The other shoe has dropped for Eli Lilly and Innovent Biologics’ bid to introduce a China-developed cancer immunotherapy to the U.S. market.
The two companies have received a largely expected FDA rejection for PD-1 inhibitor sintilimab—marketed as Tyvyt in China—in newly diagnosed nonsquamous non-small cell lung cancer, they said Thursday. The complete response letter comes after overwhelmingly negative reviews from the FDA and an external expert panel.
Consistent with the FDA’s previous attitude toward the application, the agency recommends the partners run an additional global clinical trial. The FDA says the new study should show the combination of Tyvyt and chemotherapy works at least as well as standard of care at extending patients’ lives.
Lilly and Innovent are “assessing next steps for the sintilimab program in the U.S.,” the pair said.
For Tyvyt’s application, Lilly and Innovent used the phase 3 ORIENT-11 trial, which was conducted solely in China. The study compared the Tyvyt-chemo combo against chemo alone in Chinese patients with newly diagnosed nonsquamous NSCLC. The trial used the progression-free survival marker, measuring how well a therapy could stall tumor progression or death, as its primary goal.
In hindsight, Tyvyt’s fate was spelled out for it when director of the FDA’s Oncology Center of Excellence, Richard Pazdur, M.D., penned an article in The New England Journal of Medicine in December questioning the use of clinical data generated solely or predominantly in China to seek U.S. approvals.
Echoing Pazdur’s article and a following Lancet Oncology article, the FDA chastised Lilly and Innovent for losing sight of trial diversity. The agency also took issue with the study’s comparator arm and the trial design, noting PD-1 therapy had already become the standard of care in the U.S. after showing a life-extension benefit over chemotherapy on the gold-standard overall survival marker.
Adding another wrinkle to the process, on the eve of a scheduled FDA advisory committee meeting in February, Lilly said it would price Tyvyt at an approximate 40% discount over existing PD-1s if the drug were approved. The tactic clearly didn’t work, as the FDA doesn’t consider drug prices in its reviews.
The FDA’s oncology advisers eventually voted 14-1 against approval in its current form, instead asking Lilly and Innovent to run another clinical trial. Jorge Nieva, M.D., of the University of Southern California, who cast the lone “no” vote, did point out that the availability of the so-called “me-too” drugs could drive down costs.
Meanwhile, many China-developed PD-1/L1 inhibitors with potentially lower price tags are lining up at the FDA’s door. Some had also hoped to enter the lucrative U.S. market with China-only data after Pazdur essentially encouraged such a path during an American Association for Cancer Research meeting in 2019.
Coherus Biosciences and Junshi Biosciences are awaiting an FDA decision for their China-approved PD-1 inhibitor toripalimab in nasopharyngeal carcinoma. The application is also based on China-only data, but the rare nature of the disease and its prevalence in Asian population could qualify the drug for what the FDA characterized as “regulatory flexibility.”
In addition, the FDA’s other requirements, including that a latecomer be compared with an existing PD-1 in front-line NSCLC, also raised questions about a broad portfolio of candidates, SVB Leerink analyst Daina Graybosch, Ph.D., previously noted.
The FDA rebuff is a setback for Lilly’s expanding oncology portfolio. As for Innovent, the company is dependent on tapping into the U.S. market to sustain growth.
“The company has gained tremendous experience and know-how, and established a strong registration team throughout the registrational process, allowing the company to be more confident and committed to bringing our innovative drugs to global markets through a defined pathway,” Innovent said in a statement (PDF).