An FDA rebuff looks almost certain for Eli Lilly and partner Innovent Biologics’ PD-1 inhibitor Tyvyt as an overwhelmingly negative internal FDA review ahead of an advisory committee meeting suggests the agency is unwilling to consider a drug solely based on clinical data from China.
Innovent is seeking an FDA blessing for Tyvyt (sintilimab) in combination with chemotherapy to treat newly diagnosed patients with late-stage non-squamous non-small cell lung cancer (NSCLC). But as FDA reviewers see it, the phase 3 trial used to support the application, conducted exclusively in China, was simply not enough for an approval in the U.S., an FDA document (PDF) shows.
While the FDA appears to have already set its mind on a rejection, it’s now asking an independent oncologic drugs advisory committee (ODAC) to weigh in during a meeting scheduled for Thursday. The agency’s tough stance could serve as an omen for several China-made cancer immunotherapies that are hoping to have a shot at the lucrative U.S. market.
As the FDA noted, the Tyvyt trial, dubbed Orient-11, closely resembles lung cancer trials by existing checkpoint inhibitors such as Merck’s Keytruda in the U.S. The difference, though, is that Orient-11 was conducted solely in China rather than being a global study.
Using foreign data from a single-country trial for drug applications marks a “departure from decades of [multiregional clinical trials] as the consistent approach to drug development,” the FDA said. Given that single-country nature, results from Orient-11 aren’t applicable to U.S. patients, the FDA reasoned.
What’s more, the study measured how well the Tyvyt regimen could stall tumor progression or death, known as progression-free survival (PFS), as its primary goal. But the FDA has approved PD-1/L1 inhibitors in the same setting with more clinically meaningful data on life extension. For example, Keytruda showed its addition to chemotherapy could halve the risk of death among frontline non-squamous NSCLC patients in the landmark Keynote-189 trial. Based on that finding and data from other trials, Keytruda has been well established as the standard of care for first-line metastatic NSCLC in the U.S.
Adopting a harsh tone, the FDA criticized Orient-11 for being conducted “without FDA consultation or oversight, with a comparator arm and endpoint (PFS) that do not meet U.S. regulatory standards or align with U.S. medical practice.” Only by comparing Tyvyt to an approved PD-1 therapy would the FDA be convinced of the new med’s efficacy, the U.S. drug regulator added.
The FDA has cleared drugs based on foreign data before, especially for novel therapies for underserved patient populations. But the agency said Tyvyt doesn’t deserve that “regulatory flexibility” given multiple similar drugs are available with more mature patient survival data. The Tyvyt application “does not fulfill an unmet need for U.S. patients,” the agency said.
Lilly originally licensed Tyvyt from Innovent in 2015. After seeing positive Orient-11 data, the two partners expanded the partnership in 2020 when Lilly paid $200 million up front for the PD-1 inhibitor’s U.S. rights. The drug has been approved in China for multiple cancer indications, including frontline NSCLC.
The negative opinion doesn’t come as a surprise. Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence, and colleague Harpreet Singh, M.D., stated those same arguments in a commentary published Friday in the journal The Lancet Oncology.
“The true bridge over so-called troubled waters for global drug development and regulatory harmonization will be MRCTs rather than single country trials,” Pazdur and Singh wrote in that article.
For Lilly’s part, the company believes that “the risk-benefit of the agent is demonstrable on the basis of the well-conducted study,” and that “the results of the study are indeed applicable to a U.S. population,” Jake Van Naarden, president of Lilly Oncology, said of Tyvyt and Orient-11 during an investor call Thursday.
To support that view, Innovent argues in its briefing document (PDF) for Thursday’s meeting that Tyvyt prompts similar biomedical effects between Chinese and U.S. patients. What’s more, the Chinese company pointed to an FDA meta-analysis of checkpoint inhibitors in NSCLC that showed “relatively consistent” patient survival and tumor progression outcomes in non-Asian and Asian patients.
In addition, Tyvyt’s efficacy data from the Orient-11 trial was similar to those from other anti-PD-1/L1 trials conducted in largely Western patients, the company said. In Orient-11, Tyvyt plus chemo reduced the risk of disease progression or death by 52% over chemo alone as patients on Tyvyt lived a median 8.9 months without progression, versus 5 months for the chemo group. In Keynote-189, Keytruda showed similar results, helping patients live a median 9 months without progression compared with 4.9 months for chemo.
On the more important patient survival marker, Tyvyt’s combo with chemo cut the risk of death by 35% over chemo alone as of September 2021. That result was seemingly less impressive than Keytruda and chemo’s roughly 44% reduction at a prespecified final analysis.
Nevertheless, Lilly’s Van Naarden acknowledged that “the stance of the agency may have changed or maybe we may have misinterpreted it a few years ago.”
Van Naarden was referring to Pazdur’s comment at a 2019 American Association for Cancer Research meeting, where the FDA oncology chief encouraged Chinese companies to bring competition to the U.S. PD-1/L1 landscape with their lower-cost options by duplicating foreign trials in China. At that time, Pazdur lambasted Western PD-1/L1 developers for high prices.
That comment effectively sparked enthusiasm for introducing China-made PD-1/L1s to the U.S. Besides Lilly and Innovent, Novartis has since partnered with BeiGene on the latter’s tislelizumab, while EQRx has gained exclusive rights to Cstone Pharmaceuticals’ sugemalimab. In addition, Coherus Biosciences has tapped Junshi Biosciences’ toripalimab, and other companies have struck similar deals.
These foreign companies have either bluntly stated or indirectly indicated that their products would come after the megablockbuster U.S. immuno-oncology market with pricing discounts. Lilly’s Van Naarden, for one, touted its “disruptive pricing strategy” for Tyvyt during Thursday’s call.
But fast forward to today, the FDA made a special note in its review document, making clear of a well-known FDA review standard even though it appears to be backtracking Pazdur’s 2019 comment.
“[T]he FDA may not consider drug pricing or competition in its regulatory decision making,” the agency wrote. “Cost and drug pricing should not be included as a topic for discussion in the ODAC meeting.”
The only question for ODAC members at the upcoming gathering is whether additional clinical trial reflecting a U.S. population should be required before a final regulatory decision on Tyvyt. The FDA doesn’t have to follow the advisers’ recommendations, but it typically does.
The FDA’s decision on Tyvyt could serve as a benchmark for all the other China-made PD-1/L1 ones that are lining up their applications with the FDA. By the FDA’s count, more than 25 oncology applications in various drug development phases, planned to be submitted, or currently under review are based solely or predominantly on clinical data from China.
https://www.fiercepharma.com/pharma/eli-lilly-innovent-s-pd-1-troubled-waters-as-fda-review-oncology-chief-comments-portend
