An interview with JosÃ© Baselga, MD, PhD, who helped to develop new drugs and combination therapies for the treatment of breast cancer, including the early targeted therapy trastuzumab and the more recent pertuzumab.
José Baselga, MD, PhD, speaks at the 30th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource (PER) in March.
For José Baselga, there was no escape from the field of medicine. As a child in Barcelona, Spain, it was all around him.
Catalonia, the region where Baselga grew up, has an excellent educational system that is known for generating doctors, he said, and his father and grandfather were both physicians. Eventually, all of Baselga’s siblings chose medical careers.
“Medicine was the natural thing to do,” he said.
But it was his love of a challenge that drew Baselga, MD, PhD, to oncology, a field he has helped to define as both a leader of cancer research institutions and as a researcher himself.
“I wanted to do something that was interesting and could potentially change people’s lives, and I realized that cancer was a big unsolved problem,” he said. “We had many cancer patients with very poor therapies, yet we had the sense that things were going to start moving. It was the time when oncogenes were being described and the first chemotherapies in breast cancer appeared, so I thought it was going to be a very important area for those of us who like challenges—clearly the area where we could solve the most problems in the next 30 years.”
During those three decades, Baselga has contributed significantly to the progress he envisioned.
Through his research and by leading clinical trials, the doctor has helped to develop new drugs and combination therapies for the treatment of breast cancer, including the early targeted therapy trastuzumab (Herceptin) and the more recent pertuzumab (Perjeta), and is now pursuing the development of phosphatidylinositol 3-(PI3) kinase inhibitors to fight resistance to those drugs.
When he was just 35, Baselga took on the task of building a clinical research program from scratch at Vall d’Hebron University Hospital, in his native Barcelona.
Now, at 53, he’s helping to guide one of the world’s top oncology institutions. In January, Baselga stepped into the role of physician-in-chief of Memorial Hospital at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, where, in the 1990s, he had completed a fellowship and worked as an instructor. In the job, the doctor is leading 834 attending physicians, managing patient care, and overseeing clinical and translational research.
“This is a very exciting moment in oncology, and in the next few years I plan to contribute by helping the institution and its mission,” he said. “I have no goals except to be blessed to continue at Sloan. That’s all I can ask for.”In his new role, Baselga juggles a variety of responsibilities.
The broadest involve “securing the quality and safety of the day-to-day operations of Memorial Hospital, overseeing clinical programs, having a close working relationship with department chairs, making sure we are a financially viable institution, and overseeing the expansion of the cancer center,” Baselga said.
Another goal is to expand clinical research at MSKCC, Baselga said, in areas including his own research focus—molecular targeted therapies—and immunology.
“The challenges are significant, so we need to make sure a program is in place,” he said. “That’s already happening in tumors, but, like everyone else, we need to expand on routine mutational analysis of tumors.”
Finally, Baselga is determined to streamline the process of obtaining approval for clinical trial protocols from the hospital’s decision makers.
“We cannot afford to have protocols lingering in review for months,” he said. “One of the first things I did here was to announce a new deputy physician-in-chief for clinical research, Paul Sabbatini, MD. Dr Sabbatini will help provide the capacity to implement all these changes.”
At the same time, Baselga is continuing to do the kind of work that has made him a renowned expert in the intricacies of breast cancer.
He continues to design and lead clinical trials and, as always, is running a lab, although it’s small and staffed with senior faculty to keep it operating smoothly. In addition, Baselga has his own small clinic where he sees breast cancer patients.
“It’s important that we all do what we do best, and that, in academic positions and centers, leadership continues to be involved in research,” he said. “Otherwise, it’s easy to get disconnected.”Baselga learned how to guide an oncology institution when he was invited, just two years after finishing a second fellowship at MSKCC, to become chairman of the Medical Oncology Service and director of the Division of Medical Oncology, Hematology and Radiation Oncology at Vall d’Hebron.
“It was the largest hospital in Barcelona and one of the top three in the country, and the home of the medical school, so it was a very good place—and one that I knew very, very well, since I had been there as a resident,” Baselga said. But it had virtually no oncology program.
“They said, ‘We need to build an oncology program that is very, very bright. Can you please build it?’” the doctor recalled. “It absolutely looked like a very huge task, but I thought I could do it.”
Baselga started by assessing the young talent at the hospital and working to attract the best medical oncology fellows in the country. He also lured in two or three talented doctors from other Barcelona hospitals to join the effort.
A key task in building the center was starting a vigorous philanthropy program, something that hadn’t been done at other Barcelona hospitals, Baselga said.
