Recent years have seen an added emphasis on the relationship between cancer and the activity of the immune system. Novel agents that aim to harness the immune system have already been approved in the U.S. for solid tumors (Bristol-Myers Squibb/Ono Pharmaceutical's Opdivo [nivolumab] for NSCLC and malignant melanoma, and Merck & Co.'s Keytruda [pembrolizumab] for malignant melanoma), and are in development for a plethora of other oncology indications. Most of the development has been targeted towards solid tumors, but the potential of immune checkpoint inhibitors in hematological malignancies is becoming increasingly evident.

In lymphoma, where the standard care of chemo-immunotherapy backbones can induce high levels of remission and improve survival rates, there is still an high level of unmet need for therapies that not only decrease the patients,  relapse rates, but also reduce the toxicity experienced with current therapies. Novel mechanisms that can direct patients immune systems to mount an efficient response against the malignancy are therefore a very exciting avenue. Pilot studies indicate that PD-1 blockade could be an effective therapy for relapsed/refractory Hodgkin's lymphoma, as well as non-Hodgkin lymphoma (NHL) patients.

Compelling results of early trials using immune checkpoint inhibitors in hematological malignancies were presented at the recent European Hematology Association (EHA) 20th Congress. In particular, the activity demonstrated by nivolumab in relapsed/refractory Hodgkin's lymphoma patients has elicited great interest from the audience (Armand P, 2015).

  • Alterations in chromosome 9p24 in Hodgkin's lymphoma are very common, and these alterations increase the expression of PD-1 ligands PD-L1 and PD-L2. In addition, primary Hodgkin's lymphoma cells express PD-L1. This supports the rationale for using PD-1 targeting agents such as nivolumab in this indication.
  • Nivolumab was granted Breakthrough Therapy Designation (BTD) status by the FDA in May 2014, following positive results from a Phase I trial in relapsed/refractory Hodgkin's lymphoma patients.
  • Data presented at EHA20, although from a relatively small number of heavily-pretreated Hodgkin's lymphoma patients (n = 23), showed that nivolumab induced an impressive overall response rate (ORR) of 87%, with 17% complete response (CR) and 70% partial response (PR). The progression-free survival (PFS) at 24 weeks was 86%.
  • Nivolumab's toxicity profile was similar to that observed in solid tumors, with the most common drug-related adverse events being fatigue (15%), rash (11%), diarrhea, pneumonitis, pruritus (9% each), and pyrexia (8%). Grade 3/4 adverse events included pneumonitis, which was experienced by 5% of patients.
  • The registrational CheckMate-205 study, an ongoing Phase II trial of nivolumab in classical Hodgkin' lymphoma patients who have failed autologous stem cell transplantation (ASCT), is currently recruiting participants, and with best overall response of CR or PR as the primary end point, the trial plans to recruit 120 patients and is estimated to complete in May 2017.

Another immune checkpoint inhibitor in development for Hodgkin's lymphoma, pembrolizumab has demonstrated interesting clinical activity in relapsed/refractory patients. Data presented at EHA20 and at the American Society of Hematology (ASH) 2014 annual meeting indicates that this PD-1 inhibitor can also induce responses in previously-treated Hodgkin's lymphoma patients (Shipp M, satellite symposium, EHA20; Moskowitz C, 2014).

  • The patients enrolled in the study were previously treated with Seattle Generics/Takeda's Adcetris (brentuximab vedotin) (N = 29), and the majority had a prior stem cell transplant (69% of patients) or were transplant ineligible (28%). More than half of the patients were heavily pre-treated (five or more prior therapies).
  • Pembrolizumab induced an ORR of 65% (21% CR and 45% PR), and the median duration of response had not yet been reached.

Drs. John Timmerman and Philippe Armand presented data on PD-1-targeting agents in B-cell NHL patients. The rationale for using PD-1 inhibitors stems from studies indicating that PD-1 ligand (PD-L1) is expressed in B-cell lymphomas, where tumor associated T-cells are functionally suppressed. In particular, the ABC subtype of diffuse large B-cell lymphoma (DLBCL) expresses PD-L1 and can thus be a potential target for both PD-1 and PD-L1 targeting agents.

  • The CA209-039 Phase I trial is assessing nivolumab as monotherapy and in combination with Bristol-Myers Squibbs Yervoy (ipilimumab) and lirilumab (Innate Pharma) in relapsed patients with hematologic malignancies, including NHL (specifically, follicular lymphoma [FL] and DLBCL).
  • Preliminary data from this study show that in nivolumab induced ORRs of 40% and 36% in FL and DLBCL patients, respectively. The CR rates were similar across FL and DLBCL patients (10% and 9%, respectively), while a higher proportion of FL patients experienced stable disease compared with DLBCL (60% vs. 27%).
  • It is not yet clear whether the levels of PD-L1 expression in hematological malignancies directly influences the clinical activity of PD-1-targeting agents as they do in other tumor types such as NSCLC.

These data and physician's enthusiasm for novel agents that harness the immune system are supporting the significant clinical development that these agents are currently undergoing. Phase I and II trials are combining immune checkpoint inhibitors with current and emerging therapies for hematological malignancies, and some of these trials are listed below. It is too early to speculate on the outcome of immune checkpoint inhibitors in hematological malignancies, but these agents, impressive clinical activity in other indications, the significance of immune pathways across many hematological cancers, and the physician enthusiasm for such therapies are likely to buoy their development over the next few years.

Select clinical trials of immune checkpoint inhibitors in hematological malignancies:

  • Ibrutinib (Johnson & Johnson/Janssen/AbbVie/Pharmacyclics/Imbruvica) in combination with nivolumab, for relapsed/refractory or high-risk untreated chronic lymphocytic leukemia (CLL) patients (NCT02420912).
  • ACP-196 (Acerta Pharma's novel Bruton's tyrosine kisne [BTK] inhibitor) in combination with pembrolizumab in B-cell malignancies (NCT02362035).
  • Ibrutinib in combination with MEDI-4736 (AstraZeneca's PD-L1 inhibitor) in relapsed/refractory FL and DLBCL (NCT02401048).

Dana Gheorghe, Ph.D. is a senior business insights analyst on the Oncology team at Decision Resources Group.

Bibliography:
Moskowitz C, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). ASH 2014; Abstract 290.
Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. New England Journal of Medicine. 2015; 372: 311-319.
Armand P, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated safety and efficacy results of a phase 1 study (CA209-039). EHA20; Abstract S808.

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