Roche’s GALLIUM Results Draw Skepticism about Changing Practice in First-Line Follicular Lymphoma

Roche’s (VTX:ROG) Phase III GALLIUM study of Gazyva (obinutuzumab) in first-line follicular lymphoma (FL) has low probability of changing practice in the near term despite showing an improvement in progression-free survival (PFS), most experts said.

Speaking on the sidelines of the recently concluded American Society of Hematology (ASH) meeting in San Diego, California, experts pointed to the lack so far of overall survival (OS) data as well as economic and logistical factors that would limit Gazyva’s ability to replace Roche’s Rituxan (rituximab) in clinical practice. Roche shares rose 1.7% on news of the GALLIUM results, which were shown in an oral presentation at ASH on 5 December and announced in a company press release.

Gazyva’s sales in non-Hodgkin’s lymphomas (NHL) are expected to rise from USD 36m at YE16 to more than USD 1.3bn by YE20, while Rituxan’s sales are expected to fall from USD 306m to USD 73m during the same timeframe. Rituxan is approved for NHL, chronic lymphocytic leukemia (CLL) and rheumatoid arthritis, while Gazyva is approved for relapsed/refractory FL and CLL. FL is the most common indolent NHL subtype. GALLIUM data will be submitted to regulators for an expansion of Gazyva’s label, Roche said in the 5 December press release. The company did not respond to a request for comment.

Skepticism around practice-change potential

While an OS benefit in FL would be “absolutely compelling,” said Dr Joshua Brody, assistant professor, Medicine, Mount Sinai Hospital, New York, nevertheless the question of whether GALLIUM’s PFS benefit would prompt doctors to switch from Rituxan to Gazyva was a difficult one. A comparable case, he noted, is the Phase III PRIMA study (NCT00140582), which evaluated Rituxan maintenance therapy following Rituxan/ chemotherapy induction versus no maintenance therapy. Though PRIMA showed a PFS benefit for Rituxan maintenance, it did not show an OS benefit and thus did not change practice, he explained, and the same could be true for the GALLIUM PFS results.

GALLIUM showed a 34% increase in PFS for the Gazyva arm versus the Rituxan arm, though the PFS median was not reached, according to the aforementioned press release. Threeyear PFS rates were respectively 81.9% and 77.9% by independent review, while threeyear OS rates were 94% and 92.1%. The study included 1,202 FL patients randomized 1:1. Both arms also received chemotherapy options- including cyclophosphamide/ doxorubicin/vincristine/prednisone (CHOP), cyclophosphamide/vincristine/prednisone (CVP) or Teva Pharmaceutical Industries’ (NYSE:TEVA) Treanda (bendamustine). Of GALLIUM’s total 1,401 patients, the remainder had marginal zone lymphoma, another indolent NHL histology, but they were not included in the ASH analysis.

The GALLIUM data and Gazyva’s OS benefit in CLL points to the potential for an eventual OS benefit in first-line FL, said Brody. A benefit in OSone of the study’s secondary endpoints- is difficult and time-consuming to show given the indolent nature of FL and the many therapies patients receive in their lifetimes, noted Dr Paul Hamlin, chief, Medical Oncology Service, Memorial Sloan Kettering Cancer Center, Basking Ridge, New Jersey, and Dr Deepa Jagadeesh, associate staff, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Ohio.

Meanwhile, Dr Loretta Nastoupil, assistant professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, said the GALLIUM data could shift frontline FL treatment in favor of Gazyva because it showed superiority for the newer drug. However, Jagadeesh and Hamlin noted, another factor that may hold Gazyva back is economics, as the availability of subcutaneous and biosimilar Rituxan may continue to drive preference for the older drug. Brody agreed, adding SubQ and biosimilar Rituxan are likely to see quick uptake once they become available in the US, Brody said. Cost becomes an issue, especially in the context of great discussion thereof, Jagadeesh said, adding she plans to stick with Rituxan in her practice.

The FDA has accepted the BLA for SubQ Rituxan in blood cancers, according to a 3 November press release by Halozyme (NASDAQ:HALO), whose recombinant human hyaluronidase technology was used to develop the formulation. The EMA approved the SubQ formulation for FL in March 2014; Roche markets Rituxan as MabThera in Europe, and Gazyva as Gazyvaro. Rituxan’s US patent expired in September, while it lost patent protection in Europe in 2013. EMA approval and launch of a biosimilar MabThera from Novartis (VTX:NOVN) generics unit Sandoz is expected in 2Q17, according to an analyst report.

Another factor potentially favoring Rituxan over Gazyva is the latter’s higher incidence of infusion reactions, Brody said. Infusion reactions can be quite disruptive in smaller community oncology practices, which may also affect decisions of whether to switch from Rituxan to Gazyva, he noted. Given the manageability of infusion reactions, Jagadeesh noted the impact of infusion reactions on prescribing habits is less clear.

Grade 3 or higher infusion-related reactions occurred among 12.4% of Gazyva-treated patients in GALLIUM versus 6.7% of those treated with Rituxan, according to the Roche release. The overall rate of Grade 3 or higher adverse events were respectively 74.6% and 67.8%. The potential still exists for GALLIUM to change practice, Hamlin said, based on his view that Gazyva has a better MOA than Rituxan given improved PFS. Gazyva’s higher dosage compared to Rituxan does not explain the former’s benefit, he added. Gazyva recognizes a different CD20 epitope from Rituxan and is designed to have better binding between its Fc region and the Fc-gamma-R3a expressed by effector cells and improved antibody-dependent cellular cytotoxicity (Gagez, Cartron. Curr Opin Oncol. 2014 Sep;26(5):484-91).

Patients in GALLIUM’s Gazyva arm received a flat 1,000mg dose on days 1, 8 and 15 of cycle 1 and on day 1 of seven 21-day or five 28-day cycles. On the other hand, those in the Rituxan arm received 375/ m2 on day one of eight 21-day cycles or six 28-day cycles, followed by 375mg/m2 every two months for up to two years until progression.

December 5, 2016

Alaric DeArment

Reporter, New York

Alaric DeArment covers cancer drug development for BioPharm Insight. He served as associate editor of Drug Store News from 2008 to 2014, covering branded and generic drugs from development to distribution, retail and specialty pharmacy and regulatory affairs. In 2011-2012, he edited the book Contestation and Adaption: The Politics of National Identity in China. A native of Seattle, he graduated with honors with a bachelor degree in journalism from Ball State University and also lived in China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI