The Hamilton of Medicine

Most physician-scientists are intense, motivated and focused, but Keith T. Flaherty, MD, takes it to another level. Even as a young doctor, his passion and certainty that cancer could be, and should be, cured impressed his mentors.

“You get this sense of urgency from him, this ‘I need to do this now, in whatever time I have,’” said Lynn Schuchter, MD, chief of the division of Hematology Oncology and director of the Tara Miller Melanoma Center at the Hospital at the University of Pennsylvania, where Flaherty did his fellowship. “He is the [Alexander] Hamilton of medicine. That’s what went through my mind as I was thinking about him and his work.”

As the director of clinical research and chair in oncology at the Massachusetts General Hospital (Mass General) Cancer Center, the Baltimore, Maryland, native was one of the first to investigate targeted therapy for melanoma patients with the BRAF mutation.

Flaherty said he likes it when someone says that something cannot be done so he can prove them wrong, whether it is developing a targeted therapy to shut down the BRAF mutation or designing a model of a rare NTRK fusion that few had investigated because it appeared in just 0.3% of all cancers.

“I want something I can put my shoulder into. What’s the bottleneck here? What’s the problem?” he said.

His love of challenges combined with his gift for teamwork made him a natural choice to coordinate novel coronavirus disease 2019 (COVID-19) research at Mass General after the pandemic turned the medical landscape upside-down. He brought physicians, researchers and the pharmaceutical industry to the table and described the experience as medicine on “warp speed.”

Although working in oncology is a fairly collaborative field, he said, there is still a lot of pressure to claim data or studies as your own, often resulting in people refusing to share their work. All that ego has been dropped when it comes to finding a treatment for COVID-19, he said.

“With COVID-19, that all went away. There are data dumps of every kind...it’s phenomenal. If you contact a drug company because something they have might plausibly work, they say, ‘Here, use it, we will give you this investigational drug however you want it, no charge,’ ” he said. “We have the FDA and IRBs [institutional review boards] turning around things in 24 hours or less that used to take 6 months. It’s exhilarating, because it shows you in almost every way how things could operate.”

Passion and Persistence

Flaherty, 50, wasn’t exactly forced into becoming a doctor, but his father was a cardiologist and his mother was a psychologist. They loved what they were doing and often talked about their work. Plus, the Johns Hopkins University School of Medicine looms large in Baltimore, so a medical career was always on his radar.

He studied neuroscience, the biology of the mind, as undergrad at Yale University. Yale was a hotspot for neuroscience research and Flaherty was sitting in a huge cell biology class lecture his sophomore year, when the subject clicked for him. “There was nothing about that subject that I thought was uninteresting,” he said.

Biochemistry felt dry, and he wanted an area of challenge, where discoveries were just starting. Flaherty loved that much of neuroscience was still unexplored.

“You’ve got the persisting mystery of the boundary of the mind versus the brain. How do you look at the genetic to the cellular system of the brain and wrestle down the dualism of the mind-body divide?” he said. “How do you ever fully solve that problem of ‘the soul’ and nail that down to a cellular level?”

At Johns Hopkins for medical school, he aimed for neuroscience but quickly found that it was not a good fit for him, saying it became apparent to him that there was no such thing as “applied neuroscience.” He wanted a place where science investigators and medical practitioners worked more collaboratively. Oncology seemed to offer the best opportunity for developing scientific tools and genomic research that then moved into treatment.

He was particularly interested in targeted therapy, developing cancer treatments to focus on specific genes or proteins that cancer cells produce. The spark happened in 2002, when Nature published an article on the discovery of the BRAF mutation and its link to cancer growth. Flaherty said he could not understand why the medical world did not stop what it was doing and start conducting research on ways to address the mutation since it impacted a number of cancers, including 50% of patients with melanoma.

“It turns out that people are already doing their own research and they’re busy and they already have ideas and concepts and grants,” he said.

That’s why he tells his protégés that they do not have to wait for permission. That if they are excited by something new and want to move forward, they should pursue it because that’s how the field progresses. “I tell them not to be shy about it, because no one else is going to drop what they are doing,” he said.

He was also drawn to the psychological aspects of working with oncology patients, validated by his “fantastic” month spent in the psychiatry rotation. He said he remembers vividly sitting in an internal medicine lecture where physicians talked about how patients often did not take their diagnoses seriously and a lot of time was spent on lifestyle and medication compliance.

