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. Three-year PFS rates were
respectively 81.9% and 77.9% by independent review, while three-year 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.
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’s degree in
journalism from Ball State University and also lived in China from 2001-2004.
Follow Alaric on Twitter @AlaricD_BPI