Battling the Odds in RCC: Interview With Brian Rini, MD

Photo by © ASCO/Todd Buchanan 2012

Brian Rini, MD

Ask Brian Rini, MD, and he’ll tell you his contributions to the battle against kidney cancer amount to a series of small victories in a war whose end is nowhere in sight.

As a clinical investigator, Rini said, “You learn to be humble, because most of what you do will not be successful. And, in the scheme of things, the advancements you help push forward will be relatively small.”

Despite that big-picture perspective, it’s hard for Rini—a renowned genitourinary specialist who holds posts at the Cleveland Clinic and Case Western Reserve University—to resist being excited about his latest achievement. As principal investigator on a global phase III trial of Pfizer’s axitinib (Inlyta) for patients with previously treated advanced renal cell carcinoma (RCC), Rini played a big part in moving the drug toward its approval January 27 by the FDA.

Rini’s AXIS trial demonstrated that axitinib significantly extended progression-free survival to a median of 6.7 months, compared with 4.7 months for those treated with sorafenib (Nexavar), a current standard of care for this patient population. That represents a 43% improvement.

A kinase inhibitor, axitinib is an oral therapy designed to selectively inhibit vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, which can influence tumor growth, vascular angiogenesis, and progression of cancer. The trial demonstrated that a VEGFRtargeted therapy can be effective following prior treatment options, including another VEGFR-targeted agent. It was the first trial ever to compare two kidney cancer drugs.

“I started working with this drug eight years ago, so it’s been a long road,” Rini said. “Thousands, if not tens of thousands, of people must come together to make trials like this happen, not to mention the patients. This is the fun part, when we get to the end and get results like this. It’s gratifying for all the hard work people have put in along the way.”

Research Focuses on Angiogenesis

Over the past decade, the 42-year-old, whose research has focused on RCC, prostate, and other genitourinary cancers, as well as on antiangiogenic therapy and immunotherapy, has been involved in the development of several paradigmchanging treatments for kidney cancer. All of those, he said, have fallen within the general category of antiangiogenics, which prevent the generation of blood vessels needed for cancers to grow.

Among his proudest achievements was his leadership of a phase III trial of bevacizumab (Avastin) plus standard-of-care interferon-alfa that resulted in the combination’s 2009 approval by the FDA for use in metastatic RCC. Rini was also involved in a number of phase II trials that helped promising antiangiogenic drugs move toward approval.

Due to his efforts and the work of many others, Rini said, that in 2005 “we suddenly went from almost no therapies to many promising therapies. Now, patients with metastatic disease are living over twice as long as they did before, on average two years, not from any one drug, but from the whole list of drugs. It’s harder to measure quality of life and how much better they feel, but they feel better being alive than not, and that’s the ultimate test.”

Brian Rini, MD, At A Glance

Rini confers with Laura Wood, RN, MSN, OCN, at the Cleveland Clinic.

• Is 42 years old.
• Has been married to his wife, Amalia, for 15 years and has two sons, ages 9 and 11.
• Takes piano and guitar lessons. His interest in playing the guitar is something he shares with one of his sons.

• Participates in marathons and triathlons.
• Believes that “every patient contributes to your outlook, both good and bad. Whether they do well or poorly, or have side effects or unique outcomes, it all goes into the mix of how you approach patients or identify the deficits in terms of how we care for patients.”
• Has been included in Cleveland Magazine’s list of Best Doctors, chosen by physician peers, every year from 2006 through 2011.
• Won the Sam and Maria Miller Professional Excellence Award for Clinical Research in 2011. The Miller family presents awards in several categories each year to Cleveland Clinic healthcare providers “who demonstrate exemplary service and dedication to excellence.”
• Is a fellow of the American College of Physicians.
• Has been consistently involved in committees and activities of the American Society of Clinical Oncology, including current positions on its Board of Experts and as kidney cancer specialty editor on its CancerProgress.net website.
• Has been involved in the activities of the National Cancer Institute and the Kidney Cancer Association.
• Is proud of the achievements of the fellows he’s taught, some of whom have gone on to faculty positions at institutions including the Dana-Farber Cancer Institute, Johns Hopkins University, and the University of Toronto.

While Rini recognizes that those accomplishments represent “a lot” of progress, he says they amount to “not much at the same time.” Moving forward, he’s determined to “continue to find new ideas and new drugs, and to develop them in unique ways.”

The doctor is pursuing those advancements in his role as a staff member at the Cleveland Clinic Taussig Cancer Institute, within both the Department of Solid Tumor Oncology and the Glickman Urological and Kidney Institute. He also serves as an associate professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and as leader of the Case Comprehensive Cancer Center Genitourinary Program, also associated with the university.

Rini spends about half his working hours seeing patients, and divides the other half among administrative duties, writing papers, traveling to give talks at conferences, of course, designing and running clinical trials.

New Projects Include Vaccine

Currently, those trials include a global, phase III study of a therapeutic vaccine for advanced kidney cancer, made by the Germany- based company immatics biotechnologies GmbH. Known as the IMPRINT trial and launched about six months ago, the study will compare the overall survival of patients who receive sunitinib (Sutent), a standard of care, with those who receive sunitinib plus the vaccine.

Rini has also spent time considering what must be done to battle resistance to the latest and most effective RCC therapies, suggesting in The Lancet Oncology that studies of new combination and sequential treatments look promising (2009;10(10):992-1000). And, he led a retrospective analysis showing that patients with advanced kidney cancer who develop high blood pressure while being treated tend to survive longer.

“This has been seen with many analyses of different diseases and different drugs,” Rini said of the hypertension finding. “So far, it’s just an observation. Now, we need to see who these patients are, why this association exists, and how to take advantage of it in the future.”

We suddenly went from almost no therapies to many promising therapies.

Rini also finds time to serve as director of an experimental therapeutics fellowship at Cleveland Clinic, which brings two doctors a year into the fold for a hematology/oncology fellowship focused on both patient care and clinical research.

In guiding his fellows, the doctor stresses that “taking care of patients is hard work, and you have to be on top of the details. Clinical research is that much harder, because taking care of patients on trials means more attention to details, more meticulous work in keeping track of things like tumor measurement and toxicity. I tell them that they must be tenacious about their care of patients.”

It’s exactly the kind of work Rini enjoys.

“It takes a lot of time to both take care of patients and conduct research, so I’m constantly making sacrifices in terms of everything else in life, like being with my family,” he said. “But, obviously, it’s worth it. I’m helping people who have a bad problem, and even if I’m not curing them, I’m helping them live better and longer. There aren’t many professions where you get to do that.”

Psychology Training Provides Insights Into Patients

Rini’s interest in science and math budded in high school, but, despite that and his exposure to medicine through his mother, a nurse, it didn’t occur to him to become a physician until he was in college at the University of Notre Dame, in Indiana.

Brian Rini, MD, Research Snapshot

Q: You’re frequently the lead investigator on clinical trials. Are you involved with any at the moment that you find particularly exciting?

A: Here at the Cleveland Clinic, we’re conducting a study on Sutent (sunitinib) dosing. It’s a phase II pilot study of 30 or 40 patients that started about a year ago and will continue for another six months.

Normally, Sutent is given continuously, four weeks on followed by two weeks of rest, forever or until the patient gets worse or has intolerable side effects. This study looks at giving Sutent for six months and then taking the patient off it for two months, later moving to a two-months-on, two-months-off schedule. The scheme is a little complex, but the idea is to give people extended breaks on their therapy, improving their quality of life.

Tumors will grow when patients are off therapy, but when they’re on the treatment longer, it could balance out. Hopefully, they’ll maintain disease control.

Q: Are you leading any other studies originated by your team at the Cleveland Clinic?

A: We completed a phase II study, and are now conducting another, looking at neoadjuvant approaches in advanced kidney cancer. We have a very strong urology group here, and over the last few years we’ve been interested in seeing if these drugs will shrink the primary tumor, making surgery more successful and safer.

These are difficult trials to do for a variety of reasons, but we have strong surgical volume, strength, and interest, and we did a trial with Sutent. While that drug is FDA-approved for advanced kidney cancer, giving it before surgery is experimental.

The trial we’re conducting now involves a tyrosine kinase inhibitor, Votrient (pazopanib). We’re looking at safety, and clearly there is some effect on the primary tumor. The big question is: Where we go from here? Will it be something we can incorporate into how we approach patients?

Then, rather than choosing a typical premed focus, Rini majored in psychology.

“I knew I’d be getting enough science for the rest of my life,” he said. “I wanted to do something different and still fulfill the requirements for getting into medical school. I thought psychology was interesting and potentially relevant to dealing with people and patients. It has provided some insights that translated into how I deal with patients now—and maybe, more than anything, with my kids.”

Rini earned his medical degree from the Ohio State University College of Medicine in Columbus in 1995, and then completed a residency in internal medicine, followed by a fellowship in hematology/ oncology, at the University of Chicago Hospitals in Illinois.

Rini went on to serve as an assistant clinical professor at the University of California, San Francisco in 2001 before joining the Cleveland Clinic in 2005.

He was thrilled to be back in the city where he was born and raised.

“Our kids were 3 and 5 at the time, and we knew we didn’t want to raise them in California,” Rini said. “My family was here, and we wanted to move back to the Midwest.”

It was during his residency in what he describes as “a strong oncology department” that Rini became enamored with the field that later become his specialty. He was intrigued, he said, by “the type of patients, the type of problem, the biology of the disease, and the potential for clinical research, which I had an inclination that I wanted to do.”

Rini worked with mentor Nicholas J. Vogelzang, MD, who was then director of the University of Chicago Cancer Research Center and is now head of the Genitourinary Cancer Program at the Nevada Cancer Institute—on retrospective chart reviews and other research projects, and was inspired.

“It wasn’t one particular thing,” he recalled, “but the whole of clinical research, putting patients on clinical trials to try to find new and better treatments.”

The dire prognosis for many of his patients, and the lack of curative measures, didn’t dissuade Rini from pursuing that interest. Over the years, he said, he’s developed a philosophy that has helped him stay positive.

“People come to me, or to people like me, because we’re experts in a particular disease,” Rini said, “so you take solace in that you’re giving them information, and sometimes treatment, that they can’t get anywhere else. Because kidney cancer is a relatively rare disease, there’s misinformation, or lack of information, on the Internet and in most settings. When people find their way here, we provide them a great service. We’re not curing everybody’s disease, not by a long shot, and people know that when they’re walking in the door. But they’re appreciative of the information we provide.”