Mengjie Li, Dingzhi Huang (Department of Pulmonary Medical Oncology, National Clinical Research Center for Malignant Tumors, Tianjin Clinical Research Center for Malignant Tumors, Tianjin Key Laboratory of Cancer Prevention and Control, Tianjin Medical University Cancer Hospital, Tianjin 300060, China)
Foundation Item:
National Natural Science Foundation of China (82172635) and Tianjin Medical Key Discipline (Specialty) Construction Project (TJYXZDXK-010A)
Corresponding author: Huang Dingzhi
E-mail:[email protected]
Professor Wong Ting-chi
Doctor of Oncology, Chief Physician, Doctoral Supervisor
Vice President of Tianjin Medical University Cancer Hospital
Vice Chairman of the Lung Tumor Integrated Rehabilitation Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Malignant Mesothelioma Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Cancer Clinical Research Management Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Lung Cancer Professional Committee of the Chinese Geriatric Health Care Association
Member of the Standing Committee of the Geriatric Cancer Prevention and Treatment Expert Committee of the Chinese Society of Clinical Oncology
He is a member of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association
He is a member of the Non-Small Cell Lung Cancer Expert Committee of the Chinese Society of Clinical Oncology
He is a member of the Tumor Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association
He is a member of the Tumor Precision Therapy Professional Committee of the Chinese Anti-Cancer Association
Secretary-General of Tianjin Anti-Cancer Association
He is the chairman-designate of the Lung Cancer Professional Committee of Tianjin Anti-Cancer Association
Member of the editorial board of Chinese Journal of Oncology and Chinese Clinical Oncology
【Abstract】Small cell lung cancer (SCLC) is highly malignant, aggressive, and sensitive to chemoradiotherapy, but it is highly resistant to drugs, has a short remission period, and has a poor post-line treatment effect and a very low 5-year survival rate. The rise of immunotherapy has significantly improved the survival of SCLC patients. However, how to further improve the efficacy depends on the screening of the immune benefit population, the overcoming of immune resistance, and the exploration of the optimal combination therapy mode. In 2023, SCLC reported a number of research results in first-line and late-line combination therapy, maintenance therapy and targeted therapy: first-line treatment once again verified the survival benefit of programmed cell death protein 1 (PD-1) monoclonal antibody in SCLC treatment, and the "four-drug combination" model of anti-angiogenic drugs combined with immunotherapy and chemotherapy has been explored in SCLC to see whether it can surpass the classic "three-drug combination" DLL3 (Notch inhibitory ligand) bispecific antibody has made another breakthrough, and the preliminary efficacy of antibody-drug conjugates has shown its therapeutic potential, while there has been no significant progress in first-line maintenance therapy and marker screening. The purpose of this article is to summarize the research progress of SCLC treatment in 2023.
【Keywords】small cell lung cancer, immunotherapy, targeted therapy, chemotherapy
Lung cancer is the most common and leading cause of cancer death worldwide, with 2.2 million new cases of lung cancer and 1.8 million lung cancer-related deaths worldwide in 2020 [1]. Small cell lung cancer (SCLC) accounts for 12.58% of all new lung cancers and is a highly aggressive neuroendocrine malignancy characterized by high malignancy, aggressiveness, and poor prognosis [2]. Nearly 70 percent of patients with SCLC have distant metastases at the time of initial diagnosis and are diagnosed with extensive stage-small cell lung cancer (ES-SCLC) [3]. In the era of traditional chemotherapy, the median overall survival (OS) time of SCLC patients is only 9~11 months, the median progression-free survival (PFS) time is less than 5 months, and the 5-year OS rate is <2%, so improving the efficacy is still a major clinical problem. Since 2018, the immunotherapy combined with chemotherapy model represented by the IMpower133, CASPIAN, ASTRUM-005, and CAPSTONE-1 studies has achieved a historic breakthrough, making the median OS time of ES-SCLC exceed 1 year. A number of studies have also been carried out in the fields of chemotherapy, targeted therapy and combination therapy, which have explored and demonstrated certain therapeutic potential, bringing new hope for the first-line and late-line treatment of SCLC. In 2023, many research results have been published one after another, and there are many bright spots, and this article aims to summarize the progress of SCLC treatment research in 2023.
