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)

Ixazomib

Seemingly, a direct competitor to daratumumab—ixazomib, a proteosome inhibitor, plus LEN/DEX, represents an all-oral therapeutic option for MM.

In the Phase 3 TOURMALINE-MM1 investigation, the ixazomib/LEN/DEX triplet was tested in a population of relapsed and/or refractory MM patients vs LEN/DEX alone (N=722; of note, 70% of this cohort had already received an approved proteosome inhibitor).

The primary endpoint was PFS. After a median follow up of 15 months, a 35% improvement in PFS was observed (20.6 months in the triplet arm vs 14.7 in the doublet arm; P=0.012).

“The responses were very quick for the triplet combination,” reported study investigator, Philippe Moreau, MD, University Hospital of Nantes, Nantes, France. “The median time to response occurred at 1.1 months, with a median duration of response of 20.5 months (vs 15.0 months for the control arm).”

For adverse events, “There was more thrombocytopenia with ixazomib, but it did not impact the treatment plan.” Of note, peripheral neuropathy was not an issue in this trial, a potential advantage for patients since the already-approved proteosome inhibitor, bortezomib, is associated with a peripheral neuropathy rate of 30%. Further, bortezomib is an injected drug; ixazomib is an oral medication.

Chronic Lymphocytic Leukemia (CLL) 

First up, idelalisib is a first-in-class PI3k delta enzyme inhibitor previously approved for CLL patients who can’t receive standard-of-care chemotherapy due to toxicity. As reported by Andrew Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY, idelalisib was used in combination with rituximab and bendamustine (R/B), in a cohort of relapsed/refractory CLL patients in a Phase 3 trial (N=416).

“This study asks whether idelalisib could be added to a standard-of-care in this setting,” said Dr. Zelenetz.

Results were striking. After a planned interim analysis in October 2015, the study was stopped due to obvious efficacy.

“There was a highly statistically significant improvement in PFS of 23.1 months vs 11.1 months (P<0.0001),” reported Dr. Zelenetz. “The numbers for the doublet (R/B control arm) are as expected, so this represents a substantial increase in PFS.”

The benefit was observed across all CLL risk groups. Improvement in OS was also seen: 34% of patients receiving the doublet vs 51% of individuals in the idelalisib cohort were alive after a median follow up of 12 months (P=0.008).

As far as toxicity goes, the triplet had more treatment discontinuations: 26% of patients discontinued the triple vs 13% for the combination. Yet the question to ask is, would efficacy remain and toxicity lessen with the subtraction of bendamustine?

“It’s interesting to consider if bendamustine was necessary here,” said Dr. Zelenetz, “But that can’t be answered with this trial design.”

Venetoclax

Venetoclax is an oral agent that selectively inhibits BCL2, which is a protein highly expressed in CLL cells, and through which cell death via apoptosis can be triggered—independent of p53 activity.

In a pivotal Phase 2 international trial, venetoclax monotherapy was tested in a population of relapse/refractory CLL patients with 17p deletion (N=107).

“This is a very special population with the most dismal outcomes,” said study investigator, Stephan Stilgenbauer, MD, University of Ulm, Ulm, Germany. “These patients are resistant to conventional therapy.”

The reported ORR for this study was 79.4%, with 7.7% experiencing a complete response, a result Dr. Stilgenbauer described as “remarkable.”

Additionally, the treatment allowed for rapid recovery of the patient’s immune system. “With the exception of 4 patients, there was a normalization of lymphocyte count—with a dramatic disease reduction—at a median of 22 days.”

Given these results, Dr. Stilgenbauer suggested that venetoclax was well positioned for a place in novel combinations. 

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