Jorge E. Cortes, MD: Yes, it’s an interesting trial and it’s an interesting drug. As you know, glasdegib is a smoothened inhibitor that goes to this hedgehog pathway that’s very important in embryogenesis, but it’s shut down essentially at birth. But it is very important in the maintenance of the cancer stem cells in general, and certainly of leukemia stem cells. These drugs have been mostly investigated and approved in basal cell carcinoma of the skin. That’s for some of the others, not glasdegib. But some of the others have been approved and that’s their benefit.

With this drug we did some early preclinical work in leukemia, [with] Catriona Jamieson [MD, PhD] at UCSD [University of California San Diego], and it showed some potential benefit. That led to the investigation AML [acute myeloid leukemia]. So to make the story short, after investigating single-agent and some phase I data in combinations, we took these to the randomized phase II study of low-dose Ara-C alone or in combination with glasdegib. This was meant for patients who were over the age of 55 but who had comorbidities that made them not good candidates for intensive chemotherapy. And they were defined in the study as being at least one of: 75 or older, having a performance status of 2 or greater, having a creatinine above 1.3, or having poor cardiac function, decreased ejection fraction, or some other cardiac problems.

And the median age on this study was over 75 in both groups. Sixty percent of them had cardiac issues; 50% had a performance status of 2 or more, so it was really those patients. The glasdegib is given orally, so that was continuously administrated. The cytarabine was…twice daily for 10 days. The primary endpoint was overall survival, and the study was very positive. It showed essentially a doubling of the survival from 4 months to 8 months, the median survival.

And actually, at ASCO [the American Society of Clinical Oncology annual meeting] here, we are showing the 2-year follow-up, and by 2 years you still have 20% of patients alive compared to 2% in the control arm. So a 10-fold higher probability of being alive after 2 years.

In terms of safety, these drugs have some class effect safety, some adverse events, dysgeusia and muscle cramps are the ones that stand out the most, and fatigue to some extent. And sure enough, they’re seen more. Yet, the patients were able to stay on therapy and continue seeing the benefit.

Everything else was very similar between the 2 arms. There was no increased myelosuppression. There were no increased infectious complications. A little bit more of these with combination, a little more of that with the low-dose Ara-C, but very similar [adverse] effects. So it’s a very attractive treatment option for this patient population with a good safety profile that gives us 1 more tool to add to the armamentarium.

Harry Erba, MD, PhD: I think that’s what we can say, we have another drug that we can now figure out how best to use in the management of a patient with AML.

Jorge E. Cortes, MD: There are ongoing combinations with hypomethylating agents, standard chemotherapy, so we’ll see if that can be extended to these other groups.

Transcript Edited for Clarity