1. First-line treatment of ES-SCLC
1.1 化疗联合程序性细胞死亡蛋白1（programmed cell death protein 1，PD-1单抗
The RATIONALE-312 study is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial of 457 patients evaluating the efficacy and safety of tislelizumab or placebo in combination with chemotherapy in the treatment of ES-SCLC [4]. The results of the study were presented at the 2023 World Conference on Lung Cance (WCLC) annual meeting: the median OS time of patients in the tislelizumab plus chemotherapy group and placebo plus chemotherapy group was 15.5 months and 13.5 months (HR=0.75, P=0.003 5), and the median PFS time was 4.8 months and 4.3 months, respectively (HR=0.63, P<0.0001), and the median duration of response (DOR) was 4.3 months and 3.7 months, respectively. It is worth noting that in the real world, 15%~20% of SCLC patients have brain metastases at the time of initial diagnosis, although the study presupposes brain metastasis stratification, but there is only one patient with brain metastases in the experimental group. This study reaffirmed that in addition to programmed cell death ligand 1 (PD-L1) monoclonal antibody, PD-1 monoclonal antibody combined with chemotherapy can improve the prognosis of ES-SCLC. Combined with the results of previous studies, it can be seen that immunotherapy combined with chemotherapy has extended the median OS time of ES-SCLC to 15 months. THE EXTENTORCH STUDY IS A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER PHASE III CLINICAL TRIAL EVALUATING THE EFFICACY AND SAFETY OF TORIPALIMAB OR PLACEBO IN COMBINATION WITH CHEMOTHERAPY IN THE TREATMENT OF ES-SCLC [5]. The results of the study were presented at the 2023 annual meeting of the European Society for Medical Oncology: 442 treatment-naïve patients with ES-SCLC had a median OS time of 14.6 months and a median PFS of 5.8 months in the chemotherapy arm compared with the placebo group, and was the first phase III clinical study to achieve pre-defined PFS and OS dual endpoints and double positive results.
IT CAN BE SEEN FROM THE ABOVE RESULTS THAT THE RATIONALE-312 AND EXTENTORCH STUDIES ARE SIMILAR TO PREVIOUS STUDIES, AND THE PFS AND DOR FAILED TO BREAK THROUGH THE BOTTLENECK OF 5~6 MONTHS, AND THE OS ALSO STOPPED AT 15 MONTHS. In order to further improve the efficacy, immunotherapy plus chemotherapy combined with a new treatment strategy has become an important exploration direction, among which the addition of anti-angiogenic drugs is one of the main research directions.
1.2 Chemotherapy combined with immunotherapy and anti-angiogenic drugs
ETER701 study is a randomized, double-blind, parallel-controlled, nationally multicenter, phase III study evaluating the efficacy and safety of bemosubazumab (anti-PD-L1 monoclonal antibody) and placebo + anlotinib or placebo + chemotherapy in the first-line treatment of ES-SCLC [6]. Some of the results of the study were presented at the 2023 WCLC annual meeting: a total of 738 subjects were included and randomly assigned to receive treatment according to 1:1:1, and the survival time of the four-drug combination group was significantly better than that of the chemotherapy group alone, with a median OS time of 19.3 months and 11.9 months (HR=0.61, P=0.000 2), and median PFS time of 6.9 months and 4.2 months, respectively (HR=0.32, P<0.000). 1), the median DOR was 5.8 months and 3.1 months, respectively (HR=0.31, P<0.000 1). events, TRAEs) resulted in a more than 1-fold increase in dose reduction, treatment discontinuation, and treatment death compared with chemotherapy alone. It is unclear whether a four-drug regimen can achieve a "head-to-head" (a parallel controlled trial of two or more regimens in the same study that is fully comparable between regimens) because the study did not set up the new standard regimen chemotherapy in recent years as a comparator, nor did it publish data on anlotinib plus chemotherapy. Results from the previous phase II ACTION-2 study suggest that anlotinib combined with chemotherapy can significantly improve the survival benefit of first-line treatment with ES-SCLC, with a median OS time of 19.0 months and a median PFS time of 9.0 months, which is also superior to traditional chemotherapy with chemotherapy combined with immunotherapy [7]. Considering that the "four-drug combination" model of immunization combined with anlotinib and chemotherapy has increased significantly in the ETER701 study, it cannot overturn the current status of the first-line standard treatment regimen of chemotherapy combined with immunotherapy, but it also provides a new treatment option for clinical practice.
