Precision Medicine Goes Mainstream

"Precision, personalized, individualized, targeted" — most oncologists are well acquainted with these terms, often used interchangeably to describe a model of care in which a treatment plan is based on patient characteristics and the molecular and genetic profile of the patient’s tumor. On Tuesday, President Obama introduced this concept to the nation in his State of the Union Address. “Tonight, I’m launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes—and to give all of us access to the personalized information we need to keep ourselves and our families healthier,” Obama said.

Other than describing the Precision Medicine Initiative as “delivering the right treatment at the right time,” the president provided few specifics. However, Jo Handelsman, associate director for science at the White House Office of Science and Technology, offered a few details on the administration’s website.¹ Handelsman referred to the therapeutic approach for most ailments as “one-size-fits-all” and ineffective.

She described precision medicine as “an emerging approach to promoting health and treating disease that takes into account individual differences in people’s genes, environments, and lifestyles.” As an example of the potential of precision medicine to improve lives, Handelsman and the president mentioned the case of Bill Elder, a 27-year-old medical student who is benefitting from a new targeted therapy designed for the 4% of cystic fibrosis patients who have a rare G551D mutation.^2,3

In her statement on precision therapy, Handelsman mentioned cancer treatment “entering a new era.” However, cancer treatment crossed the threshold of this “new” era decades ago. In the late 1980s, researchers at various institutions independently identified a subtype of aggressive breast cancer that overexpressed the HER2 protein.⁴ In 1998, the US Food and Drug Administration (FDA) approved trastuzumab to treat women with metastatic breast cancer that overexpressed HER2, making it the first cancer treatment with a molecular target.

Despite the success with trastuzumab, in the decade that followed, molecular or genetic factors were seldom a consideration when enrolling patients in clinical trials of novel cancer drugs. If outcomes from a trial evaluating an investigational drug proved disappointing, companies moved onto the next candidate.⁵

In some clinical trials, such as cetuximab for colorectal cancer or imatinib for chronic myeloid leukemia, the prevalence of an as-yet undiscovered resistance mutation was low enough that outcomes for patients with these genetic aberrations did not compromise overall outcomes and the manufacturer was able to secure FDA approval. Only later did researchers delve into why a stubbornly consistent percentage of patients failed to respond to certain therapies. For cetuximab, the problem was a KRAS mutation; and for imatinib, a T315I mutation. Today, drug developers have come to appreciate the benefit of sequencing a cancer’s genetic profile, engineering a drug that targets a specific biomarker, and restricting the trial to patients whose tumors test positive for the biomarker of interest. This formula may allow a targeted drug to provide a meaningful clinical response even if it does not prolong survival, and the FDA has approved several oncology drugs on that basis.⁶

The National Cancer Institute (NCI) has already thrown its weight behind precision medicine. In September of last year, the agency launched the “Exceptional Responders Initiative.” The purpose of this program is to revisit failed early-phase trials of a novel drug candidate to determine whether or not any patients had an exceptional response to the treatment.⁷ The NCI hopes to analyze tissue specimens from these patients for any molecular biomarkers that might account for the surprising response.

Trials being considered for inclusion are those in which less than 10% of patients achieved a complete or durable partial response that persisted for at least 6 months. The NCI has already identified 100 cases eligible for analysis and has also received reports of other exceptional patients from investigators of various cancer drug trials. According to the NCI, the impetus for the program was the surprising response of 1 bladder cancer patient who took part in a trial of everolimus. She achieved a complete response and maintained it for 2 years. Subsequent genetic sequencing of her tumor and the tumors of other trial participants who had partial responses identified several TSC1 mutations; TSC1 regulates a signaling pathway targeted by everolimus.

Another new approach to precision medicine in oncology is to pair patients with a drug trial based on their tumor’s genetic or molecular profile instead of their tumor type. Novartis recently launched “Signature,” a clinical trial program that matches investigational cancer drugs or approved cancer drugs being studied for new uses to patients according to predefined genetic alterations, regardless of whether they have breast cancer, lung cancer, or some other tumor type. Novartis describes this as “Protocol to the Patient” trials because the trial site will be established wherever the patient with the preselected genetic marker has been identified. Treatments being investigated in these trials include buparlisib, dovitinib, binimetinib, encorafenib, and sonidegib.⁸ Memorial Sloan Kettering Cancer Center (MSKCC) is taking a similar approach, which the center describes as “basket trials.” Patients with any of several types of cancer who possess the requisite molecular target will be enrolled in the same trial.^5,9

Oncology, which continues to advance personalized cancer care, has undoubtedly paved the way for specialists in other disease states to move forward with precision medicine initiatives. Although curing the underlying genetic aberration behind a disease like cystic fibrosis or muscular dystrophy may be years away, precision therapy offers the potential to make these and other diseases more manageable and with greater odds of survival. More details on the president’s “Precision Medicine Initiative” are expected in the coming weeks, and the program is likely to be included in his proposed budget for 2016.

References

1. Handelsman J. Precision medicine: improving health and treating disease. http://www.whitehouse.gov/blog/2015/01/21/precision-medicine-improving-health-and-treating-disease. Published January 21, 2015. Accessed January 21, 2015.
2. Somander T. Meet William Elder, Jr., a guest of the first lady at the State of the Union. Published http://www.whitehouse.gov/blog/2015/01/19/meet-william-elder-jr-guest-first-lady-state-union. January 19, 2015. Accessed January 21, 2015.
3. FDA approves Kalydeco to treat a rare form of cystic fibrosis [press release]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm. Published January 31, 2012. Accessed January 21, 2015.
4. Herceptin (trastuzumab) timeline. http://www.gene.com/media/product-information/herceptin-development-timeline. Accessed January 21, 2015.
5. American Society of Clinical Oncology. Extraordinary responders drive concept of basket trial design. http://am.asco.org/extraordinary-responders-drive-concept-basket-trial-design. Published June 24, 2014. Accessed January 22, 2015.
6. Fauber J, Chu E. FDA approves cancer drugs without proof they’re extending lives. http://www.jsonline.com/watchdog/watchdogreports/fda-approves-cancer-drugs-without-proof-theyre-extending-lives-b99348000z1-280437692.html. Published October 26, 2014. Accessed January 22, 2015.
7. National Cancer Institute. Exceptional responders initiative: questions and answers. http://www.cancer.gov/newscenter/newsfromnci/2014/ExceptionalRespondersQandA. Published September 24, 2014. Accessed January 22, 2015.
8. Slosberg ED, Kang B, Beck JT, et al. The Signature program, a series of tissue-agnostic, mutation-specific signal finding trials. J Clin Oncol. 2014;32:5s(suppl;abstr TPS2646).
9. Memorial Sloan Kettering Cancer Center. 2013 Annual report: traditional clinical trials versus basket trials. http://www.mskcc.org/annual-report/2013/traditional-clinical-trials-versus-basket-trials. Published February 2014. Accessed January 22, 2015.