AstraZeneca recently announced that its PD-L1 monoclonal antibody Imfinzi has been approved by the FDA in the United States for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after concurrent platinum chemotherapy and radiotherapy, becoming the world's first and only immunotherapy for LS-SCLC. In

the ADRIATIC Phase III clinical trial, the average overall survival (OS) of the Imfinzi group was 55.9 months, and that of the placebo group was 33.4 months, a full 22.5 months increase. This is a very groundbreaking progress, breaking the LS-SCLC treatment bottleneck of more than 30 years. AstraZeneca

"dug up the gold mine", and its lung cancer treatment map has been further expanded.

Expanding the lung cancer drug map

Before 2000, there were only three means of treating lung cancer: chemotherapy, radiotherapy and surgery, especially for patients with advanced lung cancer, who had limited options. It was not until 2004 that the EGFR target was first discovered in non-small cell lung cancer (NSCLC), which opened the way for the development of precision diagnosis and treatment of lung cancer. EGFR gene mutation is a common driver gene mutation in NSCLC, especially in Asian populations. 2024 marks the 20th anniversary of the discovery of the EGFR target. From the initial first-generation EGFR-TKI gefitinib to the current third-generation EGFR-TKI osimertinib, AstraZeneca has led the continuous development and innovation of EGFR lung cancer targeted therapy.

AstraZeneca's deep cultivation in the field of lung cancer does not stop there. In addition to EGFR targeted drugs, China's first MET inhibitor, savotinib, and China's first PD-L1 inhibitor, durvalumab, have also been launched.

As a new type of antibody drug, ADC drugs combine the high-specific targeting ability of antibodies with the potent killing effect of drugs, which can achieve precise attacks on tumor cells, especially in the field of solid tumor treatment. In particular, the emergence of DS-8201 in 2022 has set off a new round of ADC drug research and development. Various biopharmaceutical companies have laid out their plans, and their research and development and clinical applications have also made remarkable progress in recent years. The research and development focus of ADC companies at home and abroad is generally the same, mainly focusing on popular targets such as HER2 and TROP2.

AstraZeneca has lung cancer indications in both HER2-targeted ADC drugs and TROP2-targeted ADC drugs. In terms of HER2-targeted ADC, the famous trastuzumab deruxtecan (DS-8201) is the first drug approved by the FDA and China to treat HER2-mutated NSCLC, filling the gap in the field and completely changing the dilemma of no drugs available. It has become the only targeted therapy for HER2-mutated NSCLC.

In terms of TROP2 ADC, the results of the latest published summary analysis of the TROPION-Lung01 and TROPION-Lung05 clinical trials showed that datopotamab deruxtecan (Dato-DXd), jointly developed by AstraZeneca and Daiichi Sankyo, has significant clinical benefits in patients with EGFR-mutated advanced or metastatic NSCLC who are resistant to EGFR-TKIs. The drug has now submitted a biologics license application (BLA) to the FDA. Dato-DXd is expected to become the first TROP2 ADC drug in the NSCLC field, ushering in a new era of lung cancer ADC treatment. In addition, AstraZeneca has developed a proprietary pathology computing platform, the Quantitative Continuous Score (QCS), which uses artificial intelligence to accurately quantify the biomarker TROP2, aiming to provide ADC treatment guidance for those who are most likely to benefit from it. It also cooperated with Roche to transform it into a companion diagnostic product, which, if approved, can support the launch of Dato-DXd.

In the "new battlefield" of immunotherapy, the field of dual antibodies is gradually taking center stage, and AstraZeneca will naturally not miss this big outlet. This year, AstraZeneca announced at the World Lung Cancer Conference (WCLC) the efficacy and safety of its two immune dual antibody therapies, Rilvegostomig (PD-1/TIGIT) and Volrustomig (PD-1/CTLA-4), in patients with metastatic NSCLC and in combination with chemotherapy as the first-line treatment for patients with advanced NSCLC. The results showed that in NSCLC patients who had not received immune checkpoint therapy, Rilvegostomig not only had a high response rate of 61.8% in patients with high PD-L1 expression, but also had a good response rate of 29% in patients with low PD-L1 expression, which also supported AstraZeneca's rapid launch of a head-to-head Phase III clinical trial with K drug; Volrustomig combined with chemotherapy was effective even in NSCLC patients with PD-L1 expression below 1%, while traditional immunotherapy was ineffective for such patients. The remission rate for patients with non-squamous cell carcinoma was 43%, while the remission rate for patients with squamous cell carcinoma was 50%.

In terms of lung cancer layout, AstraZeneca already has three commercial varieties of immunotherapy, targeted therapy, and ADC. It is not difficult to see that China is becoming a key player in AstraZeneca's lung cancer drug layout. AstraZeneca expects to strive to bring 9 new products and 26 new indications to China by 2030. Globally, the vision is that by 2030, two-thirds of lung cancer patients will benefit from AstraZeneca's drugs.