Oncology was on the other end of that spectrum. These were people who had to live with the knowledge that they had cancer, and handle that diagnosis, but somehow break through the paralysis of having a fatal disease and continue to live.

“There is a heavy psychological component to this field, and patients need someone to hold their hand and recognize that, and not someone who just focuses on the scientific and medical aspects but sees the disease as a whole, as part of their life,” he said. “I see myself as a compassionate person, and I certainly felt that I could literally hold someone’s hand on their death bed, as well as be the person who was trying to cure them and walk with them through their diagnosis.”

That combination of passion and persistence came through in a 3-part The New York Times series published in 2010. The paper followed Flaherty, then an assistant professor at Penn, while he was working in 3 areas—kidney cancer, melanoma biology, and clinical research.

The series followed him and his patients with melanoma through the beginning clinical trial processes for vemurafenib (Zelboraf), then known as PLX4032. In many patients, their tumors went away dramatically, and Flaherty and his cohorts were trying to figure out what dose worked most effectively while minimizing adverse events.

The Times not only showcased the connection Flaherty has with his patients, but also his professional impatience. He encouraged laboratory assistants to come in on weekends to run tissue samples and pushed pharmaceutical companies to reconfigure the medication entirely.

The newspaper captured Flaherty at a moment early in his career when he kept coming up against the same obstacle—physicians were parked in 1 corner while the clinical investigators worked in another area, and neither knew what the other was up to. Flaherty could not understand why information wasn’t being shared and the science wasn’t being translated into medicine. Many people describe the process as a bridge, but Flaherty sees it more as a “hub and a wheel,” with multiple players in different areas working on a central goal.

His team’s hard work ultimately paid off. In 2011, the FDA approved vemurafenib for the treatment of patients with BRAF V600E mutation–positive, inoperable, or metastatic melanoma. It was the first targeted agent shown to improve survival in that patient population.

On July 30, 2020, the FDA approved the combination of atezolizumab (Tecentriq), cobimetinib (Cotellic), and vemurafenib for patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.

“He’s got this wonderful approach, he’s a great doctor and he’s a fantastic clinician,” said Schuchter. “The clarity of this thinking, his audacious goals. He was really crystal clear about wanting to cure cancer and didn’t think of that as a nontangible goal.”

After moving to Mass General in 2009, he started focusing more on developing combination therapies. The challenge is that pharmaceutical companies, whether large or small, rarely develop more than 1 drug to treat a disease, particularly a rare disease. It might take drugs from 4 companies to make a winning combination for a patient.

Flaherty started working directly with pharmaceutical companies, joining Clovis Oncology as an independent director in 2013. That same year he helped to found Loxo Oncology, which Eli Lilly and Company acquired in 2019. He saw many opportunities that were not being pursued and wanted to have a say when companies decided which drugs to support. He felt it was important to be part of the early conversations and get involved in the drug development process. That is to say, he wanted to be in the room where it happens.

“When you work with companies as an academic, especially when you’re involved with clinical development, by the time you meet with them, they’ve already made a lot of decisions, and you’re just handed the product of those decisions,” he said.

Getting out of the Way

A self-described hypomanic, Flaherty said he does not enjoy downtime. Until about 3 years ago, he had not been comfortable taking more than a week’s vacation. Now he’s willing to take 2 weeks off, though he still made time to talk to a reporter during his vacation. From the moment he wakes up at 5 am to exercise, his mind is on full throttle. He loves to read, particularly poetry, because poetry is created simply for the joy of writing and not for commercial purposes.

He has been married to his wife, Mira Kautzky, MD, an internal medicine specialist and instructor in medicine at Mass General, for 21 years, and the couple has 2 teenage daughters. Flaherty says he was traveling up to 300,000 miles a year at the beginning of this career and missed a lot of their childhoods. For a long time he felt almost panicked about trying to “move, move, move the field as fast as I could.”

Then, about 5 years ago, he started slowly moving away from the front lines of patient care, not completely but in a sustained way. He’s surrounded by people who are as motivated and focused as he is, and said that part of his job now is to get out of their way so that junior faculty can become leaders. As difficult as it is for him to take a step back, he said that it is a joy to see where the ambition and intelligence of the next generation will take them.

“It’s empowering to hand over the reins. I had to learn how to do it; it was hard, but super gratifying,” he said. “A day doesn’t pass without some sort of mentoring interaction, and when I look back at the end of the day, that’s usually one of the best parts.”