Hematology Drugs in the Pipeline

Stephen M. Ansell, MD, PhD

Pembrolizumab, Nivolumab

The treatment approach that I believe holds the greatest promise to fill an unmet need and make a very significant impact on patients in general is PD-1 blockade with either pembrolizumab (Keytruda, Merck) or nivolumab (Opdivo, Bristol-Myers Squibb), in patients with Hodgkin’s lymphoma. This treatment has already demonstrated high response rates in previously treated patients. Looking to the future, using these agents in combination with earlier-phase approaches is likely to make a substantial impact on how we treat patients.

Richard R. Furman, MD

ACP-196

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, MD

Selinexor

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, MD

Elotuzumab, Daratumumab

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.

Azra Raza, MD

Rigosertib

Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis and increased risk for developing into acute myeloid leukemia. Patients with MDS who receive repeated blood transfusions also are at risk for chronic iron overload.
The last drug to be approved for MDS was 10 years ago. I am particularly encouraged by the responses to a small molecule inhibitor of cellular signaling called rigosertib (Onconova Therapeutics) in both lower-risk and higher-risk MDS patients.
Rigosertib acts as a RAS mimetic. The main activity is mediated through the RAS-binding domain (RBD) found in many effector proteins, exemplifying a novel approach to block the interactions between RAS and its RBD-containing targets, such as PI3 kinase, pathways implicated in the pathogenesis of MDS.
Rigosertib is available as an IV infusion and as oral capsules. More than 1,200 patients have been treated in clinical trials worldwide. Published results have shown that rigosertib has the potential to provide survival benefit to patients with high-risk MDS and to improve hematological function in patients with low-risk MDS.
The global phase 3 INSPIRE trial — currently enrolling patients — will evaluate IV rigosertib in patients with high-risk MDS who progressed on or failed to respond to a hypomethylating agent. Oral rigosertib is being developed as a single agent for the treatment of low-risk MDS, and in combination with azacitidine (Vidaza, Celgene) for the treatment of high-risk MDS and AML.

Paul G. Richardson, MD

Daratumumab

If I had to pick the most exciting new drug to emerge in this extraordinarily productive year for multiple myeloma, I would suggest daratumumab (Janssen and Genmab) as one of the most promising and arguably transformative in the long term, when added to the ongoing impact of proteasome inhibition — such as with bortezomib (Velcade; Millennium/Takeda) and carfilzomib (Kyprolis, Onyx) — and immunomodulatory drugs, such as thalidomide (Thalomid, Celgene), lenalidomide (Revlimid, Celgene) and pomalidomide (Pomalyst, Celgene).
Daratumumab is a very potent monoclonal antibody, with a completely new mechanism of action, and we have been privileged to be on the forefront of its clinical development from phase 1 through phase 3 as part of an international team.
Targeting CD38 with this very well-engineered antibody has proven highly successful and has been validated in subsequent studies by other antibodies in the same class. Most importantly, not only has daratumumab proven feasible to administer and active as a single
agent — as we very recently published in The New England Journal of Medicine — but, when combined with other drugs, its efficacy is particularly impressive.
Daratumumab as a single agent generates major clinical responses in about a third of otherwise highly refractory patients. When combined with lenalidomide, the response rates jump dramatically. In fact, close to 80% to 90% of patients with relapsed/refractory disease appear to respond, and I think this promises enormous benefit for patients in various settings in the future, such as part of upfront treatment as well as maintenance.
It is important to recognize that elotuzumab (AbbVie and Bristol-Myers Squibb) is another very promising advance in the monoclonal antibody space that has been validated in the phase 3 setting and — in my opinion — will be approved by the regulatory authorities hopefully this year, with great potential to meaningfully and further improve patient outcome.
I think the fact that daratumumab not only has single-agent activity but — just like elotuzumab — is highly active in combination with a different target, and has multiple effects that are beyond the immuno-oncologic spectrum alone, is especially compelling.
Two other new agents warrant mention. The approval of panobinostat (Farydak, Novartis) this year as a first-in-class molecule in the area of histone deacetylase inhibition is a milestone. In my view, next-generation inhibitors show great promise. Second, the results of ixazomib (Takeda) in combination with lenalidomide and dexamethasone in relapsed, refractory myeloma in the TOURMALINE study are very exciting for an all-oral approach, with excellent efficacy and favorable tolerability. For the first orally bioavailable proteasome inhibitor to enter phase 3 studies, these results — which will be fully shared as an oral presentation at the ASH Annual Meeting and Exposition in December — are especially provocative.
With all of the above in mind, and a true plethora of important and very good options emerging for our patients in a record-breaking year, I would propose daratumumab as the most promising single agent. Its unique mechanism of action and striking activity as monotherapy, its efficacy in combination and its manageable safety profile provide a vital new therapeutic approach for this otherwise very challenging disease.