New CD20 MAbs on the CLL block: Can Arzerra stand up to Gazyva?
| Dec 10, 2013
Co-authored by Mara Jeffress, Ph.D., Associate Consultant
The 2013 American Society for Hematology (ASH) meeting is ripe with new data in the treatment of chronic lymphocytic leukemia (CLL), with particular focus on high unmet need populations, such as relapsed/refractory disease and patients “unfit” for intensive chemoimmunotherapy. Impressive results from the Phase III CLL11 trial of Gazyva® (obinutuzumab, Genentech/Roche) were presented in during the plenary session on December 8.1 On December 9, two back-to-back oral sessions highlighted several other advances in the treatment of CLL, including results from the Phase III COMPLEMENT-1 trial of Arzerra.2
The Phase III COMPLEMENT-1 trial (NCT00748189) was a randomized study of Arzerra plus chlorambucil versus chlorambucil monotherapy in 447 previously untreated chemo-ineligible CLL patients. Progression-free survival (PFS; the primary endpoint) was significantly improved, with a 71% reduction in risk of progression or death and a 22.4-month median PFS (versus 13.1 months in the control arm; HR 0.57, p=0.001). The overall response rate (ORR), complete response rate (CR), and high rate of minimal residual disease (MRD) negativity also all favored the Arzerra arm. While the overall survival does numerically favor Arzerra, the data is immature and no conclusions can be drawn at this time. A slightly higher incidence of Grade 3/4 adverse events (AEs) was reported in the Arzerra arm (50% of patients) versus the chlorambucil arm (43%). Infusion-related reactions (10% versus n/a, respectively), neutropenia (26% versus 14%) and thrombocytopenia (5% versus 10%) represented the major differences in Grade 3/4 AEs.
The COMPLEMENT-1 trial was clearly positive, adding to the growing data supporting the use of new combination regimens in patients considered “unfit” for intensive chemoinnumotherapy. These data supported U.S. Food and Drug Administration (FDA) and European Medicine Agency (EMA) regulatory applications in October 2013 for approval of Arzerra plus chlorambucil in first-line fludarabine-ineligible CLL, and successful approval is highly likely. In addition, this data supported the FDA granting Arzerra Breakthrough Therapy Status in September 2013, a coveted designation that is also held by several other agents in development in CLL: Gazyva, idelalisib (Gilead), and Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson). However, approval does not guarantee adoption. As the third anti-CD20 mAb to arrive on the CLL scene, can Arzerra distinguish itself in this rapidly crowding indication?
Results presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting this year3 served as the basis for an early (November 1, 2013) approval of Gazyva in combination with chlorambucil in newly diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy. Now, with impressive updated results and a head-to-head comparison to Rituxan in hand, Genentech/Roche is well positioned for the eventual displacement of Rituxan as a standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration). The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized patients 1:2:2 to treatment with chlorambucil alone, chlorambucil plus Gazyva, or chlorambucil plus Rituxan. Unlike the CLL11 study, the COMPLEMENT-1 trial design lacks a comparison to Rituxan, which is a more stringent comparator than chlorambucil alone – a step that was questioned by the audience members and may cost GlaxoSmithKline market share in the future.
While it is tempting to do a cross trial comparison (see Table 1), each trial enrolled different patients and used different dosing of chlorambucil. The CLL11 study used once every two weeks dosing of 0.5mg/kg, whereas the COMPLEMENT-1 trial used a dose of 10 mg/m2 on days 1-7. This increased chlorambucil exposure in the Arzerra trial might explain why the control arm in COMPLEMENT-1 performed better than in CLL11. The level of benefit in COMPLEMENT-1 was impressive, although it may have been overshadowed by the Gazyva data presented the prior day. With the caveats of cross-trial comparison mentioned above, physicians will still likely look to the raw numbers and see a difference in PFS at the median (26.7 months with Gazyva-chlorambucil and 22.4 months with Arzerra-chlormabucil) and in the overall level of PFS benefit (HR 0.18 and HR 0.57, respectively). Furthermore, there is a significant OS benefit when comparing Gazyva-chlorambucil versus chlorambucil (HR 0.41, p=0.0022), which Arzerra has not yet demonstrated due to immaturity of the data. These efficacy comparisons seem to favor Gazyva, especially in the presence of data showing significant benefit compared to Rituxan-chlormabucil as well. On the positive side, the toxicity seems to be slightly lower with Arzerra, particularly the rates of infusion reaction and thrombocytopenia ― but will this sway physicians and ultimately drive adoption?
Physicians will soon have three anti-CD20 antibodies approved in first-line CLL to choose from, in addition to a number of novel agents in development: Imbruvica, idelalisib, and ABT-199 (GDC-199, Abbvie/Genentech/Roche), all of which are presenting very promising data at ASH 2013. As these agents enter the CLL market, a natural inclination would be to combine them with an anti-CD20 antibody. Combination may offer a good opportunity for Arzerra, especially since it appears on first blush to have lower toxicity than Gazyva. Arzerra may also have a time advantage, as it is already being studied in a Phase III trial in combination with idelalisib (NCT01659021).
The COMPLEMENT-1 results aren’t the end of high profile CLL abstracts being presented at ASH this year. Tuesday is the final day of the conference and still holds one more set of data with high anticipation ― the pivotal Phase III trial of Rituxan with or without idelalisib in relapsed/refractory CLL.4 For ASH, 2013 was most certainly the Year of CLL.
1. Goede et al., Abstract 6, ASH 2013
2. Hillmen et al., Abstract 528, ASH 2013
3. Goede et al., Abstract 7004, ASCO 2013.
4. Furman, et al., Abstract LBA6, ASH 2013