Nivolumab/Ibrutinib Combo Shows Promise for Richter Transformation

Silas Inman @silasinman
Published: Saturday, Dec 03, 2016

Dr Nitin Jain

Nitin Jain, MD

Treatment with the combination of nivolumab (Opdivo) and ibrutinib (Imbruvica) showed encouraging activity and safety in a small phase II study of patients with chronic lymphocytic leukemia (CLL) and Richter transformation (RT), according to Nitin Jain, MD, at the 2016 ASH Annual Meeting.

In the small ongoing 13-patient study, the overall response rate (ORR) was 80% for ibrutinib plus nivolumab in patients with relapsed/refractory CLL, which Jain labeled as modest. In those with RT, the combination elicited a more promising ORR of 60%, which included 2 complete responses (CR). Intriguingly, Jain noted, PD-1 expression on large cells appeared to predict greater activity in this cohort.

"Of the 5 patients with Richter transformation treated, 3 have an ongoing response, with a partial remission and 2 complete responses of the Richter component," said Jain, Department of Leukemia, The University of Texas MD Anderson Cancer Center. "We noticed increased PD-1 expression on the large cells in the 2 patients [with CR] that we have studied. This is preliminary data and needs to be confirmed in a larger dataset."

Prior to the study, PD-L1 inhibition was shown to have synergistic activity when used with ibrutinib in mouse models. Additionally, prior research has revealed increased expression of PD-1, PD-L1, and PD-L2 on CLL cells, suggesting that blocking these targets could help activate T cells and promote immunological synapse formation.

"Immune dysregulation in CLL is the result of overexpression of checkpoint receptors by T cells and the respective ligands on CLL cells," said Jain. "We hypothesized that inhibition of the checkpoints will result in correction of this immune dysregulation and an antileukemia effect."

Cohort 1 of the study enrolled patients with relapsed/refractory CLL (n = 5) or RT (n = 5) and cohort 2 included those with CLL who had received ibrutinib for ≥9 months but had persistent disease (n = 3). The primary objective of the study was focused on efficacy, specifically CR rates. Secondary endpoints looked at safety and survival rates, which were not yet presented.

In the first cycle of treatment for cohort 1, nivolumab was given as a single-agent at 3 mg/kg every 2 weeks. Daily ibrutinib was added at a standard 420 mg dose for subsequent cycles. In cohort 2, wherein patients were already receiving ibrutinib, nivolumab was added at 3 mg/kg every 2 weeks in the first cycle.

The median age of patients across both cohorts was 64 years (range, 42-78). Patients had received a median of 1 prior therapy (range, 1-4). Nearly half had a 17p deletion or TP53 mutation (46%) and 8% had a 11q deletion. IGHV was unmutated for 58% of patients.

Across both cohorts, immune-related adverse events (AEs) included grade 2 pneumonitis and thyroiditis, which occurred in 1 patient each. There were no grade ≥3 immune-related AEs and no safety-related treatment discontinuation.

In the RT arm, the 3 observed responses were seen in those with unmutated IGHV. Two had trisomy 12 and the remaining patient had a 17p deletion. All responses remained ongoing, with the first CR lasting 2+ months and the second 8+ months. The third patient had an ongoing partial response for 11+ months.

In cohort 2 of the study, all patients had stable disease. Patients in this group had received ibrutinib prior to the study for 13 to 32 months. "We did not notice an incremental improvement in their tumor burden, and so 2 of these 3 patients have gone off the study, at this time," Jain said.

The 2 patients with a CR in the RT arm were further analyzed for PD-1/PD-L1 expression on the cancer cells and T cells from bone marrow specimens. Higher expression of PD-1 was seen in the CLL cells and the RT cells. PD-L1 and PD-L2 expression was seen on less than 10% of cells. PD-1 was expressed highly at baseline on CD4 effector T cells.

"Whether the expression of PD-1 or PD-L1 in the tumor samples or the T cells leads to a response remains a valid question," said Jain. "We don't have the numbers right now to do that analysis."

The phase II study continues to enroll patients with relapsed/refractory or high-risk CLL and RT. A third arm is being added to explore the addition of ipilimumab (Yervoy), Jain noted. In this new cohort, patients will receive a triplet of nivolumab, ibrutinib, and ipilimumab. "This arm should open in the next few months," he said.
Jain N, Basu S, Thompson PA, et al. Nivolumab Combined with Ibrutinib for CLL and Richter Transformation: A Phase II Trial. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 59.


<<< View more from the 2016 ASH Annual Meeting



View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
Medical Crossfire®: Clinical Updates on PARP Inhibition and its Evolving Use in the Treatment of CancersMay 30, 20181.5
Publication Bottom Border
Border Publication
x