In 2023, the WCLC announced a multicenter, single-arm, phase II CeLERrATE study evaluating the efficacy and safety of atezolizumab in combination with bevacizumab and chemotherapy in the first-line treatment of ES-SCLC [8]. A total of 53 subjects were included in the study, with a median OS of 12.7 months, a median PFS of 6.2 months, and an objective response rate (ORR) of 67.9%, which was well tolerated. However, the results of the CeLEBrATE study did not show the potential to break the bottleneck of efficacy.
The BEAT-SC study is the world's first international multicenter, randomized controlled phase III study using first-line immunotherapy combined with chemotherapy as the standard control to explore further combination with the anti-angiogenic drug bevacizumab in the first-line treatment of ES-SCLC. At present, only the official website announced that the study met the primary endpoint, atezolizumab combined with bevacizumab and platinum-containing chemotherapy as the first-line treatment of ES-SCLC made PFS benefit, no new safety signal of the combination was observed, OS data is not mature, and whether the advantages of intensive therapy can be translated into PFS and even OS benefits need to be further explored.
2. New progress in maintenance therapy after first-line treatment of ES-SCLC
Maintenance immunotherapy after 4~6 cycles of chemotherapy combined with immunotherapy is the standard treatment mode of ES-SCLC, although the remission rate is as high as more than 70%, most patients will have disease progression in the maintenance immunotherapy stage within 1 year. The improvement of maintenance therapy regimen is one of the hot directions to improve survival time. Polyadenosine diphosphate ribose polymerase (PARP) is a key enzyme in the response to DNA damage, and the high expression of PARP1 protein in SCLC makes SCLC cell lines sensitive to PARP inhibitor therapy, making it a potential targeted therapy for SCLC [9].
Previous retrospective analyses have found that treatment with temozolomide plus veliparib (PARP inhibitor) in SLFN11 (DNA/RNA helicase)-positive SCLC increases PFS and OS, suggesting that SLFN11 expression may be a predictive biomarker of PARP inhibitor efficacy [10]. The SWOG S1929 study is a phase II randomized controlled study evaluating atezolizumab in combination with talazoparib versus atezolizumab maintenance therapy and first-line atezolizumab plus chemotherapy in patients with SLFN11-positive ES-SCLC who have not progressed [11]. At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of the SWOG S1929 study were presented: a total of 106 patients with SLFN11-positive ES-SCLC were enrolled, and the median PFS time was 4.2 months and 2.8 months in the combination therapy group and atezolizumab group, respectively (HR=0.70, P=0.056), the median OS time was 9.4 months and 8.5 months (HR=1.17, P=0.300), and the incidence of grade 3 hematological TRAEs was increased > (50%:4%, P<0.001).
The SWOG S1929 study is the first prospectively designed marker-guided PARP inhibitor for the treatment of SCLC, exploring how to improve the efficacy of first-line treatment of ES-SCLC from the perspectives of marker selection population and highly effective treatment strategy. Unfortunately, the use of immunosuppressants in combination with PARP inhibitors in patients with SLFN11-positive ES-SCLC in this study did not improve the median OS time, and the median PFS time only showed a trend of benefit. Moreover, median OS time did not show an advantage over other first-line phase III studies. Finding biomarkers in SCLC that can accurately guide treatment is crucial to improve treatment efficacy, and it is believed that it will be possible in the future after continuous exploration.
