by Stephanie Hawthorne; co-authored by Len Kusdra
Treatment of chronic lymphocytic leukemia (CLL) has enjoyed somewhat of a renaissance in the past couple of years. Until recently, therapy for both front-line and relapsed disease usually consisted of a Rituxan® (rituximab, Genentech)-based regimen often in combination with chemotherapy agents such as fludarabine or Treanda® (bendamustine, Teva). While CLL is a rather indolent disease and is usually sensitive to chemotherapy, curative outcomes are rare and the disease is associated with multiple relapses and multiple lines of treatment; about 70% of patients will go on to receive second-line therapy, and about 50% will receive third-line therapy.1 The lack of clinical development of more effective agents that can induce a more durable response has remained a high unmet need. This has changed recently with the approvals of novel agents such as Gazyva® (obinutuzumab, Roche/Genentech), Imbruvica®(ibrutinib, Pharmacyclics/Janssen) and Zydelig® (idelalisib, Gilead), which have begun to shift the landscape of front-line and relapsed disease, offering physicians more options to treat CLL. The various cytogenetic subpopulations exhibit differing responses for therapy and present a challenge on how to best treat them. One such population in CLL has been those patients carrying a del17p mutation, which has been shown to be associated with poor response to chemotherapy.
Venetoclax (ABT-199/GDC-0199, AbbVie, in collaboration with Genentech) is a small molecule inhibitor of Bcl-2, a protein that promotes cell survival; its overexpression is characteristic of CLL, thus representing a tantalizing target. Venetoclax monotherapy showed impressive activity in its dose-finding Phase I trial, demonstrating objective response rates (ORR) in over 70% of patients with CLL.2 This encouraged AbbVie to push venetoclax into late-stage clinical development with the initiation of two pivotal trials: a Phase II trial (NCTO1889186) evaluating venetoclax monotherapy in relapsed patients with del17p mutation and the Phase III MURANO trial (NCT02005471) evaluating venetoclax plus Rituxan versus Rituxan plus Treanda in a broader relapsed patient population.
Results from the Phase II trial were presented at a plenary session on Monday at the 57th American Society of Hematology (ASH) Annual Meeting, and the data continue to support the robust activity of venetoclax.3 Patients (n=107) were initially treated with venetoclax on a weekly dose ramp-up schedule (20, 50, 100, 200 and 400 mg) followed by a continual dose of 400 mg until disease progression or discontinuation for other reasons; this ramp-up dosing schedule along with risk-based prophylaxis was implemented to reduce the incidence of tumor lysis syndrome (TLS), a serious adverse event that was observed in early trials with venetoclax. The primary endpoint was ORR as determined by an independent review committee (IRC) as well as by investigator review. Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. As determined by IRC, the ORR was 79.4% (95% CI: 70.5%–86.6%), the complete remission with incomplete marrow recovery (CR/CRi) rate was 7.5%, and the nodular partial remission (nPR) rate was 2.8%. Of note, 52% of patients had no CLL in the bone marrow and 40% were minimal-residual disease (MRD)-negative in the peripheral blood, suggesting deep responses with venetoclax treatment. Median time to normalization of absolute lymphocyte count was 22 days, and only four out of 87 patients evaluated did not have normalization of absolute lymphocyte counts. In measuring tumor lesion diameter, 92% of patients (89/96) had a 50% of greater reduction in their largest nodal lesion diameter from baseline measurements. There were also very encouraging signals in durability of response. Estimates showed that responses continued at one year in 84.7% of patients who exhibited any kind of response, in 100% of patients exhibiting a CRi/nPR, and in 94.4% of patients who achieved MRD-negativity. The 12-month estimate of PFS was 72.0% (95% CI: 61.8-79.8) and 12-month estimated OS was 86.7% (95% CI: 78.6-91.9). The most common Grade 3-4 adverse events were neutropenia (17% Grade 3, 23% Grade 4), anemia (18%), thrombocytopenia (15%) and infection (20%, most common being upper respiratory tract). Laboratory signs for TLS occurred during the ramp-up period in five patients with no clinical consequence and were managed through dose interruption and electrolyte management.
Based on these promising data in relapsed/refractory del17p CLL, AbbVie has submitted an application for regulatory approval with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).4 Given the efficacy results and coupled with the breakthrough status awarded to venetoclax in May 2015 for this same treatment setting, approval of venetoclax seems likely to occur in the near future. In this context, the MURANO trial will serve as the confirmatory study, as well as expanding utilization options for venetoclax to include combination regimens. Excitement for this agent will be high, particularly in light of its strong efficacy in a patient population that is particularly difficult to treat (second-line, del17p). The remission rate is impressive on its own, but more important is the durability of the responses, since del17p patients have historically lost their responses to chemotherapy quickly. The PFS rate observed in this study with venetoclax (in patients treated with a median of two prior lines of therapy) appears superior to the PFS historically reported for del17p CLL patients in the first-line setting.
Venetoclax will have to compete with both Zydelig and Imbruvica. Imbruvica is approved for relapsed/refractory CLL (and has U.S. approval specifically in del17p patients without a line of therapy designation), and Zydelig was approved in combination with Rituxan in the relapsed setting (although its European label specifies use in first-line del17p patients and the National Comprehensive Cancer Network (NCCN) also recommends its use in relapsed del17p patients5). Imbruvica and Zydelig are heavily entrenched in the CLL market,1 and new data and indications are expanding their use rapidly (including impressive results from Study 115 for Zydelig in combination with Treanda and Rituxan in relapsed CLL that were presented immediately prior to the venetoclax results6). Venetoclax may have difficulty penetrating the treatment paradigm, although its clinical data suggests it may be superior to these two agents in the del17p subset. The pivotal RESONATE trial for Imbruvica enrolled 127 patients with del17p, and in that subset Imbruvica produced a 48% ORR and six-month PFS was 83%.7 In the pivotal Study 116, Zydelig plus Rituxan produced an 80% ORR in the subset of 20 del17p patients enrolled in the trial, with a six-month PFS of more than 80% and 12-month PFS of over 60%.8 In comparison, venetoclax seems superior to Imbruvica (nearly double ORR) and possibly comparable to Zydelig (although the sample size in which Zydelig was studied was very small to draw sweeping conclusions). These comparisons will work in venetoclax’s favor and could make it the go-to drug in del17p patients. A significant concern for venetoclax may be the incidence of TLS. While the new dosing scheme utilized to minimize the risk is encouraging, the prolonged “step-up” dosing protocol and the necessary patient monitoring and potential hospitalization in high-risk groups could prove difficult to implement into regular clinical practice upon launch. Certainly the high response rates are difficult to ignore, but if the administration is viewed as cumbersome, physicians may be hesitant to adopt venetoclax into their treatment algorithm, particularly in certain patient populations such as the elderly, who are at an increased risk of TLS and are associated with comorbidities.
Despite these concerns, one must keep things in perspective: In a disease that once suffered from a lack of significant clinical advancement, the current battle among multiple highly active and novel therapies is certainly better than a stalemate of none.
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