Hematology Drugs in the Pipeline
Monday, November 23, 2015
Several clinicians from Weill Cornell Medicine were called upon by HemOnc Today to provide insight into promising new hematology drugs. Read the full report here.
Richard R. Furman, M.D.
One of the new agents that I’m most excited about is ACP-196 (Acerta Pharma), which is a second-generation inhibitor of Bruton’s tyrosine kinase (BTK). ACP-196 binds to BTK at the same amino acid residue as ibrutinib (Imbruvica; Pharmacyclics, Janssen) does, but it is more selective in its binding. Although ibrutinib targets BTK, it also binds to eight other enzymes. The most common side effects seen with ibrutinib — namely diarrhea, bruising and atrial fibrillation — are the results of these off-target effects. ACP-196, given its better selectivity, has not been associated with diarrhea, bruising or atrial fibrillation.
My hope is that we not only have an agent that works incredibly well in CLL, but now have an excellent agent that works incredibly well with no toxicities. That is really the Holy Grail of what we would hope to achieve in terms of treatment for our patients.
John P. Leonard, M.D.
One of the new agents in clinical trials that I think is very interesting is a drug called selinexor (Karyopharm Therapeutics), a selective inhibitor of nuclear export. It interferes with trafficking of molecules in and out of the nucleus. The net effect of this drug is that it affects growth signals and results in antiproliferative effects in a variety of different lymphomas.
This is exciting, in part, because it is an oral agent that seems — at least at this point — to have activity in highly aggressive lymphomas, such as large-cell lymphoma, Richter’s transformation and double-hit lymphoma. These subtypes have very little in the way of good therapies for the relapsed setting. Most novel agents have limited efficacy there. The idea that this drug potentially has activity in these aggressive relapsed lymphoma subtypes is quite exciting. It may offer a new option, and we — along with others — are now looking at it in combination with rituximab (Rituxan; Genentech, Biogen Idec) and in combination with chemotherapy to see if we can really make an impact in what are among the highest unmet need areas of lymphoma.
Ruben Niesvizky, M.D.
The most exciting findings in the pipeline for myeloma appear to be related to immune-regulation drugs. The most recent published manuscripts emphasize elotuzumab (AbbVie, Bristol-Myers Squibb), a SLAMF7 antibody, and daratumumab (Janssen), an anti-CD38 antibody.
A recent randomized trial compared elotuzumab, lenalidomide (Revlimid, Celgene) and dexamethasone with a control regimen of lenalidomide and dexamethasone in patients with relapsed/refractory myeloma. It was very encouraging to find the infusion therapy was not toxic and that elderly patients can receive this therapy without any major infusion reactions.
Further, although single-agent activity has not been demonstrated, prolongation of PFS has been shown for the elotuzumab group, particularly in patients who are naive to lenalidomide. I can foresee using elotuzumab in combination with lenalidomide and dexamethasone earlier in the disease — particularly in those patients who have not received lenalidomide — and that we will achieve long-term results, especially among the elderly or the infirm, for whom multiple comorbidities would preclude other types of therapy.
Randomized trials of daratumumab are ongoing. The New England Journal of Medicine published results from a frontline phase 2 regimen of daratumumab that showed staggering responses, particularly in patients who have gone through several lines of therapy, including proteasome inhibitors and immunomodulators. This is the first monoclonal antibody that has shown high single-agent activity, even in relapsed/refractory patients.
I can foresee seeing this agent move forward in the frontline and, more importantly, in combinations.