LOGIN 06 April 2022
Last month (24thMarch 2022), Eli Lilly announced that the FDA were unable to approve their application for sintilimab in combination with chemotherapy as a first-line treatment in metastatic non-squamous NSCLC, in the US. Thus, creating additional challenges for low-priced Chinese oncology drugs entering the US market.
Sintilimab is a monoclonal antibody programmed cell death protein 1 (PD-1) inhibitor, similar to other checkpoint inhibitors, pembrolizumab and nivolumab. Initially developed in China as part of a strategic collaboration with partner Innovent Biologics, sinitilimab was to be expanded globally to provide a lower priced PD-1 inhibitor.
Eli Lilly’s commercial plan for sintilimab was to offer a significant and transparent wholesale acquisition cost (WAC) price discount, similar to the approximate 40% discount of biosimilars compared to their branded biologics. This pricing strategy was expected to provide substantial savings for the US healthcare system. If sintilimab had been accepted by the FDA, the pricing approach could set a precedent for a wave of low-priced Chinese oncology drugs looking to launch in the US in the near future.
Data from the pivotal Phase III ORIENT-11 trial completed in China were submitted to the FDA, which demonstrated better efficacy outcomes of sintilimab in combination with chemotherapy versus placebo in combination with chemotherapy.
Study design of Phase III ORIENT 11
DCR: disease control rate, DoR: duration of response, NSCLC: non-small cell lung cancer, ORR: overall response rate, OS: overall survival, PFS: progression free survival.
Source: Based on ORIENT-11 trial publication.
However, this evidence was not sufficient for approval of sintilimab in the US. The FDA’s review recommended that before sintilimab could be approved, an additional multi-regional clinical trial (outside of China) was required comparing sintilimab to standard of care (SOC), utilising a non-inferiority design with an overall survival (OS) endpoint. This reflects concerns raised by the Oncologic Drugs Advisory Committee (ODAC) in February 2022, which were demonstrated by the committee’s 14-1 vote for a new trial. Evidence from the ODAC’s assessment suggest four key areas of concern for sintilimab:
- Appropriateness of endpoints
In ORIENT-11, the primary endpoint was PFS as assessed by Independent Radiographic Review Committee (IRRC) based on RECIST v1.1. However, all FDA approvals for PD-1 inhibitors for NSCLC to date are based on statistically significant improvement in OS. Although OS was measured as a secondary endpoint in ORIENT-11, the trial was not designed to evaluate significance. Therefore, data were considered to be descriptive only and could not be used for marketing authorisation decision-making.
- Applicability of the trial comparator to the US standard of care
The control group of the ORIENT-11 trial was chemotherapy alone. In August 2018, pembrolizumab in combination with pemetrexed was approved, making it the SOC for patients with NSCLC in the US. As a result, ORIENT-11’s control arm does not reflect the SOC for the US and the trial result is not generalisable for US clinical practice.
- Generalisability of the trial population
ORIENT-11 was conducted in China only, so the trial data cannot be used to explore the consistency of trial results across regions and patient populations, including non-squamous NSCLC patients in the US.
- Concerns regarding data integrity
The FDA have stated that a pre-trial meeting should have been held so that Innovent and Eli Lilly could be advised to use the right treatment in the control group.
These actions have forced Eli Lilly to reassess the strategy for sintilimab in the US. The decision will also most likely effect the strategy of a number of other companies, as they look to enter Chinese oncology drugs in the US market.
Future focus will be on the full impact of the FDA decision on other Chinese PD-1 inhibitors to disrupt the high prices of oncology treatment in the US.
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