will fundamentally change the way that cancer care is practiced. “Over the past few decades, the pace of information growth has rapidly increased,” Alexander says. “In the next few years the amount of data generated from multiple sources will increase exponentially, and the availability of increasingly large data sets from which to learn will grow in parallel.”
Molecular profiling, including CGP and the ability to generate that data from blood, will be increasingly available, as will machine learning algorithms that can unlock hidden information in radiology datasets-which are now only seen as images through transformation and pathology images.
Alexander foresees a transition to more of a “learning health system,” where insights will be generated from observational data and essential trial elements such as randomization will become more embedded into clinical practice.
“Technology that enables the aggregation and interpretation of such volumes of information will allow for doctors and patients to make better decisions at the point of care, and regulators and payers to better understand the risk/benefit/cost implications of new therapies in specific populations much faster,” Alexander says.
Treatments for broader populations
While most current research efforts are invested in personalized and targeted cancer treatments, GanlÃ¶v believes the future of cancer treatment will also involve advancements in treatment that can be effective in broader populations affected by cancer.
“We're already seeing this with CAR T therapies, where the first-generation CAR Ts target selective cancer types, but next-generation CAR Ts use a novel approach that can be easily produced and administered to many cancer patients at once. This drug development mindset will be seen in other areas of oncology drug development as researchers look for ways to make tangible benefits for large cancer indications or for many cancer patients rather than a few,” GanlÃ¶v says.
DNA testing plays a greater role
In the future, Costin expects that most cancer diagnoses will be done by testing tumor cells’ DNA. Treatment decisions will be based both on the cancer’s origin and the DNA drivers of the cancer.
“Many cancers will be treated initially with neoadjuvant therapy (therapy that is given prior to surgery),” Costin says. “Neoadjuvant treatments will almost always consist of a combination of several treatment modalities, with a focus on immunotherapy and targeted therapy.” Over time, chemotherapy won’t disappear, but will become much less important as both immunotherapy and targeted treatments will most likely become more effective and be less toxic.
It’s an exciting time for cancer treatment development. Keep reading MHE to stay abreast of what’s on the horizon.
Karen Appold is a medical writer in Lehigh Valley, Pennsylvania.