Small cell lung cancer drug, peak turnSmall

cell lung cancer (SCLC) accounts for about 15% of lung cancer, with about 160,000 new patients in China each year. According to the stage of disease development, small cell lung cancer can be divided into two stages: limited stage (LS-SCLC) and extensive stage (ES-SCLC), accounting for about 1/3 and 2/3 of small cell lung cancer, respectively. The treatment of small cell lung cancer is mainly chemotherapy and immunotherapy: the standard treatment of ES-SCLC 1L is immunotherapy (PD-1/PD-L1 monoclonal antibody) combined with platinum-containing double chemotherapy. Patients who progress after first-line treatment generally use other chemotherapy methods. The prognosis of small cell lung cancer is poor, and there is a high degree of unmet clinical demand. Products with new targets and new mechanisms have the potential to rewrite the SCLC clinical guidelines.

In 2022, the global SCLC market size was US$4.6 billion, which was obtained without the approval of targeted drugs. With the approval of targeted drugs, the global market size of SCLC is expected to increase to US$12.9 billion in 2031, and it is very likely that a "drug king" product of tens of billions of dollars will be born.

At present, PD-1/PD-L1 inhibitors combined with chemotherapy have firmly occupied the first-line treatment market for SCLC. When patients become resistant to PD-1/PD-L1 inhibitors, there are not many effective second-line therapies available, which is the direct reason for the poor prognosis of ES-SCLC. Based on the huge gap in the second-line treatment of ES-SCLC, a variety of new drugs such as bispecific T cell engagers (BiTEs) and antibody-drug conjugates (ADCs) are attacking this blue ocean market.

The first breakthrough was the DLL3/CD3 dual antibody. In May this year, the FDA approved Amgen's Tarlatamab for marketing through accelerated approval for ES-SCLC patients with disease progression after platinum chemotherapy. It has three important meanings for SCLC disease, for the target DLL-3, and for the T cell binder (TCE) to break through solid tumors. In the Phase 2 clinical trial DeLLphi-301, Tarlatamab significantly reduced or eliminated tumors in 40% of SCLC patients.

DLL3 is a protein present on the surface of SCLC cells. Its function is to inhibit Notch signaling. It is usually expressed only inside the cell, but it will be abnormally expressed on the surface of SCLC. Nearly 90% of SCLC cells will have abnormal expression of DLL3, while normal cells will not. This also makes DLL3 an excellent target for conquering SCLC. Currently, many pharmaceutical companies are developing several DLL3 targeted therapies for the treatment of small cell lung cancer, including antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) therapies in addition to T cell engagers (TCEs).

The exploration of ADC is in the ascendant. As of now, although no SCLC ADC drug has been approved for marketing in the world, with the development of related target drugs in recent years, the competition for SCLC clinical layout is also quite fierce. Among them, B7-H3 ADC is the most popular and has become the focus of competition among major pharmaceutical companies. B7-H3 is a transmembrane protein that belongs to the B7 family together with PD-L1. Studies have found that B7-H3 is overexpressed in tumor cells of various cancer types, including lung cancer, prostate cancer, and esophageal cancer. In small cell lung cancer, about 65% of patients have high expression of B7-H3 in their tumors. This makes it a promising therapeutic target in the field of cancer. Especially in the field of small cell lung cancer, which is short of drugs, B7-H3 has shown a relatively amazing therapeutic effect.

Daiichi Sankyo's I-DXd (Ifinatamab Deruxtecan) is the world's first B7-H3 ADC to enter Phase III clinical trials, targeting SCLC. The results of the subgroup analysis of the Phase I/II trial of I-DXd for the treatment of SCLC announced at the 2023 WCLC conference showed that among 21 patients with advanced SCLC, the ORR was 52.4%, the mPFS was 5.6 months, and the mOS was 12.2 months. Domestically, Hausen's HS-20093 and Yilian Bio YL201 followed closely and also started Phase III clinical trials, both targeting SCLC.

It is worth mentioning that the approval of Lubiventin for injection, which was previously applied by Green Leaf Pharmaceuticals, for listing in China has attracted considerable attention. Lurbectedin is an alkaloid compound developed by PharmaMar that can covalently bind to the minor groove of DNA. It was first approved by the FDA on May 15, 2020 for the treatment of metastatic adult SCLC that has progressed on platinum chemotherapy. It is the only new chemical entity approved by the FDA for the second-line treatment of relapsed SCLC since 1997. The

2023 CSCO SCLC diagnosis and treatment guidelines have included lurbectedin as a Grade III recommendation (2A) for the second-line treatment of SCLC, bringing China's second-line treatment of SCLC in line with international standards. In the 2024 guideline update, lurbectedin combined with immune checkpoint drugs was written into the annotation section of the recommended treatment for relapsed SCLC for the first time (based on the LUPER study and the 2SMALL study).

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