OR WAIT null SECS
Experts say a cancer care revolution is here. Here’s a closer look at some advancements in cancer treatments to watch.
The National Cancer Institute reports that each year, approximately 1.6 million people are diagnosed with cancer in the United States. According to the National Institutes of Health, spending on cancer care has now reached $156 billion and is projected to grow to $174 billion by 2020 at the current pace.
“Expenditures for cancer care are projected to skyrocket because the trend for treating these patients involves personalizing therapies,” says James P. Thomas, MD, PhD, medical director, Cancer Clinical Trials Office, and associate director, Translational Research, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. “The newest products and discoveries are often for small niches of patients, and treat genetically-defined populations. Therefore, the same economies of scale are not the same as treatments of the past. In fact, the initial cost of some personalized treatments can exceed $25,000 a month for many patients.”
Another reason oncology care is so expensive is the high cost to develop drugs. For example, individual immunotherapy drugs can exceed $100,000 annually for melanoma, lung, bladder, and other cancers given their clear survival advantage to standard approaches, says Santosh Kesari, MD, PhD, neuro-oncologist and chair, department of translational neurosciences and neurotherapeutics, John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California. Another pricy example is Novartis’s chimeric antigen receptor T cell (CAR-T cell) personalized genetic immunotherapy treatment for leukemia Kymriah (tisagenlecleucel), which was FDA approved in August 2017 at a cost of $475,000 for a one-time treatment.
“We now stand at the threshold of the beginning of precision-based therapies designed to interact with specific targets,” says William DeRosa, DO, FACP, chief of oncology, Summit Medical Group MD Anderson Cancer Center.
It’s also becoming more evident that what was once thought to be a single tumor type might actually have multiple, simultaneously existing and genetically unique tumor cells. This has been found in subtypes of adenocarcinoma of the lung, in addition to many other malignancies such as multiple myeloma, DeRosa says.
Researchers are gaining an appreciation for how dynamic subclone variability is-including the fact that it can drive and is responsible for tumor progression. “This, coupled with a deepening understanding of the role that the microenvironment plays, along with the use of various biomarkers, is quickly becoming the best way to identify the most effective therapy for each patient,” DeRosa says.
One approach that has greatly enhanced the understanding of the biologic underpinning of cancer is genomic sequencing. “The many companies providing this testing commercially have made it a powerful clinical tool in making therapeutic decisions by providing the ability to identify actionable mutations that can be exploited by the many targeted therapies that have been developed,” DeRosa says. For example, the discovery of EGFR, ALK, and ROS-1 mutations in non-small cell lung cancer allowed for the development of oral small molecule targeted therapies.
Here’s a closer look at some advancements in cancer treatments to watch, beginning with immunotherapies such as checkpoint inhibitors and CAR-T cells. “These agents result in the ability to unleash the power of the patient’s own immune system against their cancer in a way not previously possible,” DeRosa says. Other advances include precision oncology and biomarkers.
Advancements in immunotherapy are ongoing. This therapy entails taking immune cells from a patient, genetically reengineering them to attack the cancer, and then reinfusing them back into the patient. “Immunotherapy shows great promise in treating blood cancers,” Thomas says. “But considerable research still needs to be performed to see if this will be effective in treating solid tumor cancers like breast and lung cancer.”
Recent discoveries in immunotherapy research have shed light on how cancer cells turn off the immune system, which can allow cancers to grow and spread unchecked. “We’re using this knowledge to block the shutdown of patients’ immune systems using new checkpoint inhibitors,” explains Thomas. Checkpoints are parts of certain immune cells that need to be inactivated to start the protective response. “This allows the immune system to get back into the ballgame and fight the cancer. Considerable work remains on the best way to use these agents and how to best combine them with existing therapies.”
Initially studied in melanoma, DeRosa says checkpoint inhibitors are now rapidly expanding to treat many other cancer types, having been FDA-approved in the treatment of non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, and urothelial carcinoma.
Response rates have been impressive. Patients with advanced melanoma, for example, now have a greater than 30% chance of five-year survival with combination immunotherapy, which was unheard of in the past, Kesari says.
David Parda, MD, chair, Allegheny Health Network Cancer Institute, Pittsburgh, Pennsylvania, says checkpoint inhibitors such as Opdivo (nivolumab) are giving new hope to cancer patients. New therapies targeting the immune system are emerging regularly, with more expected in the coming year.
“Our task now is to expand on the promise of immunotherapy by investigating why some patients respond dramatically to these therapies, yet most do not,” he says, adding that the network and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins are collaborating on research and a clinical trial that will examine how Opdivo can be used most effectively for patients with esophageal cancer, an aggressive and highly lethal cancer. “Answers may lie in the individual tumor’s genetic makeup, in the combination of immunotherapy with standard therapies, or even in the timing of therapies.”
Michael V. Seiden, MD, PhD, senior vice president and chief medical officer, The US Oncology Network and McKesson Specialty Health, The Woodlands, Texas, points out, however, that at this time checkpoint inhibitors only offer a clinically meaningful response in a minority of individuals-for most tumor types it’s only effective in 15% to 20% of patients. “These drugs cost about $15,000 a month, so identifying the subset of patients who will have a great response is a high priority,” he says.
