At a quick glance, the Food and Drug Administration's decision to ask its advisers for help in vetting yet another cancer immunotherapy may seem odd.
After all, the agency has already cleared seven drugs that work like the one it's now reviewing. Known as sintilimab and developed by Eli Lilly and partner Innovent Biologics, the immunotherapy blocks a protein called PD-1, the same as Merck & Co.'s Keytruda and Bristol Myers Squibb's Opdivo. Typically, the FDA reserves its advisory committee meetings for tough decisions on which it wants help from outside experts.
Yet on Thursday, a panel of agency advisers will convene to debate sintilimab and whether the data behind it are sufficient.
Lilly's application has become a test of the regulator's views on cancer treatments developed and tested exclusively in China. A handful of companies are using that blueprint in an attempt to speed new therapies to the U.S. market, raising concerns from some of the agency's top cancer drug evaluators.
The drugs could also usher in greater price competition in a market filled with products costing well over $100,000 a year. In a statement Wednesday, Lilly indicated that, should sintilimab win approval, it plans to price the drug at a significant discount to the sticker price of competing branded medicines.
Briefing documents posted by the FDA, however, showed its staff to be highly skeptical of Lilly's and Innovent's drug. The meeting is scheduled to run through 3 pm Eastern time on Thursday and will feature presentations by Lilly and by the FDA.
Here is an overview of the issues at stake, as well the potential implications of the FDA's forthcoming decision.
What is sintilimab?
Sintilimab was discovered by Innovent, a biotech based in Suzhou, China. As a checkpoint inhibitor like Keytruda and Opdivo, sintilimab could have considerable value. These types of drugs have become standard treatment for many tumor types and are viewed as the backbone of future drug combinations. Nearly every large drugmaker invested in oncology has sought to have one, among them Lilly, a latecomer to cancer immunotherapy.
Lilly partnered with Innovent in 2015. Since then, Innovent has won approval of sintilimab in China, where it is sold as Tyvyt for a type of lymphoma. That clearance encouraged Lilly to broaden its alliance with Innovent in 2020 and test sintilimab in several tumor types, including lung cancer, one of the most common cancer types in the U.S. and a target for many drugmakers.
What results are supporting Lilly and Innovent's application?
The application currently under review is for use of sintilimab alongside standard chemotherapy in patients recently diagnosed with advanced non-small cell lung cancer, the disease's most common form. A combination of Keytruda and chemo is currently the standard of care for most patients, after a Phase 3 study showed in 2018 that treatment cut the risk of cancer progression or death by nearly half compared to chemo alone. Multiple other drug combinations are available as well.
Lilly and Innovent have recreated a similar result in a roughly 400-patient late-stage study called ORIENT-11. A regimen of sintilimab and chemo bested chemo on measures of survival and disease progression, leading the partners to seek approval in the U.S. But the study was run entirely in China and chemotherapy is no longer the bar to clear in lung cancer, two factors that appear to be influencing the FDA's thinking. The agency is expected to make a decision by March.
What do Lilly and Innovent aim to offer with their drug?
Lilly is attempting to position sintilimab as a comparable, lower-cost alternative to Keytruda, a product profile that, in theory at least, could drum up some demand. High cancer drug prices can leave patients with substantial out-of-pocket costs, particularly when they must take several in combination. Such "financial toxicity" has become an increasing concern as more and more new products reach market with annual list prices of over $100,000 or even $150,000.
Immunotherapies are a chief culprit and could continue to be for years. Keytruda, for example, generated more than $17 billion in sales in 2021. Biosimilar competitors to Keytruda, Opdivo and other similar drugs, meanwhile, aren't expected until later this decade.
At an industry meeting three years ago, the FDA's oncology chief, Richard Pazdur, appeared to suggest competition from China was a way to lower prices. Pazdur even laid out a regulatory strategy for prospective checkpoint blockers from China that involved, for instance, mimicking the trials Merck ran for Keytruda in lung cancer.
Jacob Van Naarden, head of Lilly's cancer drug business, hinted at competitive pricing on a conference call last week and the company confirmed by emailed statement that it plans to price sintilimab at a sizable discount to other medicines like it.
