FDA Review Policies for PD-1/PD-L1 Inhibitors Spark Expert Debate

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 oncol - ogy drugs in a timely way and this is unlikely to change, agreed Wayne Pines, president, Health Care, APCO Worldwide, Washington, DC. It’s like - ly 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 FDA may choose to become more critical on reviews and require larger studies for approval, or require longerterm monitoring and stronger label warnings

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 longerterm 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 latercomers 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 tumours, 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.

September 5, 2016

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 degree in journalism from Ball State University and also lived in China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI