Lilly/Innovent's PD-1 Inhibitor Tyvyt Faces Likely FDA Rejection Amid Regulatory Pushback on China-Only Trial Data

Compiled by newborn

Recently, Eli Lilly/Innovent Bio's PD-1 inhibitor Tyvyt (sintilimab, developed in China) encountered a regulatory setback in the United States. According to a report by the overseas biopharmaceutical website Fierce Pharma, prior to the advisory committee meeting, an internal FDA review had issued an overwhelmingly negative assessment of Tyvyt, indicating that the agency is unwilling to consider approving a drug based solely on clinical data from China.

Currently, Eli Lilly/Innovent Bio is awaiting FDA approval to use Tyvyt in combination with chemotherapy as a first-line treatment for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) patients. However, a document on the FDA’s website shows that, according to FDA reviewers, the Phase 3 clinical trial conducted solely in China to support the above application for Tyvyt is far from sufficient to secure approval in the United States.

Although the FDA seems to have decided to reject, the agency now requests an independent Oncologic Drugs Advisory Committee (ODAC) to discuss and vote at a meeting scheduled for Thursday. The agency's tough stance on Tyvyt may be a harbinger for some China-produced cancer immunotherapies that are expected to enter the U.S. market at lower prices.

As the FDA pointed out, the Tyvyt trial, known as Orient-11, is very similar to existing checkpoint inhibitor lung cancer trials such as Merck's Keytruda. However, the difference is that Orient-11 was conducted only in China rather than as a global study.

FDA pointed out that using foreign data from a single-country trial for drug applications marks a "departure from decades of (multi-regional clinical trials) as the consistent approach to drug development." FDA believes that, considering the nature of a single country, the results of Orient-11 are not applicable to American patients.

More importantly, this research measured the primary goal of the Tyvyt regimen—namely, to what extent it could delay tumor progression or death, also known as progression-free survival (PFS). However, the FDA has already approved PD-1/L1 inhibitors for use in the same setting, with more clinically meaningful data on extending life. For instance, in the landmark Keynote-189 trial, combining Keytruda with chemotherapy reduced the risk of death by half for first-line non-squamous NSCLC patients. Based on this finding and data from other trials, Keytruda has been established as the standard treatment regimen for first-line metastatic NSCLC in the United States.

FDA Adopts a Stern Tone, Criticizing the Orient-11 Trial for Proceeding "Without FDA Consultation or Oversight, Using a Comparator Group and Endpoint (PFS) That Do Not Conform to U.S. Regulatory Standards or Align with U.S. Medical Practices." The Agency Added That Only by Comparing Tyvyt with Approved PD-1 Therapies Can the FDA Be Confident in the Efficacy of This New Drug.

FDA Previously Approved Drugs Based on Foreign Data, Especially New Therapies for Underserved Patient Groups. However, the agency stated that given the more mature patient survival data available for several similar drugs, Tyvyt does not deserve "regulatory flexibility." The agency noted that the Tyvyt application "does not meet the unmet needs of American patients."

Eli Lilly initially obtained the license for Tyvyt from Innovent Bio in 2015. After observing the positive data from the Orient-11 trial, the two parties expanded their partnership in 2020, with Eli Lilly prepaying $200 million for the U.S. rights to Tyvyt. The drug has been approved in China for various cancer indications, including first-line NSCLC.

The negative opinion within the FDA's internal review is not surprising. Richard Pazdur, Director of the FDA's Oncology Center of Excellence, and colleague Harpreet Singh expressed the same view in a commentary published last Friday in The Lancet Oncology. In the article, Pazdur and Singh wrote: "In the so-called troubled waters of global drug development and regulatory harmonization, the true bridge will be MRCTs (multinational clinical trials), not single-country trials."

As for Eli Lilly, the company believes that "based on well-conducted research, the risk-benefit profile of the drug is clear," and "the results of the study are indeed applicable to the U.S. population," said Jake Van Naarden, President of Eli Lilly Oncology, during an investor conference call last Thursday when discussing Tyvyt and Orient-11.

To support this view, Innovent Bio stated in a briefing document (PDF) from last Thursday's meeting that Tyvyt has triggered similar biomedical effects between patients in China and the United States. Moreover, the company pointed out that a meta-analysis by the FDA on NSCLC checkpoint inhibitors showed "relatively consistent" outcomes in patient survival and tumor progression for both non-Asian and Asian patients.

In addition, the company stated that the efficacy data of Tyvyt from the Orient-11 trial is similar to data from other major anti-PD-1/L1 trials primarily conducted on Western patients. In the Orient-11 trial, compared with chemotherapy alone, Tyvyt plus chemotherapy reduced the risk of disease progression or death by 52%; the median PFS for patients in the Tyvyt plus chemotherapy group was 8.9 months, compared to 5 months in the chemotherapy group. In the Keynote-189 trial, Keytruda showed similar results: the median PFS in the Keytruda plus chemotherapy group was 9 months, compared to 4.9 months in the chemotherapy group.

In terms of the more critical patient survival metrics, as of September 2021, Tyvyt + chemotherapy reduced the risk of death by 35%. This result appears less impressive compared to Keytruda + chemotherapy, which reduced the risk of death by 44% in a pre-specified final analysis.

Nevertheless, Jake Van Naarden, president of Eli Lilly Oncology, acknowledged, "The agency's position may have changed, or we may have misunderstood it a few years ago."

Jake Van Naarden was referring to comments made by Richard Pazdur, director of the FDA's Oncology Center of Excellence, at the 2019 American Association for Cancer Research (AACR) meeting. At the conference, Richard Pazdur encouraged Chinese companies to bring competition to the U.S. PD-1/L1 field by replicating foreign trials in China at a lower cost. At that time, Richard Pazdur criticized the high pricing of Western PD-1/L1 developers.

This comment actually sparked enthusiasm for introducing China-produced PD-1/L1 inhibitors to the U.S. market. Apart from Eli Lilly and Innovent Bio, Novartis later collaborated with BeiGene to develop tislelizumab, while EQRx secured exclusive rights to CStone Pharmaceuticals' sugemalimab. Additionally, Coherus Biosciences partnered with Junshi Biosciences to develop toripalimab, and other companies have reached similar deals.

These companies, either explicitly or indirectly, indicated that their products would enter the highly lucrative U.S. immuno-oncology market at discounted prices. For instance, Eli Lilly's Van Naarden boasted about its "disruptive pricing strategy" for Tyvyt during a conference call on Thursday.

But fast forward to today, the FDA specifically pointed out in its internal review documents, clarifying a well-known FDA review standard, although this seems to be a step back from Pazdur's comments in 2019. The agency wrote, "The FDA may not consider drug pricing or competition in regulatory decisions, and costs and drug pricing should not be discussed as topics at ODAC meetings."

The only question for ODAC members in the upcoming meeting is whether more clinical trials reflecting the U.S. population are needed before making a final decision on Tyvyt. The FDA is not obligated to follow ODAC's recommendations, but it usually does.

FDA's review decision on Tyvyt can serve as a benchmark for all other China-produced PD-1/L1 products that are submitting marketing applications to the FDA. According to the FDA, there are over 25 oncology applications at various stages of drug development planned for submission or currently under review, with these applications being fully or primarily based on clinical data from China.

Article Reference Source: Eli Lilly, Innovent's PD-1 in troubled waters as FDA review, oncology chief's comments portend likely rejection