"Our U.S. commercial plan for sintilimab, should it be approved, is to provide a significant and transparent [wholesale acquisition cost] price discount that will be in line with some of the deeper discounts we've seen for biosimilars relative to their branded comparators, an approximate 40% discount," Lilly said in its Wednesday statement. "That having been said, the drug is not currently approved in the U.S. and may not get approved. We think it's important to respect FDA process and look forward to tomorrow's [meeting].
Why is the FDA paying such close attention to this application?
Several trends in cancer drug development are converging in this review. With seven similar drugs already approved and more on the way, pharma companies have been criticized for taking a "me-too" approach when research dollars might be better spent on cancer medicines that work in new ways.
Furthermore, the FDA is increasingly scrutinizing cancer immunotherapy approvals it previously granted. A handful that the agency cleared under its "accelerated approval" pathway — meant to speed promising new drugs to market — have since come up short in confirmatory testing. A few drugmakers have withdrawn previously approved indications, while others like Regeneron and Incyte have pulled new applications.
Although Lilly and Innovent are seeking a standard approval for sintilimab, they are doing so amid an apparent shift in the FDA's thinking.
In particular, the regulator's cancer drug division appears to be taking a tougher line on cancer drugs developed in China. Over the past few months, Pazdur has co-authored two articles in leading medical journals expressing concern over the data being used in support of those drugs. One, published in Lancet Oncology last week, specifically named sintilimab.
"We understand the stance of the agency may have changed, or maybe we may have misinterpreted it a few years ago," Lilly's Van Naarden conceded last week.
What does the FDA think?
The key problem, Pazdur argued in the Lancet paper, is that sintilimab's pivotal trial was conducted only in China. That development plan conflicts with international guidelines that favor studies conducted in multiple countries.
Single-country trials may not be able to fully capture crucial differences in treatment effects related to genetics as well as medical practices, Pazdur argued. Moreover, multi-country trials may be more efficient to conduct, help build medical infrastructure and more quickly advance new standards of care.
Briefing documents released Tuesday emphasized those points. The results from Lilly's key trial "are not applicable to the U.S. population and U.S. medical practice," and the "patients enrolled in ORIENT-11 differ from U.S. patients."
Sintilimab "does not fulfill an unmet need," staff scientists added. They've asked outside experts to vote on whether an additional trial is necessary, and if so, what that study should look like.
Lilly has outlined an additional trial in China, the U.S., and Europe that would test two different doses of sintilimab. The FDA prefers a study against an approved checkpoint inhibitor.
What are the potential ripple effects of the FDA's decision?
Sintilimab could bring lower-cost competition to a top-selling drug to the U.S. market. Similar drugs from EQRx and Coherus Biosciences, each discovered and mainly tested in China, are also nearing regulatory reviews. Both Lilly and EQRx have spoken openly about challenging others on price, though they haven't divulged specific details.
But the FDA is not charged with considering the potential prices a pharmaceutical company may or may not set. And an approval, meanwhile, would come with trade-offs that FDA reviewers appear unwilling to make.
In the Lancet article, Pazdur noted that "at least 25 applications" of cancer drugs "based solely or predominantly" on data from China are either in the works or under review. An approval of sintilimab could open the door to others, enabling drugmakers to use China-based studies to quickly get medicines to market that don't match what patients need, Pazdur wrote.
A rejection, as now seems likely, could mean sintilimab won't see the U.S. market, at least in lung cancer, until a new study is run. Some analysts expect Lilly to balk if the FDA turns back sintilimab and demands a U.S. trial against stronger competition. It could also force other biotechs looking to follow in Lilly's footsteps, like EQRx, to change their plans.
For its part, EQRx has said it plans to start a head-to-head study this year comparing its checkpoint inhibitor sugemalimab against approved drugs, a trial that could potentially allay some of the FDA's concerns. Results won't be available for a while yet, however.
Coherus, meanwhile, may be better positioned. Its drug toripalimab is being evaluated for use in a rare type of head and neck cancer that is more common in Asia than the U.S., making a multi-region clinical trial tougher to enroll. Though FDA reviewers didn't mention toripalimab specifically, they noted such a situation "may warrant regulatory flexibility." A review deadline is set for April.
Note: This story has been updated to include comment from Lilly on their planned pricing for sintilimab.