ONCAlert | 2018 ASCO Annual Meeting

Emerging Targeted Therapies and Immunotherapies in CLL

Published Online: Jun 12,2017
Prospects for patients with chronic lymphocytic leukemia (CLL) have improved with the use of targeted agents such as ibrutinib (Imbruvica); however, complete remissions (CR) are rare, and treatment options for patients relapsing after treatment with ibrutinib remain limited.1 The potential synergy of ibrutinib with other treatment strategies, including immunotherapeutic and targeted approaches, is currently being investigated in various clinical trials with the hope of identifying novel combinations that increase responses and improve duration of response.
New targeted agents in development in CLL include second-generation inhibitors of Bruton’s tyrosine kinase (BTK) designed to improve safety and efficacy, and novel inhibitors of phosphoinositide 3-kinase (PI3K).2,3 Emerging therapies in CLL also include novel immunotherapeutic regimens using immune checkpoint inhibitors and adoptive immunotherapy using modified T lymphocytes.4

Venetoclax (Venclexta), a selective inhibitor of the B-cell lymphoma-2 (BCL-2) family of proteins, which regulate cellular apoptosis and oncogenic functions, is a standard-of-care treatment of relapsed or refractory 17p deletion (del[17p]) CLL, alone or in combination with rituximab (Rituxan), and has activity in patients relapsing or refractory to ibrutinib or idelalisib (Zydelig).5 The combination of venetoclax and rituximab plus bendamustine in patients with relapsed/refractory CLL, based on findings from the phase III MURANO study.6 Pretreating CLL cells with a BTK inhibitor, such as ibrutinib, has been shown to increase the dependence of CLL cells on BCL-2, enhancing CLL killing in response to venetoclax in cell culture studies.7
Supported by this rationale, the clinical utility and safety of a sequenced regimen of ibrutinib monotherapy for 3 cycles followed by combination therapy with ibrutinib and venetoclax is being explored in an ongoing phase II study in 78 patients with relapsed/ refractory CLL and in previously untreated patients with high-risk CLL, defined as the presence of either del(17p), mutated TP53, 11q deletion (del[11q]), unmutated IGHV, or ≥65 years.8 A phase II study is also evaluating ibrutinib plus venetoclax as a frontline therapy in a planned cohort of 150 patients with CLL.9
Potential synergy of BTK and BCL-2 inhibition is also being explored in a phase Ib/II study in patients with relapsed/refractory CLL, using a combination of obinutuzumab (Gazyva), ibrutinib, and venetoclax started sequentially, with gradual escalation of the venetoclax dose.10 The regimen was tolerated with toxicities consistent with those of the single agents. Response has been evaluated in 6 of 12 patients treated in the phase Ib portion of the study, with an ORR of 100% (5 partial responses [PRs] and 1 CR).10

