Nivolumab Safe and Effective for Treatment of Various Subtypes of Non-Hodgkin Lymphoma

Nivolumab, a monoclonal antibody that targets programmed death-1 (PD-1) receptors on T cells, has previously been shown to produce durable responses in patients with solid tumors, and recent results from a phase Ib study published in the Journal of Clinical Oncology show that the drug was well tolerated in patients with a variety of lymphoma subtypes and multiple myeloma (MM).

In this open-label, dose-escalation, cohort-expansion study, Alexander M. Lesokhin, MD, of Memorial Sloan Kettering Cancer Center in New York, and authors evaluated the safety and efficacy of nivolumab monotherapy in 81 patients with various hematologic malignancies, including:

  • 10 with follicular lymphoma (FL)
  • 11 with diffuse large B-cell lymphoma (DLBCL)
  • 10 with other B-cell lymphomas
  • 13 with mycosis fungoides (MF)
  • 5 with peripheral T-cell lymphoma (n=5)
  • 5 with other T-cell lymphomas
  • 27 with MM

Adult patients were eligible for the study if they had an Eastern Cooperative Oncology Group performance status of 0-1 with detectable or measurable disease and had received at least one prior chemotherapy regimen. Patients were excluded if they had central nervous system involvement, concomitant secondary malignancies, active autoimmune disease, prior transplantation, prior treatment with immune checkpoint antibodies, or concurrent treatment with receptor activators of nuclear factor-кB ligand inhibitors.

Patients were enrolled between August 2012 and April 2015. The median number of prior systemic treatment regimens was three (range = 1-12 regimens).

During the dose-escalation phase, patients were treated with 1 mg/kg or 3 mg/kg of nivolumab as a one-hour infusion at weeks one and four, then every two weeks for up to two years until disease progression, unacceptable toxicity, or complete response. The maximum-tolerated dose was not reached, so patients in the cohort expansion were treated with 3 mg/kg of nivolumab.

The overall median follow-up was 66.6 weeks (range = 6-81.6 weeks), and durations of response ranged from six to 81.6 weeks. (See TABLE for response rates associated with nivolumab.)

“With continued nivolumab therapy, the depth of objective responses may improve as demonstrated by one patient with DLBCL with an initial partial response (at 16 weeks) that converted to a complete response (at 72 weeks) with extended treatment,” the authors wrote. “Response durations exceeded one year for two (one each with FL and DLBCL) of three patients who achieved a complete response and six months for patients with FL who achieved a partial response.”

All patients with non-Hodgkin lymphoma (NHL) and MM who received at least one dose of nivolumab monotherapy were included in the safety evaluation (primary endpoint) and anti-tumor activity analysis (secondary endpoint).

Sixty-five percent of patients experienced treatment-related adverse events (AEs; n=53), most of which were grade 1 or 2. However, 15 of these (18%) were grade 3 AEs, two had grade 4 AEs, and one had a grade 5 AE.

Immune-mediated AEs occurred in 34 percent of patients (n=28), and again, most of these were grade 1 or 2. These AEs responded without treatment or interruption of nivolumab in 46 percent of patients (n=13); 15 patients required treatment for these AEs, five of whom had to discontinue nivolumab.

Overall, 15 percent of patients (n=12) discontinued nivolumab due to AEs. One death occurred due to fatal pneumonitis in a 51-year-old woman with small lymphocytic B-cell lymphoma.

Fluorescent in situ hybridization (FISH) was performed in 27 patients to evaluate the tumor cells and immune-infiltrating cells for expression of immune-modulating proteins, including PD-L1 and PD-L2. Genetic alterations within the 9p24 locus were detected in three patients. “Genetic alterations of PD-L1 and PD-L2 were rare among the NHLs evaluated in this study – a stark contrast to the frequent 9p24.1 alterations in HLs [from previous studies],” the authors wrote. Analysis of immunohistochemical staining also revealed that “PD-L1 and, to a lesser extent, PD-L2 proteins were expressed by nonmalignant cells within the tumor microenvironment in NHLs, including certain FLs.”

“These data highlight the likely differences in the frequency of 9p24.1 alterations and associated expression of the PD-1 ligands in specific lymphoid malignancies,” they concluded. A phase II study is ongoing to assess the role of the PD-L1 and PD-L2 biomarkers as predictors of response to nivolumab in patients with DLBCL and FL.

“Nivolumab may have some activity in NHLs, specifically in FL, DLBCL, and some subsets of T-cell lymphoma,” Dr. Lesokhin told ASH Clinical News. “These early results are encouraging, but at this point it is probably too early to say how this therapy will ultimately fit in with current treatment paradigms for various subtypes of NHL.”

Dr. Lesokhin also discussed the limitations of the study, noting, “this trial was an initial safety study in a variety of different blood cancers, [and] the patient populations are quite heterogeneous. Thus, definitive conclusions about single agent efficacy cannot be made.”


Reference

Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase Ib study. J Clin Oncol. 2016 June 6. [Epub ahead of print]

TABLE. Efficacy Outcomes Associated With Nivolumab Treatment
Tumor Objective Response Complete Response Partial Response Stable Disease Median PFS in weeks
B-cell lymphoma (n=31) 8

(26%)

3

(10%)

5

(16%)

16

(52%)

23

(95% CI 7-44)

    DLBCL (n=11) 4

(36%)

2

(18%)

2

(18%)

3

(27%)

7

(95% CI 6-29)

    FL (n=10) 4

(40%)

1

(10%)

3

(30%)

6

(60%)

NR

(95% CI 7-NR)

    Other B-cell
lymphoma
(n=10)
0 0 0 7

(70%)

11

(95% CI 3-39)

T-cell lymphoma (n=23) 4

(17%)

0 4

(17%)

10
(43%)
10

(95% CI 7-33)

    MF (n=13) 2

(15%)

0 2

(15%)

9

(69%)

10

(95% CI 7-35)

    PTCL (n=5) 2

(40%)

0 2

(40%)

0 14

(95% CI 3-NR)

    Other CTCL (n=3) 0 0 0 0 7

(95% CI 6-NR)

    Other non-CTCL
(n=2)
0 0 0 1

(50%)

10

(95% CI 2-18)

Multiple myeloma 1

(4%)

1

(4%)

0 17

(63%)

10

(95% CI 5-15)

PFS = progression-free survival; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; NR = not reached; MF = mycosis fungoides; PTCL = peripheral T-cell lymphoma; CTCL = cutaneous T-cell lymphoma

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