The potential for changes to FDA oncology drug
application review and approval policies has drawn contrasting expert opinions
following comments by a high-ranking agency official bemoaning copious
PD-1/PD-L1 inhibitors in development.
Comments made by Dr Richard Pazdur, Head of
the FDA Office of Oncology, likely just reflect a personal desire for better
company investment in other drug targets, several experts said. However, others
said the agency could require larger studies and longer-term monitoring to
discourage a crowded development space, as well as place me-too products on a
lower review priority. Companies entering the space late still could leverage
novel applications for PD-1/PDL1 inhibitors in new combinations or using them
in unexplored populations, one expert noted.
At last month’s ASCO conference in Chicago,
Pazdur was quoted in a Reuters article questioning the industry’s current
approach asking: “would we be better off spending those resources into looking
at more novel drugs?” when discussing PD-1/PD-L1 inhibitors. He also noted that
“the number of similar drugs in development at the same time is a first in the
oncology field and latecomers to the PD-1 market will likely be relegated to
‘niche’ indications.”
Bristol-Myers Squibb’s (NYSE:BMY) Opdivo
(nivolumab) and Merck’s (NYSE:MRK) Keytruda (pembrolizumab) are examples of
PD-1 inhibitors that have been approved for non-small-cell lung cancer (NSCLC)
and melanoma. The former is additionally indicated for renal cell carcinoma and
Hodgkin’s lymphoma. AstraZeneca’s (LON:AZN) durvalumab and Roche’s (VTX:ROG)
Tecentriq (atezolizumab) are both PD-L1 inhibitors under investigation for the
treatment of lung cancer. Tecentriq was recently approved in locally advanced
or metastatic urothelial carcinoma.
The FDA did not respond in time for comment.
Possible policy
changes debated
Pazdur’s comments will not signal any change
in FDA policy such as accepting only innovative therapies beyond PD-1 and PD-L1
inhibitors or reviewing additional PD-1 therapies negative - ly, said Matthew
Weinberg, CEO of consultancy The Weinberg Group, Washington, DC. The FDA has
been aggressive in approving new oncology drugs in a timely way and this is
unlikely to change, agreed Wayne Pines, president, Health Care, APCO Worldwide,
Washington, DC. It’s likely that Pazdur’s intentions were just to encourage
innovation in the space over policy change, said Dr David Lim, president and
principal consultant, Regulatory Doctor, Roanoke, Virginia.
The comments indicate Pazdur’s personal views
appealing for more breakthrough therapies with new targets rather than
me-too/follow-on therapies, Weinberg and Pines said. The comments likely do not
apply to all cancer immunotherapy, rather just the PD-1/PD-L1 inhibitors, Dr
Grant Williams, president, Williams Cancer Drug Consulting, Philadelphia,
Pennsylvania.
However, the FDA could potentially increase
the bar for approval concerning PD-1/PD-L1 inhibitors as more is learned about
their safety profiles, Lim explained. The FDA may choose to become more critical
on reviews and require larger studies for approval, or require longer term
monitoring and stronger label warnings, he added.
Yet, the comments could still signal a change
in FDA policy, said Nigel Smart, vice president, Smart Consulting Group, West Chester,
Pennsylvania, with the agency giving greater priority to reviewing drugs with
improved therapeutic value as opposed to me-too drugs.
Whilst the FDA won’t change its overall
policy, it’s possible me-too PD-1/PD-L1 inhibitors may no longer qualify for
the FDA’s breakthrough designation or for accelerated approval, said Williams.
Breakthrough designation allows more access to agency advice and communication,
and the accelerated approval path allows early approval based on surrogate
endpoints, he noted. Both are available when there is an advantage over
available therapy, he said. Thus, PD-1/ PD-L1 inhibitors may have to go through
the full development pathway of showing clinical benefit in a large randomized
study before approval is granted, he said.
Niche market
options
Whilst Pazdur mentioned that latecomers would
be relegated only to the “niche markets”, one unnamed oncologist countered that
this was unlikely. Companies developing novel PD-1/PDL1 antibodies are often
doing so for the purpose of new combinations, said the oncologist and Williams.
Whilst a PD-1/PD-L1 inhibitor might offer nothing new in non-niche indications
such as lung cancer, where there are approved PD-1 inhibitors, combining them
with a novel therapy could provide patient value as it could boost response
rates, explained the oncologist. This is especially important given the
heterogeneity in response rates and the need for combinations to boost
responses in certain individuals, he said.
For example, Tesaro (NASDAQ:TSRO) has its own
PD-1 inhibitor yet to enter clinical trials, said the oncologist. However, the
company intends to use it primarily in novel immunotherapy combinations, such
as with anti-LAG-3 or anti-TIM-3 antibodies, as opposed to monotherapy trials
in solid tumors, the oncologist explained. Other companies are looking at
combining their own PD-1/PD-L1 inhibitors with other immunotherapy targets such
as Ox40, GITR, 4-1BB amongst others, he added. This news service reported on 5
July that Pfizer has planned a Phase I trial for its PD-L1 inhibitor in
combination with a 4-1BB agonist and an Ox40 agonist.
The unnamed oncologist noted that companies
developing PD-1 inhibitors are now focusing on niche areas that have not
received much attention, such as mesothelioma, so breakthrough approval could
still be attainable for PD-1/PDL1 drugs in these cases. Williams agreed, noting
breakthrough therapy is not dependent upon mechanism of action, but rather,
upon the patient population being treated and whether an unmet medical need is
being addressed. Even some of the bigger players entering the race later are
targeting more niche populations with unmet needs, said the unnamed oncologist
and Williams.
For example, Pfizer (NYSE:PFE) and Merck KGaA
(ETR:MRK) are collaborating to develop their PD-L1 inhibitor, avelumab, in
smaller patient populations such as Merkel cell carcinoma, said the unnamed
oncologist. Some companies are selecting patients using genetic subgroups where
PD-1/PD-L1 inhibitors may work best in unserved populations and leverage FDA
opinion, said Williams.
Hamish McDougall
Reporter, London
Hamish has a BSc in Neuroscience
from the University of Sussex and is primarily covering the neuroscience
indications for BioPharm Insight. Prior to joining us he was assistant
commissioning editor for a well-known collection of biomedical journals at
Expert Reviews, including Expert Review of Gastroenterology & Hepatology,
Expert Review of Clinical Pharmacology and Expert Review of Respiratory
Medicine.
Jennifer C. Smith-Parker
Journalist, London
Jennifer is an award-winning
biopharmaceutical industry journalist. Prior to joining BioPharm Insight
Jennifer was Associate News Editor at FDA Week, covering FDA regulatory policy
for all FDAregulated product areas. She also worked at The Monitor, where she
covered health, environment and science issues and conducted a year-long
project on indigent healthcare services. She was awarded the Texas Medical
Association’s Anson Jones journalism award for an article on breast cancer. Jennifer
graduated from New York University with a bachelor’s with Honors in History and
Journalism. Follow her on Twitter @JsmithParker
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