Rociletinib could become a “game changer” in treating EGFR-mutation driven lung tumors which have become treatment resistant

by Bruce Sylvester: Rociletinib, an investigative therapy for treatment resistant EGFR-mutation driven lung tumors, shows activity against the most common resistance mutation, and it significantly improves clinical  outcomes.

Researchers reported findings from a phase I/II clinical trial of rociletinib on April 30, 2015 in the NEJM/New England Journal of Medicine.

“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,” said lead investigator and author Lecia  Sequist, MD, Associate Professor, Department of Medicine, Harvard Medical School in Boston and attending physician at the Massachusetts General Hospital Cancer Center in Boston. “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.”

As background the authors noted that non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. In approximately 12 percent of patients, and higher among those of Asian descent, the tumor is driven by EGFR, epidermal growth factor receptor, mutations, which stimulate uncontrolled cellular growth.

Tyrosine kinase inhibitors (TKIs) such as erlotinib (Tarceva) and afatinib (Gilotrif) block EGFR activity, thereby causing regression of tumor growth. But development of the additional T790M mutation causes resistance to first-generation TKI therapy.

The investigators enrolled 130 NSCLC patients with tumors resistant to first- or second-generation TKIs.

Study sites were in the U.S., France and Australia.

In phase I, the researchers tested increasing dosages of oral rociletinib, which inhibits both the original EGFR driver mutations as well as the T790M resistance mutation, for toxicities and for best dosing.

In phase II, limited to subjects with treatment resistance confirmed to be caused by the T790M mutation, they tested subjects at twice-daily rociletinib doses of 500, 625 and 750 mg.

They reported that in almost 60 percent of the 92 participants who received doses deemed to be effective, there was tumor shrinkage and significant symptom relief. And the effects have lasted up to 9 or 10 months.

Notably, since rociletinib targets mutated forms of EGFR, harsh side effects of wider EGFR inhibition did not appear. The only significant side effect was increased blood sugar, which was controlled with blood-sugar-lowering treatment.

“This is a potential game changer for lung cancer patients whose disease is driven by EGFR mutations,” said investigator and author D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado Cancer Center in Denver. “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.”