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Rociletinib shows promising activity against treatment-resistant EGFR-mutated lung cancer

Date:
April 29, 2015
Source:
Massachusetts General Hospital
Summary:
A new targeted therapy drug against EGFR-mutation driven lung tumors that have become resistant to current therapies shows activity against the most common resistance mutation, significantly improving outcomes for patients.
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A new targeted therapy drug against EGFR-mutation driven lung tumors that have become resistant to current therapies shows activity against the most common resistance mutation, significantly improving outcomes for patients. Results of the phase I/II clinical trial of rociletinib (previously known as CO-1686) are being published in the April 30 New England Journal of Medicine. Preliminary results of the trial were previously presented at the 2014 meeting of the American Society of Clinical Oncology.

"Our finding that rociletinib is an active treatment for EGFR-mutant tumors that have developed T790M-driven resistance is a great leap forward for patients because until now we have not had an effective personalized therapy for them," says Lecia V. Sequist, MD, MPH, of the Massachusetts General Hospital (MGH) Cancer Center, principal investigator of the trial and corresponding author of the NEJM paper. "The EGFR-directed therapies erlotinib and afatinib have become the standard of care for U.S. patients with this form of lung cancer. But while they work great initially, resistance sets in after an average of around a year. In 50 to 60 percent of cases that resistance is driven by the T790M mutation."

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, and in about 12 percent of patients -- an even higher percentage in those of Asian ancestry -- the tumor is driven by EGFR (epidermal growth factor receptor) mutations, which stimulate uncontrolled cellular growth. Drugs like erlotinib (Tarceva) and afatinib (Gilotrif) -- called tyrosine kinase inhibitors (TKIs) -- block EGFR activity, leading to regression of tumor growth and relief of symptoms. Development of the additional T790M mutation induces resistance to first-generation TKIs, and a group of second-generation EGFR inhibitors did not prove to be effective against tumors with T790M. In addition, all prior EGFR inhibitors often caused significant skin inflammation and diarrhea.

A total of 130 NSCLC patients whose tumors had become resistant to first- or second-generation TKIs enrolled in the trial at 10 centers in the U.S., France and Australia. The phase I portion of the trial tested increasing dosages of rociletinib -- an oral medication that inhibits both the original EGFR driver mutations as well as the T790M resistance mutation -- to test for toxicities and determine the most effective dose. The phase II portion, which was limited to those with treatment resistance confirmed to be caused by the T790M mutation, tested additional patients at twice-daily rociletinib doses of 500, 625 and 750 mg.

In almost 60 percent of the 92 participants in who received doses at levels determined to be effective, treatment resulted in tumor shrinkage and significant symptom relief, results that Sequist says have lasted up to 9 or 10 months. Since rociletinib only targets mutated forms of EGFR, the unpleasant side effects of broader EGFR inhibition did not occur. The only significant side effect was an increase in blood sugar levels, which was easily controlled with blood-sugar-lowering medications.

"This is a potential game changer for lung cancer patients whose disease is driven by EGFR mutations," says D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado Cancer Center and the study's senior author. "Previously, once tumors learned to evade treatment with first-line EGFR inhibitors, we had no second targeted treatment. With these promising results, it is looking extremely likely that we now have a therapy that will keep people alive, well and in the game."

Sequist acknowledges that resistance to rociletinib does develop but notes that the drug's lack of action against nonmutated EGFR may make it a better candidate for combining with other drugs to combat the next level of resistance. "We are entering a new era of breakthroughs for treating EGFR-mutant cancer. Rociletinib and other 3rd generation EGFR TKIs will have an enormous impact both as individual treatments and in novel combination regimens," she says.

"It's important to understand how much of a difference this drug has made in the lives of the patients in the trial," Sequist stresses. "An additional year of cancer control can mean the birth of a grandchild or the ability to attend weddings and graduations. I witnessed patients being able to go on amazing trips with their families -- to run, bike, row, swim and literally to climb mountains -- because their disease was under control and their symptoms were improved. For many patients this drug was truly a miracle in their lives."


Story Source:

Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.


Journal Reference:

  1. Lecia V. Sequist, Jean-Charles Soria, Jonathan W. Goldman, Heather A. Wakelee, Shirish M. Gadgeel, Andrea Varga, Vassiliki Papadimitrakopoulou, Benjamin J. Solomon, Geoffrey R. Oxnard, Rafal Dziadziuszko, Dara L. Aisner, Robert C. Doebele, Cathy Galasso, Edward B. Garon, Rebecca S. Heist, Jennifer Logan, Joel W. Neal, Melody A. Mendenhall, Suzanne Nichols, Zofia Piotrowska, Antoinette J. Wozniak, Mitch Raponi, Chris A. Karlovich, Sarah Jaw-Tsai, Jeffrey Isaacson, Darrin Despain, Shannon L. Matheny, Lindsey Rolfe, Andrew R. Allen, D. Ross Camidge. Rociletinib inEGFR-Mutated Non–Small-Cell Lung Cancer. New England Journal of Medicine, 2015; 372 (18): 1700 DOI: 10.1056/NEJMoa1413654

Cite This Page:

Massachusetts General Hospital. "Rociletinib shows promising activity against treatment-resistant EGFR-mutated lung cancer." ScienceDaily. ScienceDaily, 29 April 2015. <www.sciencedaily.com/releases/2015/04/150429182434.htm>.
Massachusetts General Hospital. (2015, April 29). Rociletinib shows promising activity against treatment-resistant EGFR-mutated lung cancer. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/04/150429182434.htm
Massachusetts General Hospital. "Rociletinib shows promising activity against treatment-resistant EGFR-mutated lung cancer." ScienceDaily. www.sciencedaily.com/releases/2015/04/150429182434.htm (accessed May 23, 2017).

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