In addition, Baselga recognized that Spain’s public health system was uniquely positioned to conduct clinical research.
“We had a huge number of patient referrals, and the government began to provide financial support, and we grew and grew and grew,” he said. “When I left, it was the largest clinical research program in Europe.”
It took nearly 15 years before the effort hit a plateau.
“I had exceeded every single one of my initial goals, and I found myself 49 and wondering ‘Now what? What’s next?’” Baselga said. “I wasn’t unhappy, and I could have stayed there, but I was ready for the next challenge.”
Taken with the idea that a move to the United States would make sense for his family, particularly because it would allow his children to attend American universities, Baselga looked for a new opportunity and found it at Massachusetts General Hospital. Starting in 2010, he served as chief of its Division of Hematology/Oncology and associate director of its Cancer Center, and also as a professor of Medicine at Harvard Medical School.
But it was just a few years later that MSKCC made him an offer he couldn’t refuse.
“I have a really deep esteem for the institution,” he said. “I know its potential, which is huge, its power, its size, its commitment, and its focus on cancer. When this opportunity came, I felt it was the kind of opportunity you cannot let pass by. I couldn’t say no. I said, ‘This is it.’”Baselga is particularly excited to be back at MSKCC because, 20 years ago, it was the place where he launched his career.
Having earned his MD from the Universitat Autònoma de Barcelona in 1982 and completed residencies at Vall D’Hebron and the State University of New York Health Science Center in Brooklyn, Baselga landed at MSKCC for a fellowship.
“I was there a week and I already knew this was what I wanted to do, to train in oncology,” Baselga said.
The fledgling doctor bloomed under the mentorship of Larry Norton, MD, now deputy physician-in-chief for Breast Cancer Programs, and John Mendelsohn, MD, who co-chaired the pharmacology program at MSKCC before going on to serve as president of The University of Texas MD Anderson Cancer Center in Houston from 1996 until 2011.
“Larry was a terrific clinical mentor, one of the best investigators who really knows how to design a trial and how to ask questions,” Baselga said. “I learned from John anything that relates to basic science in the lab. I was blessed by having both of them teaching me.”
As part of his work toward the PhD he earned at the Universitat Autònoma de Barcelona in 1992, Baselga joined Mendelsohn in developing cetuximab (Erbitux), the monoclonal antibody now approved for the treatment of colorectal and head and neck tumors. Baselga conducted all the preclinical work involved with combining cetuximab and chemotherapy, and then led clinical trials of the drug.
The effort helped Baselga formulate “a defining theme in my career: trying to be there at the interface between clinic and patient. Basic scientists continue to make discoveries, and I think physicians have to be placed in a situation where they can conflate that quickly to patients.”Baselga was still at MSKCC when he participated in early trials of trastuzumab, which has so dramatically improved outcomes for patients with HER2-positive breast cancer.
After initially collaborating with the leader of the effort, Dennis J. Slamon, MD, PhD, on phase I trials of the drug, Baselga conducted phase II trials at MSKCC, collaborating with Norton and Mendelsohn.
While Slamon tested trastuzumab plus cisplatin in his phase II trial, Baselga and colleagues conducted a single-agent study that proved trastuzumab had clinical activity on its own.1 Baselga’s team also demonstrated a synergy between paclitaxel and trastuzumab, a controversial idea that nevertheless led to a phase III study of trastuzumab in which one group of participants also received paclitaxel. That work led to the use of trastuzumab in first-line treatment.
“Had that trial not had a paclitaxel arm, trastuzumab could not be in the market today,” Baselga said.
Much more recently, Baselga was coleader of early studies of trastuzumab used before surgery in patients with HER2-positive breast cancer.2
“It was the first convincing evidence, in a randomized fashion, that complete remission is a marker of true clinical benefit in neoadjuvant breast cancer therapy,” Baselga said. “Now, people are applying that, and the FDA may reconsider approving new therapies in HER2-positive breast cancer based on complete remission at the time of surgery.”
Along the way, the doctor experienced some “eureka” moments.
In his phase II trial of trastuzumab, he worked with a patient whose disease had progressed on every other available therapy, and then recurred as a tumor in her chest wall. The median survival for such patients was less than half a year.
“It occurred to me to biopsy her tumor, and it was strongly HER2-positive,” Baselga said. “We offered her trastuzumab, and she had a complete remission of her disease. I’ve been following her for many, many years, and the last time I checked, she was free of disease after all these years.