3. New progress in the second-line and late-line treatment of SCLC
3.1 靶向DLL3(delta-like ligand 3)的双特异性抗体药物
DLL3 is a single-shot transmembrane protein and Notch inhibitory ligand attached to the cell surface, which is highly expressed in 85% of SCLCs, and is also widely expressed in neuroepithelial stem cells in large cell neuroendocrine carcinoma of the lung and elsewhere, with little or no expression in normal tissues [12]. DLL3 is abnormally high on the cell surface, making it the most popular therapeutic target [13]. The main types of drug development targeting DLL3 are: DLL3-targeted antibody-drug conjugate (ADC) (e.g., Rova-T), DLL3-targeting T cell binder (e.g., Tarlatamab, BI 764532, etc.), DLL3-targeting chimeric antigen receptor (CAR) therapy (e.g., DLL3-targeting CAR-T lymphocyte therapy), CAR-Natural Killer Cell Therapy targeting DLL3).
The DeLLphi-300 study (NCT03319940) is a Phase I dose-finding trial evaluating taratumab (AMG 757) in patients with SCLC who have progressed or relapsed after platinum-based first-line chemotherapy [14]. The results of the study were presented at the 2022 WCLC Annual Meeting: taratuzumab achieved an ORR of 23 percent for the post-line treatment of SCLC, with a median DOR of 13.0 months, a median OS of 13.2 months, and a median PFS of 3.7 months. Although its ORR and median PFS time are not outstanding, the median DOR is as long as 13 months, which is far higher than the average level of general SCLC treatment drugs (5~6 months), which is a milestone breakthrough. Safety and efficacy results from the DeLLphi-300 study (NCT03319940) taratuzumab in patients with baseline brain metastases in SCLC were presented at the 2023 ASCO Annual Meeting [15]: A total of 192 subjects were enrolled, including 48 (25%) patients with previously treated and stable brain metastases at baseline, 142 (74%) patients without brain metastases, and 2 (1%) The ORR of patients with brain metastases and those without brain metastases was >19.6% and 25.0%, and the disease control rates were 58.7% and 50%, respectively, in patients with baseline brain metastases and 25.0% without brain metastases, and the disease control rates were 58.7% and 50%, respectively , the median DOR was 14.9 months and 13.0 months, the median OS time was 13.2 months and 15.5 months, and the median PFS time was 3.7 months. The most valuable aspect of this study is that patients with brain metastases can also achieve durable remissions. In 2023, the results of the Phase II DeLLphi-301 study of talatumab in the treatment of SCLC with more than two lines of treatment were published in The New England Journal of Medicine: the ORR in the 10 mg and 100 mg dose groups of talatazumab was 40% and 32%, respectively, and the median OS time in both dose groups was more than 13 months, of which 10 The median duration of PFS in the mg dose group was 4.9 months, similar to that of first-line chemotherapy plus immunotherapy, and further maturation of DOR data is expected [16]. Based on the above results, talatazumab has become an important drug in the post-line treatment of SCLC, and it is worth exploring how to combine it with other treatments in the future and whether it can further improve the efficacy.
The NCT04429087 (1438.1) study is a first-in-human, open-label, dose-escalation Phase I clinical trial BI764532 the treatment of DLL3-positive tumors [17]. BI764532 is an IgG-like T cell redirected bispecific antibody targeting DLL3/CD3 with potent preclinical anti-DLL3-positive cell and xenograft antitumor activity in anti-tumor models. The results of the NCT04429087 study were presented at the 2023 WCLC Annual Meeting: a total of 107 patients were treated with ≥1 μg/kg BI764532, including 47 cases (53%) for SCLC and 9 cases (8%) for large cell neuroendocrine carcinoma of the lung, and the incidence of TRAEs was 86%, most of them were grade 1 and 2, which were controllable after symptomatic treatment, and only a few subjects (4% The most common TRAEs were cytokine release syndrome, with 63 cases (59%), most of which were grade 1 or 2 (61/63), which were controllable after symptomatic treatment, and the ORR was 18% and the disease control rate was 41% in all subjects who received BI764532, and tumor shrinkage was observed in subjects treated with ≥90 μg/kg BI764532, with an overall ORR of 25%, including 26% in SCLC subjects , 60% of participants with large cell neuroendocrine carcinoma of the lung, had a long duration of response, and the median DOR was not reached. BI764532 has a similar mechanism of action to talatamab and has shown similar preliminary efficacy in SCLC. The study also provided an unexpected surprise, demonstrating for the first time that BI764532 could be a potentially highly effective drug for large cell neuroendocrine carcinoma of the lung.
