First PD-L1 Inhibitor Approved in China: Imfinzi Emerges as a Game-Changer for Stage III Lung Cancer Treatment

Following the “soul-bargaining” price negotiation of RMB 4.36, AstraZeneca has once again become a headline topic. On December 9, the National Medical Products Administration (NMPA) website announced the approval of AstraZeneca’s marketing application (JXSS1800040/41) for the PD-L1 monoclonal antibody Imfinzi (durvalumab; durvalumab injection; Chinese brand name: Yingfeifan; abbreviated as “I Drug”). This marks another major new drug approval for AstraZeneca in China this year, following the approvals of osimertinib for first-line treatment of non-small cell lung cancer (NSCLC) and olaparib for first-line treatment of ovarian cancer, further strengthening AstraZeneca’s oncology business in China.

Imfinzi is indicated for the treatment of unresectable Stage III non-small cell lung cancer (NSCLC) that has not progressed following concurrent chemoradiotherapy. It is the sixth immune checkpoint inhibitor marketed in China; however, the preceding five were all PD-1 monoclonal antibodies. Imfinzi is the first PD-L1 monoclonal antibody approved in China. What are the differences between PD-1 monoclonal antibodies and PD-L1 monoclonal antibodies?

As shown in the figure above, PD-L1 and PD-1 function as a ligand-receptor pair. Their recognition and binding provide tumor cells with an “escape route” from immune system-mediated killing. Specifically, tumor cells express PD-L1 on their surface, while T cells express PD-1. When PD-L1 binds to PD-1, T-cell activity is inhibited, thereby abrogating their cytotoxic function and allowing tumor growth. Consequently, blocking the PD-L1/PD-1 interaction can restore the ability of T cells to kill tumor cells. Both PD-1 antibodies and PD-L1 antibodies have been developed based on this rationale.

So, is there a difference in antitumor efficacy between PD-L1 antibodies and PD-1 antibodies? Theoretically, anti-PD-1 monoclonal antibodies block the binding of PD-1 to PD-L1 while also inhibiting the interaction between PD-1 and PD-L2, which may potentially increase the risk of autoimmunity; in contrast, anti-PD-L1 monoclonal antibodies preserve the interaction between PD-L2 and PD-1, thereby potentially reducing the impact on immune homeostasis.

Clinical trial data indicate that the efficacy of PD-1 and PD-L1 antibodies is comparable in certain tumor types. It is widely acknowledged that PD-1 inhibitors currently achieve an objective response rate of approximately 30%, thereby leaving room for PD-L1 antibodies in the market. Consequently, neither PD-1 nor PD-L1 antibodies represent an absolute choice for every cancer type or individual patient. Treatment selection should be based on a comprehensive assessment of multiple factors, including tumor type, disease progression status, patient condition, drug tolerance, and response rates. In some cases, PD-1 and PD-L1 antibodies may even play complementary roles. Returning to the focus of today’s news, we will provide further details on Drug I.

Stage III Lung Cancer: The Promised Land for Imfinzi

The Phase III non-small cell lung cancer (NSCLC) indication for which Imfinzi has recently received approval represents a highly specialized niche within the lung cancer field. It is precisely by initially targeting this niche market that Imfinzi has managed to secure its position amidst intense competition.

Based on disease severity, lung cancer is classified into Stage I, Stage II, Stage III, and Stage IV. Stage I and Stage II lung cancers are both in the early stages of the disease, with no spread of cancer cells. Surgical resection of the pulmonary tumor mass combined with chemotherapy and radiotherapy constitutes a highly effective treatment regimen, with clinical management aimed at cure. The 5-year survival rate for Stage I lung cancer can reach 70%–90%, while for Stage II lung cancer, it can reach 50%–70%. In contrast, by Stage IV, cancer cells have metastasized to distant sites outside the thoracic cavity, such as distant lymph nodes, liver, bones, or brain. At this stage, surgery is no longer feasible, and the likelihood of clinical cure is low; therefore, the primary goals are to prolong survival and improve quality of life. The 5-year survival rate for Stage IV lung cancer is only approximately 5%.

Stage III Lung Cancer: Although cancer cells have spread, they remain confined within the thoracic cavity, metastasizing to lymph nodes in other regions of the thorax or to other major organs within the chest. Therefore, stage III lung cancer is also referred to as locally advanced lung cancer. Although it is difficult to surgically remove all cancer cells in stage III lung cancer, there is still a considerable hope for cure compared with stage IV lung cancer. For a long time, the standard treatment for stage III lung cancer was concurrent chemoradiotherapy, but the outcomes were unsatisfactory. Based on U.S. survival data for non-small cell lung cancer (NSCLC) from 1999 to 2010, the 5-year survival rates for patients with stage IIIA, IIIB, and IIIC disease were approximately 36%, 26%, and 13%, respectively.

Imfinzi Demonstrates Significant Clinical Benefits in Stage III Lung CancerIn the Phase III, multicenter, randomized, double-blind, placebo-controlled PACIFIC trial, one year of consolidation therapy with Imfinzi following concurrent chemoradiotherapy in patients with stage III lung cancer significantly extended median progression-free survival (PFS) from 5.6 months to 17.2 months compared with standard care. The 18-month PFS rate increased from 26.7% to 49.5%, and the time to distant metastasis was prolonged from 16.2 months to 28.3 months, delaying disease progression by nearly one year. Meanwhile, the risk of death was reduced by 32%.

PACIFIC Study PFS Data

The 3-year overall survival (OS) data from the PACIFIC study, updated at the ASCO 2019 conference, demonstrated that Imfinzi significantly prolonged median OS compared with placebo (not reached vs. 29.1 months). The 3-year survival rates were 57.0% and 43.5% in the two groups, respectively. The clinical significance of these findings is that they offer a higher chance of cure for patients with stage III lung cancer.

Imfinzi is the first immunotherapy to demonstrate a significant overall survival benefit in unresectable stage III lung cancer, and it now provides a powerful treatment option for patients with stage III non-small cell lung cancer in China.

Global Latecomer, China First: Drug I Emerges as a Dark Horse in the PD-1/PD-L1 Race

In terms of global market entry sequence, Imfinzi did not hold a first-mover advantage in the PD-1/PD-L1 market. It launched nearly three years later than the PD-1 antibodies Opdivo and Keytruda, and one year later than the comparable PD-L1 antibody Tecentriq. However, in the Chinese market, Imfinzi was not significantly behind Opdivo and Keytruda, and even reached the market earlier than Tecentriq.

In terms of market performance, Imfinzi’s combined sales revenue for the first three quarters of 2019 reached $1.045 billion, representing a 180% increase from $371 million in the same period of 2018. Moreover, its quarterly revenue trend is approaching that of Tecentriq, demonstrating that despite being a late entrant, its market performance is by no means inferior, making it a dark horse in the PD-1/PD-L1赛道.

Quarterly Sales of PD-1/PD-L1 Drugs

Unlike its global debut, where Imfinzi was first launched for urothelial carcinoma, its initial indication in the Chinese market was stage III lung cancer—a strategic and prudent choice. Within 12 months of its launch in China, Keytruda achieved sales exceeding RMB 2 billion. Meanwhile, sintilimab and toripalimab, despite having narrower labeled indications, each generated approximately RMB 330 million in sales within a single quarter, underscoring the robust market demand for PD-1/PD-L1 inhibitors. Now approved as the only PD-1/PD-L1 antibody in China specifically indicated for stage III lung cancer, Imfinzi not only benefits from differentiation in its indication but can also leverage AstraZeneca’s synergistic advantages in the Chinese lung cancer sector to rapidly expand its market presence.

Globally Approved PD-1/PD-L1 Drugs and Indications

Note: 1) Red shading indicates that the indication is marketed only in China; red font indicates that the indication is approved in China. 2) Relevant biomarkers are not shown. 3) Indications include those granted conditional approval.

Certainly, the niche indications where Imfinzi holds an advantage or is building one are not limited to stage III NSCLC. On November 30, the FDA granted priority review status to Imfinzi’s application for first-line treatment of small cell lung cancer (SCLC). To date, although Opdivo and Keytruda have also been approved for SCLC, they are both indicated only as third-line therapies, meaning that PD-L1 inhibitors have taken the lead over PD-1 inhibitors in expanding treatment options for patients in this field. SCLC accounts for 15% of all lung cancer cases, representing a substantial market. Although Imfinzi is expected to gain approval for this indication about a year later than Tecentriq, the competition between these two PD-L1 inhibitors remains too close to call at present.

According to data from PharmaCube’s NextPharma, there are 47 PD-L1-related projects under development in China, with only eight having advanced beyond Phase II clinical trials. The indications targeted by these domestic PD-L1 programs encompass a broad range of prevalent malignancies and tumors with distinct prevalence in China, including ovarian cancer, small cell lung cancer, gastric cancer, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, breast cancer, biliary tract cancer, hepatocellular carcinoma, and colorectal cancer.