Thanks to the work of Drs. Alice Shaw and Jeff Engelman, important discoveries are being made about ALK-positive non-small-cell lung cancer at Mass General.

Two studies authored by physician-scientists at the Mass General Cancer Center show that ceritinib, a targeted cancer therapy drug, is an effective new treatment option for patients with ALK-positive non-small cell lung cancer (NSCLC).

Jeff Engelman, MD, PhD
Jeff Engelman, MD, PhD

These studies, published by Alice Shaw, MD, PhD and Jeffrey Engelman, MD, PhD, reveal that ceritinib can be used to treat tumors that have become resistant to crizotinib, a targeted therapy used to treat ALK-positive NSCLC. Both studies also show that ceritinib is a successful therapy for lung cancer tumors that haven’t previously been treated with crizotinib.

NSCLC is the leading cause of cancer death in the U.S., and is expected to account for over 85% of the country’s 224,000 new cases of lung cancer in 2014. Around 5% of NSCLC cases are driven by mutations in the ALK gene, which can lead to uncontrolled tumor growth and survival.

“Crizotinib has become a standard treatment agent for patients with advanced, ALK-rearranged NSCLC, but patients invariably develop resistance, leaving their treatment options limited,” says Dr. Shaw. Drs. Shaw and Engelman, along with the experts at the Center for Thoracic Cancers, have focused their research on determining how tumors acquire resistance to targeted therapies like crizotinib, and identifying new therapies to combat this resistance.

Studies Show the Potential for an Exciting New Therapy

The first study, published in the New England Journal of Medicine, analyzed the results of a 130 patient, phase 1 – or “first in human” – clinical trial that tested the safety and tolerability of ceritinib for individuals with advanced ALK-positive NSCLC. The study gave researchers a first look at ceritinib’s antitumor activity in humans.

Tomographic scans taken at baseline (left) and after 3.5 weeks of ceritinib treatment (right) in a patient with crizotinib-resistant disease.
Tomographic scans taken at baseline (left) and after 3.5 weeks of ceritinib treatment (right) in a patient with crizotinib-resistant disease.

Researchers found that ceritinib caused ALK-positive tumors to rapidly deteriorate. Around 60% of study participants experienced dramatic shrinkage in the size and number of their tumors. “We found ceritinib to be highly effective in the majority of crizotinib-resistant patients, as well as those who had never received the drug, with mostly mild and manageable side effects,” says Dr. Shaw, the lead author on the paper.

Unfortunately, as with crizotinib, the majority of patients in the trial eventually developed resistance to ceritinib. Most patients acquired resistance after an average of seven months. Still, patients whose tumors have kept responding to ceritinib have continued to receive the drug – some even after two years.

The second study, published online in Cancer Discovery, found that ceritinib is able to overcome several ALK mutations that are known to foster crizotinib resistance. The study identified two additional mutations that cause tumors to become resistant to both crizotinib and ceritinib. “These findings help us understand both the benefit and limitations of ceritinib and the need to develop ALK inhibitors that can overcome these more recalcitrant mutants,” says Dr. Engelman, senior author of both the Cancer Discovery and the NEJM papers.

Building On a Record of Groundbreaking Lung Cancer Research

“We found ceritinib to be highly effective in the majority of crizotinib-resistant patients, as well as those who had never received the drug, with mostly mild and manageable side effects,” says Dr. Shaw.

Drs. Shaw and Engelman’s research is the latest example of the pioneering efforts in targeted cancer therapy taking place at the Center for Thoracic Cancers.

In 2011, Dr. Shaw served as the principal investigator for an early-stage clinical trial that led to the accelerated FDA approval of crizotinib in the treatment of patients with ALK-positive NSCLC. In 2013, she and her team published the results of a phase 3 trial that demonstrated that crizotinib is a safe and effective alternative to standard chemotherapy for patients with advanced ALK-positive NSCLC tumors.

This research is continuing at a rapid pace. Preliminary data from the NEJM study prompted the FDA to designate ceritinib a “breakthrough therapy” in 2013. The drug’s manufacturer, Novartis Pharmaceuticals, has applied for accelerated FDA approval. Dr. Shaw is currently serving as the principal investigator for two phase 2 clinical trials. Two phase 3 trials – one being offered at the MGH – are currently enrolling patients.

To learn more about how you can support lung cancer research at the Center for Thoracic Cancers, contact us.