The upregulation of inhibitory immune checkpoint pathways that control the T-cell response represents a major mechanism by which cancer cells escape elimination by the immune system. CLL cells express elevated levels of checkpoint inhibitory molecules, including programmed death 1 (PD-1), and its main ligands, PD-L1 and PD-L2.11 This provides a strong rationale to investigate immunotherapy with PD-1 checkpoint inhibitors in CLL, which is expected to enhance the activity of anti-CLL T- effector cells, resulting in immune-mediated elimination of CLL cells. The small molecule inhibitor ibrutinib has immunomodulatory properties because it also blocks interleukin-2–inducible T-cell kinase (ITK), in addition to BTK, producing a shift in the balance of T-helper cell populations.
Adding ibrutinib with PD-1 checkpoint blockade has enhanced antitumor activity in preclinical models, including ibrutinib-resistant lymphomas.12 An ongoing phase II trial is investigating combined checkpoint inhibitor therapy with the PD-1 inhibitor nivolumab (Opdivo) and ibrutinib in patients with relapsed/refractory CLL or Richter’s transformation (RT), or untreated patients with high-risk del(17p) CLL.13 An initial report of the first 12 patients was presented at the 2016 ASH Annual Meeting, reporting activity in ibrutinib-naive patients with relapsed/refractory CLL (PRs in 3 of 5 patients) or RT (2 of 4 patients), including 1 patient with del(17p), unmutated IGHV, complex karyotype CLL.14
A single-arm phase II study has previously demonstrated activity of ibrutinib in combination with rituximab in patients with high-risk CLL.15 The therapy was well tolerated and produced a response rate (ORR) of 95%, including a CR of 8% and a PR of 87%, and an 18-month progression-free survival (PFS) rate of 78% in all patients and 72.4% in patients with del(17p) or a TP53 mutation.15
Promising clinical activity of ibrutinib in combination with the CD20-targeted monoclonal antibody ofatumumab (Arzerra) has been reported from a phase I/II trial in 71 patients with relapsed/ refractory CLL; the combination produced a high ORR (71% to 100% in different dose schedules) and an estimated 12-month PFS of 75% to 89%.16 Frontline treatment with ibrutinib plus obinutuzumab is currently being compared with chlorambucil plus obinutuzmab in the phase III iLLUMINATE study in 212 treatment-naive patients with CLL, with results expected in late 2017.17
Ibrutinib has also been combined with the investigational glycoengineered CD20 antibody ublituximab (TG-1101). In a phase II study, 88% of patients (n = 41) with relapsed/refractory CLL responded to the combination, and the ORR was 95% among patients with high-risk (del(17p), del(11q), or TP53 mutation) CLL, including a subset (n = 3, 15%) who achieved negative minimal residual disease (MRD).18
The phase III GENUINE study (n = 126 patients) was designed to validate this combination in patients with previously treated high-risk CLL.19 According to recently released top-line data, the study met the primary endpoint by demonstrating a significant increase in ORR with ibrutinib plus ublituximab versus single-agent ibrutinib (80% vs 47%; P <.001).20
“We believe that the rapid responses seen in our phase II study with ublituximab plus ibrutinib are validated here in our phase III GENUINE study and are important markers of improved overall efficacy and patient outcomes,” stated study chair Jeffrey Sharman, MD, medical director for hematology research for the US Oncology Network in a prepared statement.
The combination of ibrutinib with obinutuzumab is the focus of a phase I/II study in 32 previously untreated patients with CLL, with safety, tolerability, dose-limiting toxicity, and ORR as primary outcomes.21

Recent outcomes from the randomized, placebo-controlled, phase III HELIOS study in patients with relapsed/refractory CLL have confirmed that the addition of ibrutinib to bendamustine and rituximab (BR) was beneficial and tolerable.22 After a median follow-up of 17 months, median PFS was not reached in the ibrutinib group versus 13.3 months in the placebo group (HR, 0.203; P <.0001), demonstrating a reduction of the risk of progression and death by 80%. PFS at 18 months was 79% versus 24% (P <.0001), and PFS benefits of ibrutinib were maintained in subgroups including refractoriness to purine analog therapy, del(11q), and unmutated IGHV. The ORR was 82.7% versus 67.8% (P <.0001), and the median OS was not reached in either group.23
Current trials evaluating ibrutinib in combination with chemotherapy as frontline therapy include a phase II study evaluating the addition of short-course udarabine to ibrutinib23 and a phase II study investigating ibrutinib plus udarabine, cyclophosphamide, and rituximab (FCR) in younger patients (<65 years).24
An ongoing phase III study of the German CLL Study Group has been designed to directly compare frontline standard chemoimmunotherapy (FCR, BR) therapy in physically fit patients with CLL who do not have del(17p) or TP53 mutations with combination regimens of targeted drugs, specifically rituximab plus venetoclax, obinutuzumab plus venetoclax, and obinutuzumab plus ibrutinib plus venetoclax.24

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Emerging Targeted Therapies and Immunotherapies in CLL
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