“I love these moments in which you realize a number of things,” he continued. “First, if you’re able to identify what drives the tumor and apply appropriate therapy, you can cure disease. The second is the value of good clinical research. Why are we offering all our patients conventional therapies that have limitations when, in some cases, we have fantastic ideas that are likely to change the outcome of the disease? It speaks to the importance of expanding our clinical research efforts, trying to find the right clinical trials and, once we have them, making sure to enroll as many patients as possible to answer questions quickly.”Baselga’s research into new therapies for HER2-positive and other forms of breast cancer coalesced with a splash a little over a year ago. At the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, the doctor announced the results of three practice-changing studies, two of them involving treatments for HER2-positive disease. The papers were published within six weeks of each other, with Baselga as lead author.
Pertuzumab, a recently approved breast cancer drug that Baselga helped develop, blocks the HER2 protein, above blue, from pairing with other members of the HER family, specifically HER3, green. Illustration courtesy of Genentech.
In the CLEOPATRA trial, Baselga and colleagues established that adding pertuzumab to trastuzumab generated a progression-free survival (PFS) benefit for patients with late-stage, HER2-positive disease.3 In NeoALTTO,4 they found that lapatinib plus trastuzumab in the neoadjuvant setting improved pathologic complete response for patients in that population.
Meanwhile, in BOLERO-2,5 Baselga and his co-authors found that adding everolimus to exemestane in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer improved PFS.
Until the CLEOPATRA trial, pertuzumab— which was initially developed alongside trastuzumab—had been languishing in Genentech’s pipeline, Baselga noted.
While investigators had discovered that pertuzumab worked by a different mechanism of action than trastuzumab, he said, they shelved the drug after it performed poorly in a phase II, single-agent study. Baselga, however, saw in the data that pertuzumab worked best in combination with trastuzumab.
“So I went back to the company and said, ‘Let’s do a study with the two drugs together,’ ” the doctor recalled. “That was the basis for the CLEOPATRA study that led to the approval of pertuzumab.”
By Baselga’s best guess, there are probably many other promising drugs being kept on the back burner by pharmaceutical companies, and others that have been dismissed entirely. Even Herceptin “almost didn’t make it,” he pointed out.
“What’s reassuring is that we can only do better,” he said. “There is much more hope than we think, and probably much better drugs out there that we have not even seen.”
The “recipe for success” in bringing such drugs to the fore, he said, will involve testing new therapies in the patients most likely to benefit, and in earlier stages of disease.
“In initial clinical trials, we were telling patients with different degrees of HER2 overexpression that only tumors with very high HER2 benefited from therapy,” Baselga recalled. “Had we not enriched our clinical trials with those patients, Herceptin wouldn’t be on the market. So, choose your patient population wisely. If you have a good clinical model that tells you which way to go, just do it. You can refine the question later, but prove that the drug is going to work in the setting where it’s most likely to work. That idea has given me a lot of food for thought.”Baselga is applying those insights to his latest work, which is largely focused on developing therapies against the enzyme PI3K, a field he described as “huge and very, very exciting.”
At the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, he presented results of a study that showed dramatic improvement in patients with ER-positive breast cancer who have a mutation in PI3K alpha and were treated with an inhibitor specific to that mutation, a compound known as BYL719.6
“I have an interest in this because the tumors that were resistant to trastuzumab had a mutation in PI3,” he said. “A lot of companies have compounds that target these mutations, and the clinical models leave no question that, if you have a mutation in PI3 kinase, those cell lines are extremely sensitive to PI3K inhibitors; the difference is huge.”
In testing such drugs in patients, Baselga has followed his own advice, enrolling only those who harbor PI3K mutations. “Sure enough,” he said, “we’ve seen a very high response rate, and there’s no question in my mind that these drugs will be approved in breast cancer.”
“Now that we know that,” he added, “an important question is: Do patients without the mutation benefit? It’s a good question, but in the meantime we’re making progress in the population most likely to benefit.”
Looking ahead, Baselga is confident about the prospects for improved treatment, or even cure, of subtypes of breast cancer.
How could he be less than optimistic, he wonders, after witnessing a median survival of six months give way to a 90% cure rate in those with early HER2-positive disease, along with significant progress in other cancers, such as melanoma?
“If we can now learn how to combine these therapies in the right way, then we can make great strides,” he said.
Baselga intends to remain at the heart of the group of scientists working toward solutions, he added.
“I’m very blessed and fortunate to be working on what I like,” he said. “I see, in many areas, people who have to spend a lot of hours working at things that don’t really give them a sense of happiness or purpose. So, even though I work long hours, I don’t think my life is one of sacrifice, but of privilege.”