CAR-T cell therapy genetically engineers the patient’s own T cells, a type of white blood cell known as a lymphocyte, to attack the cancer. They are then reinfused back into the patient.
“This therapy will be life-saving in a small portion of children and young adults with acute lymphoblastic lymphoma and has encouraging results in patients with a recurrence of non-Hodgkin lymphoma. Additionally, early clinical trial data on chronic lymphocytic leukemia, lymphoma, and multiple myeloma suggests this technology might have broad applicability in the treatment of blood cancers,” Seiden says. “Along with immune-oncology drugs and other immune enhancing strategies, checkpoint inhibitors and CAR-T cells are rapidly bringing advances in immunology to patients with advanced cancers.”
FDA’s approval of Kymriah marked the first time that the agency approved a gene therapy. The drug, a CAR-T cell therapy, is for treating certain pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. “While $475,000 is the price of one treatment, it is anticipated to be a much less costly alternative compared to patients who require ongoing care measured in years,” DeRosa says.
Dong Zhang, PhD, associate professor of biomedical sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York, sees precision oncology as the future of oncology treatment. Precision oncology means that before treating a cancer patient, the oncologist will first obtain a molecular profile of the patient’s tumor to see if a treatment strategy has been proven to be effective for that specific kind of tumor.
The profiling can be based on gene transcription pattern, mutation pattern (BRCA1/2), overexpression of a known oncogene (e.g., HER2 in breast cancers, EGFR in lung cancers), or other biomolecular markers. A patient’s tumor profiling can be used for diagnosis, treatment, or both. For example, several molecularly targeted agents have been approved to treat some blood cancers, breast cancers, lung cancers, and skin cancers.
A new family of precision oncology drugs, called PARP inhibitors, has been effective in killing cancer cells in patients with a certain genetic background. Two examples of PARP inhibitors include Lynparza (olaparib), which FDA approved for adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had a complete or partial response to platinum-based chemotherapy, in August 2017. Earlier, FDA approved Rubraca (rucaparib) in 2016 for treating patients with a BRCA mutation associated advanced ovarian cancer who were treated with two or more chemotherapies. Previously in 2014, FDA approved olaparib capsules for treating patients with certain BRCA-mutated advanced ovarian cancer who were treated with three or more prior lines of chemotherapy.
Zhang explains that women carrying BRCA1 or BRCA2 (BRCA1/2) mutations are often at a higher risk of developing breast and ovarian cancers. “Human beings have two copies of each gene, one copy from each parent. For women carrying BRCA1/2 mutations, they inherited one good copy and one bad copy of the BRCA1/2 gene from their parents,” he says. “During the development of breast or ovarian cancers, the good copy either mutates or becomes deleted in tumor cells. However, the non-tumor cells in those women still likely maintain the good copy.”
Since both copies of the BRCA1/2 gene either mutate or become deleted in tumor cells, the DNA repair pathway is not functional in those tumor cells and is replaced by another type of DNA repair process that is heavily relied on by an enzyme called PARP. Further blocking of the PARP enzyme by PARP inhibitors (PARPi) will severely compromise the tumor cells’ ability to repair DNA and likely lead to death of those cells.
The name of this cell death process is therefore called synthetic lethality or synthetic killing. “Since the non-tumor cells still have the good copy of BRCA1/2 genes, the DNA repair pathway is still functional. Therefore, PARPi will likely not harm the non-tumor cells that much,” Zhang explains. “Clinical trials of PARPi showed that PARPi is more effective in killing cancer cells that have lost both copies of BRCA1/2 while having less toxic effects to non-tumor cells, as reflected by fewer side effects. Therefore, this synthetic lethal family of drugs should have fewer side effects compared to conventional chemotherapy drugs.”
Another breakthrough occurred in May, with the FDA granting accelerated approval of a treatment for patients whose cancers have a specific genetic feature (also known as a biomarker). This is the first time the agency approved a cancer treatment based on a common biomarker rather than where the tumor originated in the body.
Keytruda (pembrolizumab) is indicated to treat adult and pediatric patients with unresectable or metastatic solid tumors that have a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Specifically, it is for patients with solid tumors that have progressed following prior treatment and don’t have satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs. “This heralds the future of drug approvals by the genomic signature,” DeRosa says. MSI-H and dMMR tumors contain abnormalities that prevent proper repair of DNA.
FDA previously approved Keytruda to treat certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.
The revolution in immune-oncology is clear; it will make tremendous changes in oncology healthcare. “It will affect the short and long-term use of various other oncology-related services, as well as decrease hospitalization rates,” Kesari says. “Combination treatments with traditional surgery, radiation, and chemotherapy will evolve over time.”
Nonetheless, as the cost of cancer care continues to rise, the challenge ahead is to not only do the best for each patient therapeutically but given the potential financial consequence of therapy to the patient, strive to give the most efficacious treatment at every step of the treatment continuum, DeRosa concludes.
Karen Appold is a medical writer in Lehigh Valley, Pennsylvania.