Promising Therapies in Multiple Drug Classes Being Explored for B-Cell Lymphomas

Wayne Kuznar

May 2015, Vol 6, No 4 - NCCN 2015 Updates


Hollywood, FL—Targeted therapy in B-cell lymphoma is rapidly expanding beyond anti-CD20 antibodies. Some of the emerging therapies are conjugated antibodies, treatments that target signaling pathways or apoptosis, immunomodulatory drugs (IMiDs), and immune checkpoint inhibitors, said Andrew D. Zelenetz, MD, PhD, Vice Chair, Medical Informatics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, at the 2015 National Comprehensive Cancer Network conference.

The major challenge in the development of new therapeutics—both CD20-­directed and non–CD20-directed—in lymphoma is that few patients enter into clinical studies. “We have too many drugs to test and not enough patients to test them in,” Dr Zelenetz said.

The CD20-directed cytolytic antibodies that have already been approved by the FDA include rituximab (Rituxan), ofatumumab (Arzerra), and obinutuzu­mab (Gazyva); the latter 2 are approved for the treatment of patients with chronic lymphocytic leukemia (CLL).

A head-to-head phase 2 clinical trial in patients with relapsed indolent non-­Hodgkin lymphoma (NHL) showed a trend toward higher overall response rates (ORRs) and complete remissions with obinutuzumab compared with ri­tuximab, with comparable safety and progression-free survival (PFS) seen at this early time point, said Dr Zelenetz.

Monoclonal Antibodies

Blinatumomab (Blincyto) is a T-cell–engaging bispecific monoclonal antibody that received accelerated FDA ­approval in December 2014 for the treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

Blinatumomab “brings the T-cell in juxtaposition to the B-cell, so that you can get signaling through the T-cell, to induce cytotoxic cell death,” Dr Zelenetz said.

In indolent lymphomas with a variety of histologies, the response rates to blin­atumomab have been 70% to 80%. In a phase 1 study of patients with indolent lymphoma, blinatumomab monotherapy used for only 4 to 8 weeks produced durable responses.

Antibody Drug Conjugates

Antibody drug conjugates are meant to deliver miniscule amounts of drugs, which normally have a narrow therapeutic index when given systemically, specifically to the tumor. Several antibody drug conjugates are in development for B-cell lymphoma and have shown “exciting clinical activity,” said Dr Zelenetz.

Pinatuzumab vedotin is a monoclonal antibody drug conjugate that targets CD22; polatuzumab vedotin is an antibody drug conjugate that targets CD79b. In the phase 2 ROMULUS study in patients with relapsed or refractory NHL, the median PFS was 5.4 months with pinatuzumab plus rituximab and 5.2 months with polatuzumab plus rituximab in the subset of patients with heavily pretreated diffuse large B-cell lymphoma (DLBCL).

“I would argue that picking the winner is really a matter of flipping a coin,” Dr Zelenetz said. “The PFS in this study is quite remarkably similar.”

In relapsed or refractory follicular lymphoma, however, polatuzumab had greater clinical activity than pinatuzu­mab, as evidenced by 40% versus 10%, respectively, of complete responses.

Targeting Critical Signaling Pathways

Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor and other key signaling pathways. Ibrutinib (Imbruvica), which targets BTK, has already been approved for the treatment of patients with CLL or mantle-cell lymphoma (MCL).

In relapsed or refractory activated B-cell–like subtype DLBCL, responses were observed with ibrutinib, and were stronger in patients with CD79B and MYD88 L265P mutations. Ibrutinib has demonstrated relatively modest activity in relapsed or refractory follicular lymphoma, with an ORR of 28%.

The PI3K enzyme is involved in several signaling pathways. The prototypical drug for the inhibition of PI3K delta is idelalisib (Zydelig), which is already approved for use in relapsed CLL, relapsed follicular lymphoma, and small lymphocytic lymphoma. In double refractory indolent NHL, the response rate to idelalisib was 57% in a phase 2 study, with an 11-month PFS.

“The major question for both of these pathway inhibitors is, ‘How do we integrate them earlier in the treatment in a way that fundamentally changes the natural history of the lymphomas we’re treating?’” said Dr Zelenetz.

Targeting Apoptosis

ABT-199 is a potent and selective second-generation BCL-2 inhibitor. In relapsed or refractory CLL, the ORR to ABT-199 monotherapy is nearly 80%, with a complete response rate of 23%.

ABT-199 has shown good activity in patients whose disease is refractory to fludarabine and patients with p53 mutations. In early data of patients with MCL, the ORR to ABT-199 was 70% to 80%. The use of ABT-199 warrants further clinical study in multiple NHL histologies, said Dr Zelenetz.

Immunotherapies

The IMiD lenalidomide (Revlimid) has been combined with rituximab for the treatment of indolent follicular lymphoma, with an ORR of 98% and a complete response rate of 87%, “and this has translated to durable responses in a variety of subtypes of indolent lymphoma,” Dr Zelenetz said.

In DLBCL, the response to lenalidomide is substantially different by the cell of origin, with “a pretty impressive 53% response rate among the non–germinal center tumors,” he noted. This is surprising, given the substantial activity in follicular lymphoma, a germinal center tumor.

The addition of lenalidomide to the R-CHOP (rituximab, cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone) regimen overcomes the adverse impact of a non–germinal center cell ­­of origin.

Immune checkpoint blockade has a rationale for use in patients with lymphoma based on the tumor microenvironment. There are a number of important checkpoints in the regulation of the immune response that are active in lymphomas, including PD-1 and PD-1 ligand 1 (PD-L1) or 2.

The preliminary results with nivolu­mab (Opdivo) and pidilizumab suggest antitumor activity, which “seems to be based on modulation of the tumor microenvironment given low-level PD-L1 expression on tumor cells,” Dr Zelenetz said.

Combining these agents with rituximab shows potential for improving response.