The Hematology Pipeline Features New Immune Therapies, and Targeted Agents

February 2017 Vol 10, Special Issue: Payers’ Perspectives In Oncology: ASH 2016 Highlights - Emerging Therapies
Wayne Kuznar

San Diego, CA—Immunotherapy, especially chimeric antigen receptor (CAR) T-cell therapy, and targeted agents continue to dominate the pipeline of therapies for hematologic malignancies. The following agents are some of the main drugs showing promising results that are under investigation and were featured at the 2016 American Society of Hematology meeting.

Acute Myeloid Leukemia

In a phase 2 study involving 132 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), the hedgehog signaling pathway inhibitor glasdegib added to low-dose cytarabine improved the median progression-free survival (PFS) from a mean of 4.9 months with low-dose cytarabine monotherapy to 8.8 months with the addition of glasdegib to low-dose cytarabine (see Glasdegib, a Hedgehog Inhibitor, Nearly Doubles Survival in AML or High-Risk MDS).

Entospletinib, an oral selective inhibitor of spleen tyrosine kinase, had significant clinical activity in a phase 1b/2 study of 12 patients with treatment-naïve AML. The 10 patients who completed the monotherapy lead-in period and induction chemotherapy attained complete response.

In a dose-escalation study of crenolanib, an oral pan-FLT3 inhibitor, involving patients with FLT3 mutation–positive relapsed or refractory AML, the overall response rate (ORR) was 36% in the 11 patients who were evaluable for response, which improved to 67% in those who received ≤2 previous therapies.

B-Cell Malignancies

Acalabrutinib monotherapy was well-tolerated and was associated with a 79% ORR in a phase 1/2 study involving 33 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) that was intolerant to ibrutinib (Imbruvica).

The irreversible selective Bruton’s tyrosine kinase inhibitor GS-4059 produced a median PFS of 39 months and an ORR of 86% in the long-term follow-up of a phase 1 multicenter study involving 28 patients with relapsed or refractory CLL. Responses were achieved irrespective of cytogenetics, IGHV hypermutation, or CLL-related mutation profile. Of the 28 patients included in this study, 17 are still participating in the study; 11 have received treatment for >3 years.

In a global phase 2 study, infusions of CTL019 resulted in complete remission or complete remission with incomplete blood count recovery in 82% (41 of 50) of pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) 3 months after receiving CTL019 infusion. The estimated relapse-free rate in patients who responded to CTL019 therapy was 60% 6 months after infusion of CTL019. The manufacturer expects to file for FDA approval of CTL019 in early 2017 for the treatment of pediatric and young adult patients with relapsed or refractory B-cell ALL.

RP6530, a novel dual PI3K inhibitor, produced consistent responses in patients with heavily pretreated relapsed or refractory B-cell malignancies. In the patients with Hodgkin lymphoma, the ORR was 29% and the disease control rate was 64%.

The administration of anti-CD19 CAR T-cells KTE-C19 achieved complete responses that were durable for >1 year in more than 75% of patients with diffuse large B-cell lymphoma in a phase 2 clinical trial. Nearly 50% of patients had a complete response, which is 6-fold higher compared with historical outcomes in this patient population (see Health Plans Must Monitor the Oncology Pipeline to Apply Appropriate Coverage Criteria, Maintain Treatment Value).

The second-generation PI3K inhibitor INCB050465 effects a high rate of rapid and deep responses, according to results from an open-label phase 1/2 study in patients with non-Hodgkin Lymphoma (NHL). In the study of 41 patients with B-cell malignancies, the ORR was 49%. In the 28 patients with NHL, the ORR was 64%, with 9 complete response or complete metabolic responses.

Multiple Myeloma

In a pilot clinical trial, 6 of 12 patients with advanced multiple myeloma had a very good partial response to anti-CD19 CAR T-cell administration (CTL019) after autologous stem-cell transplantation.

In a phase 1a/1b study of the selective histone deacetylase inhibitor citarinostat in combination with pomalidomide (Pomalyst)/dexamethasone in 56 patients with relapsed or refractory multiple myeloma, the confirmed ORR was 46%, and the median PFS was 6.5 months.

In a phase 1/2a study of indatuximab ravtansine, an antibody–drug conjugate comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid DM4 was combined with pomalidomide/dexamethasone or lenalidomide (Revlimid)/dexamethasone in patients with multiple myeloma. Of the 43 evaluable patients who received indatuximab ravtansine plus lenalidomide/dexamethasone, the ORR was 77%. The ORR was 54% among the 13 patients who were previously exposed to lenalidomide and bortezomib (Velcade). Of the 14 patients who received indatuximab ravtansine plus pomalidomide/dexamethasone, the ORR was 79%, and the median duration of response was 12.7 months, both of which are considerably higher than the 31% ORR and the median duration of response of 7 months reported for pomalidomide and dexamethasone alone, investigators reported.

In a phase 1b open-label study, the anti-CD38 monoclonal antibody isatuximab, in combination with carfilzomib (Kyprolis) was associated with a 66.7% ORR and an acceptable safety profile in patients with heavily pretreated multiple myeloma.

Myelodysplastic Syndrome

Subcutaneous administration of the hypomethylating agent guadecitabine (SGI-110) showed clinical activity in a phase 2 clinical trial involving 43 patients with high-risk MDS and 7 patients with chronic myelomonocytic leukemia. Of the 44 evaluable patients, 32% had a complete response, and the ORR was 71% (68% in MDS and 83% in chronic myelomonocytic leukemia). The median overall survival for the entire cohort was 14 months (see Novel Hypomethylating Agent Active in Patients with High-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia).

Polycythemia Vera

In an international phase 3 study involving 254 patients with polycythemia vera, ropeginterferon alfa-2b was noninferior to hydroxyurea in achieving a complete hematologic response, while reducing the rate of treatment-emergent adverse events.

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Last modified: February 21, 2017
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