February 2016 Edition Vol.11, Issue 2

At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers

At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers (continued)

Acute Myeloid Leukemia (AML)

There hasn’t been a new drug approval in AML in decades, but if the data hold, the FLT3 inhibitor, midostaurin, will interrupt that streak.

“FLT3 is an activating mutation that occurs in about 30% of patients with AML,” said Richard Stone, MD, of the Dana-Farber Cancer Institute, Boston, MA, reporting on this study with midostaurin. “And, about three quarters of these patients have the ITD (internal tandem duplication) or TKD (tyrosine kinase domain) mutation, which has a particularly poor prognosis.”

In the CALGB 10603 Phase 3 trial, standard-of-care chemotherapy, plus or minus midostaurin, was given to newly-diagnosed AML patients with the FLT3 mutation (N=717).

“This is very much of a real world trial,” said Dr. Stone. “We’re taking patients right from diagnosis on forward.”

Results of this investigation showed that after a follow up of 57 months, the median overall survival (OS) was 74.7 months in the midostaurin plus chemotherapy arm vs 25.6 months for the chemotherapy alone arm (P=0.008). Treatment with midostaurin was also favored by patients in the comparative rates of event-free survival (P=0.003).

This benefit was also seen for the more dire FLT3 molecular subtypes, prompting Dr. Stone to suggest that, “Midostaurin plus chemotherapy should be studied in FLT3 wild type and/or older AML patients.”  

Commenting on the results, Mark Levis, MD, Johns Hopkins University, Baltimore, MD, noted that FLT3 has been targeted before. “We’ve been trying to develop FLT3 inhibitors for some time—at least 6 have made it as far as Phase 3 trials.”

So how is midostaurin any different from those that have come before? “Its advantage against some of the other compounds is the fact that it’s active in both ITD and TKD mutations,” said Dr. Levis, and further, it’s multi-targeted. “What we’ve learned about AML in the last few years from whole genome sequencing is that the disease at diagnosis is more polyclonal.” So, an agent that is highly selective against FLT3 would be more effective in the relapse setting, which tends to be more clonal, than in treatment-naive patients, where Dr. Levis suggested midostaurin should be positioned. 

Multiple Myeloma (MM)

Recently FDA-approved daratumumab for the treatment of MM is an antibody drug targeted to the cell surface glycoprotein CD38. “This target is highly expressed in myeloma cells,” said Torben Plesner, MD, Vejle Hospital, Vejle, Denmark. The drug has several distinctive killing mechanisms. “First, by immune-mediated (killing) via complement or other innate mechanism; second, by directly engaging multiple myeloma cells; and third, by the immunomodulatory function of daratumumab that eliminates T-regs — cells that suppress the immune response,” explained Dr. Plesner.

In the Phase 1/2 GEN503 trial, daratumumab was combined with the standard-of-care combination of lenalidomide/dexamethasone (LEN/DEX) in a cohort of relapsed and refractory MM patients (N=32).

Prior to this study, single-agent therapy with daratumumab demonstrated an overall response rate (ORR) of 31% with a median OS of 19.9 months; and the LEN/DEX doublet demonstrated an ORR of 60.6% and a median progression-free survival (PFS) of 11months. In the GEN503 study, the combination of all three agents surpassed the previous benchmarks demonstrating an ORR of 81% and OS was 90% at 18 months.

Regarding adverse events, there were no surprises: “We saw no new safety signals with the addition,” said Dr. Plesner. The most common events were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasm (44%).

Phase 3 investigations with the triplet are ongoing. 

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