Different from PD-1 and PD-L1 immunotherapy, this type of DLL3-based bispecific antibody drug is closer to immune cell therapy. Its mechanism of action is to recruit more T cells into tumor tissues, similar to current cell therapies (e.g., CAR-T), with high rates of cytokine release syndrome. Fortunately, the cytokine release syndrome produced by DLL3 bispecific antibody drugs is mild, basically grade 1 or 2. Bispecific antibodies and immune cell therapies that enrich immune cells may become important breakthroughs and potential flashpoints for the treatment of SCLC in the future.
3.2 靶向B7-H3的ADC
B7-H3, also known as CD276, is a type I transmembrane protein and an important member of the B7 immune co-stimulatory and co-inhibitory family, and its ligand is not yet known. Basic research evidence shows that B7-H3 is a co-inhibitory receptor that plays a role in tumor immune evasion through its inhibitory effect on T cells. B7-H3 is moderately to highly expressed (immunohistochemistry 2+ or 3+) in 65 percent of patients with SCLC and is associated with reduced disease progression and overall survival [18-19]. I-DXd (DS-7300) is a B7-H3-targeting ADC drug that ligates the topoisomerase I inhibitor DXd to a humanized anti-B7-H3 monoclonal antibody via a cleavable tetrapeptide linker.
At the 2023 WCLC Annual Meeting, we updated the results of a subgroup analysis of 21 patients with advanced metastatic SCLC in the first-in-human phase I and II study of I-DXd (DS7300-A-J101 study): with a median follow-up of 11.7 months, an ORR of 52.4 percent, a median PFS of 5.6 months, a median OS of 12.2 months, and a median DOR of 5.9 months for ES-SCLC treated with I-DXd [20]. This suggests that I-DXd has great clinical potential for the treatment of SCLC. A phase II study (IDeate-1, NCT05280470) of I-DXd in patients with ES-SCLC who have received first, second, and third lines of prior therapy is ongoing [21]. Although the failure of several phase III studies of Rova-T has raised questions about the ADC drugs of SCLC, the preliminary data and potential of I-DXd undoubtedly bring new hope to ADC drugs, and the follow-up results are worth looking forward to.
4. Summary
In 2023, ES-SCLC research has made great progress, and two phase III studies have once again confirmed that PD-1 monoclonal antibody combined with chemotherapy can improve SCLC survival, and from the published data of first-line immunotherapy combined with chemotherapy, the OS time of many studies is more than 15 months, and the OS time of 15 months is already the bottom line of first-line therapy. However, there are obvious bottlenecks in PFS and DOR of chemotherapy combined with PD-1 and PD-L1 monoclonal antibodies. The four-drug combination of immunotherapy combined with chemotherapy and anti-angiogenic drugs refreshes the OS time of first-line therapy, but it lacks a "head-to-head" comparison with standard first-line therapy, and has a high incidence of TRAEs, which has not yet become the new standard. There has been no significant progress in new marker-based maintenance immunotherapy regimens. DLL3/CD3 bispecific antibody drugs have made certain breakthroughs, revealing a new therapeutic direction. As a new type of treatment, ADC has only just begun to show its promise, and new targets for the treatment of SCLC still need to be explored in the future. Overall, the treatment of SCLC has gradually entered a stage of rapid development.
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