PRECISION MEDICINE COMING OF AGE

"Precision medicine" has become quite the catchphrase since it was highlighted last week by President Barack Obama in his State of the Union speech, but oncologists have already been using this phrase for some years, and have also been applying this approach to the treatment of their patients for some years.

In his speech, the president described precision medicine as using genomics to "deliver the right treatment at the right time."

"I want the country that eliminated polio and mapped the human genome to lead a new era of medicine . In some patients with cystic fibrosis, this approach has reversed a disease once thought unstoppable," he said, adding that this kind of personalized medicine could lead to cures for cancer and diabetes.

Coincident with the speech in its timing, an editorial published online January 20 in the Journal of Clinical Oncology gives an overview of the progress that precision medicine has made to date in cancer.

Editorialist Howard Kaufman, MD, from the Rutgers Cancer Institute of New Jersey in New Brunswick, discusses both targeted therapy, which he describes as "promising" but not yet widely adopted, and he also highlights the significant progress that is being made in tumor immunotherapy, and looks ahead to the potential for "precision immunotherapy." But perhaps the greatest hope lies in combining these two approaches together, as is already under investigation in melanoma, he suggests.

"The practicing oncologist will need to be fully familiar with the clinical application of targeted therapy and tumor immunotherapy to provide high-quality cancer care in this new era," he writes.

Precision Medicine in Oncology

Dr Kaufman elaborates what the catchphrase means when applied to oncology: "the basic foundation of precision medicine is that each tumor in individual patients may harbor different subsets of genomic mutations."

"Targeted therapy can thus be designed on the basis of a knowledge of which mutations are present at any given time, and a precise and highly personalized treatment plan for each patient can be developed," he continues.

This approach has resulted in the use of a number of targeted drugs in the treatment of non-small cell lung cancer (NSCLC) and melanoma.

For NSCLC, there are EGFR inhibitors such as erlotinib (Tarceva) and related agents for tumors that harbor EGFR mutations (found in about 10% to 15% of white patients, and up to 40% of Asian patients), and also drugs such as crizotinib (Xalkori) for tumors that harbor ALK rearrangement (found in about 4% to 5% of NSCLC), and shown recently to also be active in tumors with ROS1 rearrangement (found in about 1%).

In melanoma, there are a number of drugs targeting BRAFmutations (found in about 50% of melanoma), and more recently there have also been drugs targeting MEK mutations, which are used in combination with BRAF inhibitors to overcome the resistance that develops to BRAF inhibitors alone.

In his editorial, Dr Kaufman says this approach of drugs targeting mutations in tumors is "promising," but there are several barriers that limit its widespread clinical adoption, including:

• the need to collect and properly store tissue
• lack of cost-effective companion diagnostic tests
• limited funding for bioinformatics infrastructure
• issues related to patient accrual in clinical trials targeting highly selected subsets of patients
• barriers across industry that block rational combination regimens
• the need to better understand mechanisms of drug resistance and how to monitor patients for emergence of resistance.

Progress in Immunotherapy

Dr Kaufman also highlights the progress that is being made in tumor immunotherapy, which, similar to the advances in tumor therapy, has resulted in several new strategies for cancer therapy. These new strategies include, among others:

• T-cell checkpoint inhibitors (e.g., ipilimumab [Yervoy] and the new programmed death inhibitors pembrolizumab [Keytruda] and nivolumab [Opdivo])
• oncolytic viruses (GVAx and talimogene laherparepvec [T-VEC])
• chimeric antigen-receptor T-cells (such as CD19 under development at the National Cancer Institute in collaboration with Kite Pharmaceuticals, and CTL019 being developed by the University of Pennsylvania with Novartis).

"Immunotherapy is associated with several unique features, most notably the potential for inducing durable clinical responses, lack of typical drug resistance, and the induction of autoimmune-like toxicities," Dr Kaufman writes. He highlights the fact that the responses seen with immunotherapy are different to what has been seen previously in cancer. The response may be slow in onset, but it can be quite durable, he notes. "Thus, unlike chemotherapy and targeted therapy where resistance to treatment develops, immunotherapy effects appear to be long lasting, and in some cases may result in complete eradication of cancer."

"These are exciting times," he writes, "although there are still several critical hurdles than remain before the full clinical potential of tumor immunotherapy can be realized and broadly applied."

More research is needed into both basic and translational immunology, and better integration and co-operation between researchers in industry, academia, and government regulatory agencies will be important, as there are already clinical data showing improved outcomes when different immunotherapy approaches are combined. In addition, there is a need for new diagnostic approaches in the clinic where tumors can be assessed for tumor-infiltrating immune cells, soluble factors, and host immune regulatory genes.

"Just like we can now determine the unique genetic changes in an individual patient's cancer, we can know the immune profile in patients and select appropriate immunotherapy to help treat specific cancers," Dr Kaufman added in a statement.

"The potential of precision immunology to identify defects in the cancer immunity cycle of individual tumors in a single patient is now possible, and — once validated and standardized — can be used to inform treatment decisions that have the potential to improve the outcomes for all patients with cancer," he commented.

Changing the Paradigm 

"Precision medicine is changing the paradigm for how we approach cancer treatment in the modern era," Dr Kaufman declares.

"There is already some intriguing data that targeting the cancer cell through precision medicine and the immune system through what I have called "precision immunology" can have synergistic activity against cancer," he says.

"This is best exemplified by melanoma in which both targeted therapy and immunotherapy seem to have a role," he continues. "Since 2011, seven new drugs have been approved for the systemic treatment of advanced melanoma, three are targeted therapy and four are immunotherapy agents. Clinical trials combining these drugs are well under way."

Dr Kaufman reports serving in a consulting or advisory role for Alkermes, Amgen, Merck, Merck Serono, and Prometheus; and having received research funding from Bristol-Myers Squibb/Medarex.

J Clin Oncol. Published online January 20, 2015. Editorial