Editor's note: Small cell lung cancer (SCLC) has a high degree of malignancy, rapid progression, and early metastasis, and most patients with small cell lung cancer are diagnosed in the extended-stage (ES-SCLC). The traditional first-line treatment regimen for ES-SCLC was EP (cisplatin etoposide)/EC (carboplatin etoposide), with a median PFS of 5.2-5.8 months, while the median OS of PD-1/PD-L1 antibody combined with EP/EC was prolonged, but the median PFS was still 5.1-6.1 months, and more effective chemotherapy-based combinations need to be explored urgently.
Professor Zhong Diansheng from Tianjin Medical University General Hospital is the executive editor-in-chief of this issue of "Expert Group Draft", and together with Professor Meng Fanlu from Tianjin Medical University General Hospital, he shared the progress of first-line anti-angiogenic therapy for extensive-stage small cell lung cancer, providing more references for doctors and patients.
Expert presentation
Zhong Diansheng
Director of the Department of Medical Oncology, Tianjin Medical University General Hospital, Doctoral Supervisor, Professor, Chief Physician
Member of the Oncology Branch of the Chinese Medical Association
Member of the Lung Cancer Group of the Respiratory Branch of the Chinese Medical Association
Member of the Lung Cancer Committee of the Chinese Anti-Cancer Association
He is a member of the Multidisciplinary Cancer Diagnosis and Treatment Committee of the Chinese Anti-Cancer Association
Member of the Vascular Targeting Committee of the Chinese Society of Clinical Oncology
He is a member of the Multidisciplinary Diagnosis and Treatment Committee of the Chinese Medical Doctor Association
Member of the Standing Committee of the Cancer Chemotherapy Committee of the Chinese Medical Education Association
Member of the Standing Committee of the Tumor Metastasis Committee of the China Medical Education Association
Chairman of the Multidisciplinary Diagnosis and Treatment Committee of Tianjin Medical Doctor Association
Chairman of the Targeted Therapy Committee of Tianjin Anti-Cancer Association
Chairman of the Multidisciplinary Diagnosis and Treatment Committee of Lung Tumors of Tianjin Medical and Health Association
Vice Chairman of the Oncology Branch of Tianjin Medical Association
Vice Chairman of the Lung Cancer Special Committee of Tianjin Anti-Cancer Association
Vice Chairman of the Special Committee of Multiple Primary and Unknown Primary Tumors of Tianjin Anti-Cancer Association
Vice Chairman of the Oncology Committee of Tianjin Medical and Health Association
Vice Chairman of the Palliative Care Committee of Beijing Oncology Society
Director of Tianjin Anti-Cancer Association
Meng Fan Road
Deputy Chief Physician of the Department of Medical Oncology, Tianjin Medical University General Hospital, Ph.D
Vice Chairman of the Targeted Therapy Committee of Tianjin Anti-Cancer Association
Vice Chairman of the Immunotherapy Committee of Tianjin Anti-Cancer Association
Director General of the Oncology MDT Special Committee of Tianjin Medical Doctor Association
Secretary-General/Standing Committee Member of the Lung Tumor MDT Special Committee of Tianjin Medical and Health Association
Member of the Standing Committee of the Oncology Committee of Tianjin Association of Integrative Medicine
Member of the Medical Oncology Branch of the China Association for the Promotion of International Exchange in Health Care
Member of the Lung Cancer Committee of the Chinese Geriatric Health Care Association
Member of the Young Expert Committee of Lung Cancer Medicine of Beijing Medical Award Foundation
Member of the Lung Cancer Youth Committee of Tianjin Anti-Cancer Association
Title: Advances in first-line anti-angiogenic therapy for extensive-stage small cell lung cancer
◾ Author: Zhong Diansheng Meng Fanlu
1. Research progress of anlotinib combined with chemotherapy for first-line ES-SCLC
Anlotinib is a small molecule multi-target TKI that can inhibit tumor angiogenesis and tumor cell proliferation by inhibiting VEGFR1-3, FGFR1-4, PDGFRα/β, c-Kit, etc., and has the ability to inhibit SCLC cell proliferation. ALTER1202 studies have confirmed that compared with placebo, anlotinib has brought both OS and PFS benefits to patients with third-line and above SCLC. Can the effectiveness of anlotinib be generalized to first-line therapy? In recent years, anlotinib in combination with chemotherapy has been tried in multiple phase II clinical studies for the first-line treatment of ES-SCLC (Table 1).
Table 1
ETER701研究
The data from the Phase II anlotinib study are encouraging, but what about the data from the Phase III study? ETER701 study is a multicenter, double-blind, placebo-controlled phase III study in which eligible patients with ES-SCLC were randomized (1:1:1) to receive benmelstobart+anlotinib+EC or placebo+anlotinib+EC or placebo+EC for 4 cycles followed by maintenance treatment with benmelstobart+anlotinib or placebo + anlotinib or placebo. The co-primary endpoint is PFS as assessed by an independent review committee (IRC) and OS in the intention-to-treat population. From May 18, 2020 to December 18, 2021, 738 patients were enrolled for randomization. The results showed that median PFS was 6.9 and 4.2 months in the Benmelstobart + anlotinib + EC arm and placebo + EC arm, respectively (Figure 1), and median OS was 19.3 and 11.9 months, respectively in the two arms (Figure 2).
