Three More Drugs Judged “Breakthroughs”

Three companies separately announced in September that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to one of their experimental oncology drugs. The agents are under development for the treatment of certain leukemias and breast and lung cancers.

Introduced in July 2012, the Breakthrough Therapy designation is similar to the agency's Fast Track designation. Both programs, which offer frequent meetings and correspondence with the FDA as well as rolling review of sections of the approval application, are reserved for drugs that treat serious or life-threatening conditions. Additionally, Breakthrough Therapies demonstrate evidence of substantial improvement over existing therapies on one or more clinically significant endpoints, entitling their developers to even greater interaction with the FDA.

The oncologic drugs volasertib (Boehringer Ingelheim Pharmaceuticals; Ridgefield, CT), entinostat (Syndax Pharmaceuticals; Waltham, MA), and alectinib (Roche; Basel, Switzerland) are the most recent recipients of the Breakthrough Therapy designation:

• Designed to inhibit polo-like kinase 1 (PLK1), volasertib is being evaluated for the treatment of patients ages 65 or older with previously untreated acute myeloid leukemia who are ineligible for the intensive chemotherapy regimen typically prescribed. PLK1 plays a role in regulating mitosis, and inhibiting this enzyme may lead to prolonged cell cycle arrest and, ultimately, cell death. In a phase II study, patients who received volasertib in combination with low-dose cytarabine experienced higher objective response rates and an improvement in event-free survival compared with patients receiving cytarabine alone.

• A histone deacetylase inhibitor, entinostat is under development for the treatment of advanced estrogen receptor–positive breast cancer, in combination with exemestane (Aromasin; Pfizer), in postmenopausal women whose disease progresses following treatment with an aromatase inhibitor. According to Syndax, entinostat may reverse resistance to hormone therapy, prolonging survival when given in combination with an aromatase inhibitor such as exemestane. A phase II study in these patients showed that entinostat, when added to exemestane, extended both progression-free and overall survival.

• A second-generation inhibitor of the anaplastic lymphoma kinase (ALK), alectinib (RO5424802/CH5424802) is being assessed in patients with ALK-positive non–small cell lung cancer that has progressed despite treatment with crizotinib. According to data from a phase I dose-escalation study presented at the European Cancer Congress in Amsterdam, the Netherlands, on September 30, the overall response rate was 59% among 37 evaluable patients.

As of September 20, the FDA had received a total of 89 requests for Breakthrough Therapy designation, of which 28 have been granted and 40 denied; the rest are pending review. The agency does not disclose any other information about the drugs unless they receive marketing approval.