Transforming CLL: Gazyva Impresses, But Many Others on its Tail
| Dec 9, 2013
Co-authored by Greg Wolfe, PhD, Senior Consultant
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age of diagnosis at 71 in the U.S. and nearly 40% of patients older than 75 at the time of diagnosis.1 Standard treatment for “fit” patients is aggressive chemotherapy, but existing comorbidities in elderly patients frequently preclude use of these highly toxic regimens. Limited treatment options exist for “unfit” patients, and the most common choices include chlorambucil and Rituxan® (rituximab, Genentech/Roche) – alone or in combination. More recently the combination of Rituxan with Treanda® (bendamustine, Teva) has emerged as a common option in the U.S., although the combination is not approved for this setting. To fill the unmet need for treatment options, a number of novel agents have recently entered clinical development for CLL in elderly, newly diagnosed patients. Phase III trials are ongoing or recently completed for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), and Gazyva® (obinutuzumab, Genentech/Roche). Results from Stage I of the Phase III trial of Gazyva were presented at the ASCO 2013 in June2, and on December 8 during the plenary session final results from Stage II of this pivotal trial were reported at the American Society of Hematology (ASH).3
The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized 781 newly diagnosed “unfit” patients to treatment with chlorambucil alone, chlorambucil plus Gazyva, or chlorambucil plus Rituxan. The definition of “unfit” in this trial wasn’t based on patient age but was defined by the level of comorbidities; patients were included if their total Cumulative Illness Rating Scale (CIRS) score was above 6 and/or creatinine clearance was less than 70 ml/min. The first stage of this trial compared the efficacies of each combination arm with the chlorambucil monotherapy arm; the second stage compared the efficacies of the two combination arms and was designed to show superiority of Gazyva versus Rituxan. Results for Stage I were updated and final results of Stage II were presented for the first time.
Updated Stage I results continued to showed clear and robust activity for Gazyva in combination with chlorambucil compared with chlorambucil alone. PFS (the primary endpoint) was significantly improved, with an 82% reduction in risk of progression or death and a 26.7-month median PFS. The level of benefit was very impressive, although perhaps not surprising since chlorambucil is not a very active agent. Rituxan plus chlorambucil also showed a strong level of benefit compared with chlorambucil alone, with a 66% reduction in risk of progression or death and a 16.3-month median PFS. Results of Stage II, which compared efficacy and safety of the combination arms, showed that Gazyva plus chlorambucil is significantly superior to Rituxan plus chlorambucil with regard to the primary endpoint of PFS (26.7 versus 15.2 months), with a 61% reduction in the risk of progression or death. The overall response rate (ORR), complete response (CR), and high rate of minimal residual disease (MRD) negativity (see Table 1) also all favored the Gazyva arm. Overall survival favored the Gazyva arm as well, although this interim analysis is very premature (<15% of events) and the difference did not reach statistical significance when comparing Gazyva-chlorambucil versus Rituxan-chlorambucil (HR 0.66, p=0.0849). Notably, however, the OS benefit was significant when comparing Gazyva-chlorambucil versus chlorambucil (HR 0.41, p=0.0022). A greater incidence of Grade 3/4 adverse events (AEs) was reported in the Gazyva-chlorambucil arm (70% of patients) versus the Rituxan-chlorambucil arm (55%). Infusion-related reactions (20% versus 4%, respectively), neutropenia (33% versus 28%) and thrombocytopenia (10% versus 3%) represented the major differences in Grade 3/4 AEs. While these AEs are of course concerning, the large magnitude of efficacy benefit means that these toxicities are unlikely to sway physicians away from use of the drug, especially since they are easily monitored and resolvable.
Results from Stage I of the trial served as the basis for regulatory filings for Gazyva in newly diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy and on November 1, 2013, the FDA approved Gazyva for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. Now with the Stage II results in hand, the measures that clearly stand out are the CR rate, the number of patients who achieve negative MRD (in both the peripheral blood and the marrow), and PFS. All of these measures strongly favor Gazyva. CR and MRD-negativity speak to the depth of response that is achieved. Results of the CLL11 trial and the approval of Gazyla represent an improvement upon the efficacy of Rituxan and the first step toward the eventual displacement of Rituxan as a standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration).
Within chemo-ineligible/“unfit” newly diagnosed CLL, where will Gazyva fit? As mentioned, development in this indication is crowded with promising new agents seeking to transform the treatment paradigm. Results from the COMPLEMENT-1 trial of Arzerra plus chlorambucil versus chlorambucil monotherapy in previously untreated chemo-ineligible CLL patients will be presented at ASH on Monday December 9, 20134, although it was previously announced via press release to have met its primary endpoint by extending PFS from 13.1 months to 22.4 months (HR 0.57). With this data, CLL will soon have three anti-CD20 antibodies to choose from. In addition, Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) is also seeking approval in this same patient population, and the relapsed/refractory CLL setting is rife with development by Imbruvica, idelalisib (Gilead), and ABT-199 (GDC-199, Abbvie/Genentech/Roche), all of which are presenting very promising data at ASH 2013. A natural inclination would be to combine these agents with an anti-CD20 antibody, or potentially with each other, as well as bring these agents into the broader and/or upfront CLL population. CLL is very likely to be transformed in the next few years, with potentially more options than physicians know what to do with.
1. Kantar Health, CancerMPact® Patient Metrics United States, accessed June 4, 2013.
2. Goede et al., Abstract 7004, ASCO 2013.
3. Goede et al., Abstract 6, ASH 2013
4. Hillmen et al., Abstract 528, ASH 2013