Figure 1.Comparison of ORR and PFS between the four-drug group and the platinum-containing two-drug group
Figure 2.OS in the four-drug group versus the platinum-containing two-drug group
ETER701 study also compared the results of the immunization + anlotinib + chemotherapy group (four-drug group) with the anlotinib + chemotherapy group (three-drug group). The ORR was similar between the two groups (81.3% and 81.2%), and the median PFS of the two groups was 6.9 months and 5.6 months, respectively, reducing the risk of disease progression by 68% and 56%, respectively, which was significantly better than that of the chemotherapy alone group, and the immune + anlotinib + chemotherapy group had a more obvious advantage; In terms of OS phase, the four-drug group brought a significant OS phase improvement in SCLC (19.3 months), which was significantly higher than that of the three-drug group (13.27 months). The incidence of grade 3 or above treatment-related adverse events in the four-drug group and the three-drug group was 94.3% versus 87.0%, and the incidence of grade 5 adverse events was 2.5% versus 1.6%, respectively.
2. Exploration of surufatinib in the first-line treatment of ES-SCLC
As a small molecule multi-target drug, surufatinib has also been explored in the first-line treatment of ES-SCLC. At the 2022 ESMO IO, data from the Phase Ib/II study of the efficacy and safety of surufatinib + toripalimab + EP in the first-line treatment of SCLC initiated by the team of Professor Zhang Li from the Cancer Center of Sun Yat-sen University were announced. The primary objective of the surufatinib + toripalimab + EP regimen Phase I.b is to evaluate the safety profile of surufatinib and confirm the RP2D; The primary objective of Phase II is to evaluate PFS and secondary endpoints, including ORR, DCR, OS, and safety. The study began with 3+3 dose escalation of 150 mg (DL1), 200 mg (DL2) and 250 mg (DL3) of surufatinib in combination with a fixed dose of toripalimab and EP, followed by maintenance therapy with toripalimab plus surufatinib after four cycles of combination therapy. As of November 20, 2022, 27 patients (Phase I.b DL2, n=6; Phase II, n=21) were enrolled and treated, and the recommended dose (RP2D) for the Phase II trial of surufatinib was determined to be 200 mg. Of the 19 patients whose efficacy is evaluable at present, 18 achieved PR and 1 achieved SD (Fig. 3), with an ORR of 94.7% and a DCR of 100% (Table 2), and median PFS and OS have not yet been achieved.
Figure 3.Depth of tumor response
Table 2.Evaluation of efficacy
3. Results of the CeLEBrATE study
The CeLEBrATE study is a single-arm, phase II study of 53 patients with ES-SCLC who have not received prior systemic therapy and received atezolizumab in combination with EC and bevacizumab induction therapy, followed by atezolizumab plus bevacizumab maintenance therapy, to evaluate the efficacy and safety of immunotherapy in combination with chemotherapy and bevacizumab in the first-line treatment of ES-SCLC. The primary endpoint was 1-year OS rate, with secondary endpoints being ORR, PFS, and safety. The median follow-up was 19.1 months. The results showed that the ORR was 67.9%, the median PFS was 6.2 months, and the median OS was 12.7 months (Figure 4)
Figure 4.Study Results: PFS and OS
四、BEAT-SC研究进展
The BEAT-SC study is currently the world's first phase III multicenter confirmatory study in the field of ES-SCLC to explore atezolizumab in combination with chemotherapy (ACE) and bevacizumab with first-line immunotherapy + chemotherapy as the standard control group. In an interim analysis, a four-drug regimen consisting of atezolizumab plus bevacizumab and chemotherapy reduced disease progression and improved PFS compared with atezolizumab plus chemotherapy. In 2024, ASCO published the latest data from the study, which showed that bevacizumab + ACE significantly prolonged PFS (investigator-assessed) compared with placebo + ACE, 5.7 months versus 4.4 months, stratified HR of 0.70, P=0.0060 (Figure 5), and the PFS of the two groups of independent reviews also made a difference, 6.0 months versus 4.4 months, The stratified HR was 0.67 (0.52-0.87) (Fig. 6), and the OS data in the experimental group were immature, but the OS of atezolizumab plus chemotherapy in the control group reached 16.6 months, which has become the longest OS data reported in the current Asian phase III clinical study with first-line immunotherapy combined with chemotherapy.
In terms of safety, the patients in the bevacizumab + ACE group were well tolerated, and there were no significant differences in the overall adverse events and serious adverse events between the two groups, and more adverse events of special concern, including proteinuria and hypertension, were observed in the bevacizumab + ACE group. No new safety signals were observed.
Figure 5.Investigator-assessed PFS
Figure 6.Independently reviewed PFS
conclusion
In conclusion, the use of anti-angiogenic drugs in the first-line treatment of ES-SCLC has shown promising prospects, and it is expected that more research results will be published to rewrite the guidelines for the first-line treatment of ES-SCLC.
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