By Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Rituxan® (rituximab, Roche/Genentech) forms the backbone of virtually every aspect of therapeutic management for B-cell non-Hodgkin’s lymphoma (NHL); however, while clinically effective, approximately 20% of patients with indolent NHL (iNHL) are considered Rituxan-refractory. This poses an unmet need for patients, leaving them historically with only chemotherapy as a treatment option, although with the July 2014 approval of Zydelig® (idelalisib, Gilead) in relapsed/refractory follicular lymphoma there is now a new option for these patients. In addition to the clinical unmet need in these patients, Genentech and Roche have their own need to consider. With the approaching U.S. patent expiration of Rituxan, the companies are hoping to leapfrog ahead of potential biosimilar competitors with the next-generation anti-CD20 antibody, Gazyva® (obinutuzumab) as Rituxan’s heir apparent.
Gazyva is a third-generation, humanized anti-CD20 IgG1 monoclonal antibody that has been glycoengineered to enhance its antibody-dependent cellular cytotoxicity (ADCC). It has been shown to bind with high affinity to the CD20 type II epitope, resulting in the induction of ADCC that is five- to 100-fold greater than observed with Rituxan and shown to be more potent at inducing cell death.1 This in vitro data translated into clinically meaningful benefit in patients with newly diagnosed chronic lymphocytic leukemia (CLL) when the CLL11 trial showed superiority of Gazyva with chlorambucil in prolonging progression-free survival (PFS) compared to Rituxan plus chlorambucil,2 which led to its approval in CLL in 2013 and its “debut” appearance into B-cell malignancies. Roche and Genentech are hoping to expand Gazyva’s use in other B-cell malignancies and have initiated concurrent trials in iNHL and diffuse large B-cell lymphoma (DLBCL).
GADOLIN (NCT01059630) was an open-label, randomized Phase III study investigating the efficacy and safety of Gazyva in combination with Treanda® (bendamustine, Teva/MundiPharma/Symbio) compared with Treanda alone in 396 patients with Rituxan-refractory iNHL. Patients who had progressed within six months following Rituxan-based therapy were randomized to receive Treanda + Gazyva for six cycles or Treanda alone for six cycles; patients in the Treanda + Gazyva arm who had not progressed after six cycles were given Gazyva monotherapy as maintenance every two months for up to two years. Enrolled patients in this trial had received a median of two prior lines of therapy. At the 2015 American Society of Clinical Oncology (ASCO) annual meeting, initial response and survival results were presented that showed the trial had met its primary endpoint of significantly prolonging PFS.3 According to independent review, the median PFS was 14.9 months in the Treanda arm, and the median was not yet reached in the Gazyva + Treanda arm, with an associated hazard ratio (HR) of 0.55 (p = 0.00011). Subgroup analysis of PFS suggested two patient types in which the benefit with Gazyva was less convincing: patients with non-follicular indolent NHL (HR 0.94; 95% CI 0.45-1.90) and patients who had received more than two prior lines of therapy (HR 0.80; 95% CI 0.43-1.48), although in both of these subsets the patient sample size was relatively small. There were no significant differences in objective response rate (ORR: 63.0% Treanda vs. 69.1% Gazyva + Treanda) or complete response rate (CR: 12.2% Treanda vs. 11.2% Gazyva + Treanda) at the end of induction as determined by independent review. In looking at the Kaplan-Meier plots, one question that arises is how much of the PFS improvement was conferred by Gazyva maintenance as opposed to Gazyva + Treanda given the lack of difference in ORR and by the fact that that the PFS curves overlap initially and only begin to separate at approximately the time induction is completed. No differences in OS have yet been observed ― median OS is not reached in either arm ― the data are not mature enough to make any conclusions; longer-term data will be required to make final assessment.
The toxicity of the combination was relatively mild with no significant differences in adverse events between the arms. Grade 3 or higher adverse events were seen in 62% and 67% of patients receiving Treanda or Gazyva + Treanda, respectively, the most notable being neutropenia (26.3% vs. 33.0%, respectively) and infusion-related reactions (3.5% vs. 8.8%, respectively). Interestingly, more Grade 3 or higher thrombocytopenia (16.2% vs. 10.8%), anemia (10.1% vs. 7.7%) and pneumonia (5.6% vs. 2.6%) were seen in the Treanda-alone arm. As evidenced by the relatively tolerable safety profile, 90% and 80% of patients received at least 90% of the dose intensity of Gazyva and Treanda, respectively, in the combination arm; 77% received at least 90% of the dose intensity in the Treanda monotherapy arm.
These impressive results led to the independent data monitoring committee (IDMC) stopping the trial due to the high level of benefit.4 In the press release, the companies guided filing for regulatory approval with the Food and Drug Administration (FDA) and European Medicines Agency (EMA), and with these results regulatory approval is not far off. While GADOLIN will support approval, how Gazyva will fare in its uptake is unclear. Potentially impinging on physician enthusiasm is the use of Treanda monotherapy as the comparator arm, a choice of therapy that, while commonly utilized when the trial was initiated, does not currently reflect clinical practice. Zydelig is now the currently preferred treatment regimen in Rituxan-refractory follicular lymphoma, used in about one-quarter of patients.5 Zydelig thus represents Gazyva’s closest competitor in indolent NHL at the moment.
Will the level of PFS improvement in GADOLIN be convincing enough for physicians to adopt a next-generation anti-CD20 antibody in Rituxan-refractory patients, or will physicians prefer an agent with a novel mechanism of action (e.g., PI3K inhibitor Zydelig) before trying Gazyva? The compelling 28-month PFS that Gazyva plus Treanda confers in these patients is indeed hard to ignore, especially in a patient population that has relapsed following first-line standard of care and for which no cure exists. Zydelig’s current approval in follicular lymphoma is based on a single-arm study in Rituxan-refractory patients who had received a median of four prior lines of therapy. In that study, single-agent Zydelig produced a 57% ORR .6 While the ORR may be arguably similar (given the difference in patient pretreatment in the two studies), the fact that Gazyva has been shown to significantly improve PFS in a randomized study may represent a more clinically relevant metric and physicians may be sufficiently convinced to switch their treatment practice. Additionally, the subgroup analysis showing less benefit in more heavily pretreated patients could spur use of Gazyva in earlier lines to maximize benefit.
Making landfall in the relapsed setting, Roche’s goal to replace Rituxan appears to be on track. A supportive Phase II trial (GAUSS, NCT00576758) is comparing Gazyva head-to-head with Rituxan, and the Phase III GALLIUM trial (BO21223, NCT01332968) is comparing Gazyva + chemotherapy versus Rituxan + chemotherapy in previously untreated iNHL. In addition to Zydelig, Imbruvica® (ibrutinib, Pharmacyclics/Janssen), Revlimid® (lenalidomide, Celgene) and duvelisib (AbbVie/Infinity) are also vying for a piece of the NHL space, with multiple Phase III trials ongoing.
For now, though, Gazyva is well-poised to shift the sands once more in the ever-changing and exciting iNHL landscape.
1. Robak T. GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies. Curr Opin Investig Drugs. 2009;10(6):588-96.
2. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-10.
3. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(suppl; abstr LBA8502)
4. Genentech press release. 3 Feb 2015.
5. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.
6. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18.