It was her contribution to one of the fastest drug approvals in FDA history that drew Alice Tsang Shaw, MD, PhD, out of the background and into the spotlight.
Photo courtesy of ESMO ©
Dr Shaw discusses crizotinib research during a press briefing at ESMO 2012.
Shaw was conducting research on mouse models of lung cancer at the Massachusetts Institute of Technology (MIT) in Cambridge when she walked away from the lab and into a key role in the development of the oral tyrosine kinase inhibitor crizotinib for the treatment of non-small cell lung cancer (NSCLC).
As the second targeted therapy for patients with NSCLC, and the first for the subset with a chromosomal rearrangement of the anaplastic lymphoma kinase (ALK
) gene, crizotinib represented an important milestone. Further, the drug was approved by the FDA under the trade name Xalkori just five years after it was first tested in patients, making its development swift in comparison to other cancer treatments, according to a 2011 agency report.1
During her time at MIT, Shaw had been aware that researchers at Massachusetts General Hospital (MGH) in Boston were developing crizotinib to target MET
in gastrointestinal cancers. But while the drug also targeted the ALK gene, no one knew at the time that ALK proteins played a role in NSCLC. Then, in 2007, Japanese researchers made the “incredible discovery” that ALK
was a target in a subset of lung cancer patients, Shaw recalled.
Inspired by the earlier identification of another targetable mutation in NSCLC, Shaw had already decided to leave the lab at MIT, join the staff at MGH, and play a more translational role in bringing novel therapies to patients with the disease. She arrived just in time to help develop crizotinib.
Shaw was on hand when MGH began adding patients with NSCLC to its existing phase I trial of the targeted therapy, and she went on to lead the expansion trial that paved the way for the FDA’s approval of crizotinib in 2011.2
The doctor and her colleagues presented their results at the 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO).
It was clear from the beginning that crizotinib held enormous promise, Shaw recalled.
The first patient enrolled in the trials “was in his 40s, was very, very sick, and had gone through many therapies,” she said. “Because his tumor was positive for ALK, he was started on this therapy, and he had an amazing response. We knew in early 2008 this was going to be a new kind of paradigm in lung cancer.”
Shaw described the breakthrough as an example of “serendipity in science and medicine,” and the same might be said of her decision to switch her focus from benchside to translational research.
Since she made that change, Shaw has won broad recognition for her contributions to the treatment of NSCLC, including the use of crizotinib to target the ROS1
gene rearrangement and research into other emerging agents.
Focusing on Targeted Therapies
Today, Shaw serves as an attending physician in MGH’s Center for Thoracic Cancers, an assistant professor of Medicine at the affiliated Harvard Medical School, and a clinical investigator at MIT’s David H. Koch Institute for Integrative Cancer Research.
She is running trials of next-generation ALK inhibitors designed to work after patients develop resistance to crizotinib. And, she’s seeking better therapies for the patients whose mutations are not yet treatable with targeted medications, including those whose tumors express mutated KRAS
“Most of our patients don’t have known targets,” Shaw said. “We need to find more molecular targets and develop effective targeted treatments to help those patients whose only option is standard chemotherapy. There are exciting new targets and trials coming along, so I’m optimistic.”
To pursue those goals, Shaw must give her attention to a variety of tasks.
Based primarily at MGH, she spends about half her time treating patients both in the clinic and hospital, and the other half conducting research.
Her research time, in turn, is split between her leadership of phase I through III clinical trials and “trying to study specific areas from a basic standpoint that we can translate quickly into the clinic.”
While Shaw no longer runs her own lab, she works with collaborators who do. One is Jeffrey A. Engelman, MD, PhD, director of the Center for Thoracic Cancers at MGH, who partners with Shaw on her translational work.
“I help supervise a postdoc in his lab who’s working on the projects,” said Shaw, who also guides other medical oncology fellows. “Jeff is his research mentor and I’m his clinical mentor. It highlights the way this field is evolving, which is that no single person can do everything.”