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Small cell lung cancer (SCLC) is highly aggressive, metastasis-prone, and although it is sensitive to chemotherapy and radiotherapy such as etoposide and platinum, it is prone to progression, with a 5-year survival rate of less than 10%1. With the advent of immunotherapy and the exploration in the field of SCLC, PD-1/PD-L1 inhibitors combined with chemotherapy have significantly improved the overall survival (OS) of patients with extensive-stage SCLC2-5, but their efficacy in limited-stage SCLC still lacks high-level evidence-based medical evidence. The success of this ADRIATIC study fills the gap in the field of PD-1/PD-L1 inhibitors and promotes the survival benefit of limited-stage SCLC to a new level. On this occasion, Yimaitong invited Professor Ying Cheng, NPI of ADRIATIC Research, to share the exploration process of PD-L1 inhibitors in SCLC and analyze the design and clinical value of ADRIATIC research.
Expert Profile
Prof. Ying Cheng
- First-level professor, doctoral supervisor, postdoctoral workstation supervisor
- He enjoys the special allowance of the State Council and has made outstanding contributions to young and middle-aged experts from the Ministry of Health
- Director of Jilin Provincial Cancer Center
- Director of Jilin Provincial Lung Cancer Diagnosis and Treatment Center
- Vice President of the Chinese Society of Clinical Oncology (CSCO).
- Member of the International Alliance for Lung Cancer (IASLC) Rare Tumors Committee
- Chairman of the CSCO Small Cell Lung Cancer Professional Committee
- Chairman-elect of the CSCO Clinical Research Expert Committee
- He is the chairman-designate of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association
- Vice Chairman of CSCO Non-Small Cell Lung Cancer Professional Committee
- Vice Chairman of CSCO Tumor Big Data Expert Committee
- Vice Chairman of the Lung Cancer Committee of the Oncology Branch of the Chinese Medical Association
- Vice Chairman of the Multidisciplinary Diagnosis and Treatment Committee of Tumors of the Chinese Medical Doctor Association
- Member of the Expert Group on Standardized Diagnosis and Treatment of Common Tumors of the National Health and Family Planning Commission
- Chairman of the Oncologist Branch of Jilin Medical Doctor Association
- Chairman of the Oncology Professional Committee of Jilin Provincial Medical Association
- 2023 "Global Highly Cited Researcher" in the field of clinical medicine
Mountains and rivers are in doubt: a rugged journey of SCLC immunity exploration
As a refractory tumor, the treatment of SCLC has progressed very slowly, and chemotherapy has been the standard treatment option for SCLC that has not changed for nearly 30 years, but the median survival time is only 8-10 months6, recurrence of drug resistance is almost inevitable, and there is a lack of effective treatment after drug resistance. With the advent of PD-1/PD-L1 inhibitors, researchers have tried to use combination regimens to treat extensive-stage SCLC, in order to break the "survival bottleneck" of chemotherapy alone and rewrite the standard treatment of the previous 30 years6. The exploration of pembrolizumab and nivolumab in the first-line treatment of extensive-stage SCLC has failed one after another, and failed to significantly improve the OS7,8 of patients, casting a shadow on the road of exploration. The success of the Phase III clinical study of durvalumab versus atezolizumab in combination with chemotherapy in the first-line treatment of ES-SCLC (CASPIAN study and Impower133 study) demonstrated the OS benefit of PD-L1 inhibitor combination chemotherapy in patients with extensive-stage SCLC2,3. The CAPSTONE-1, ASREUM-005 and RATIONALE-312 studies have successively "hit the line"4,5,9, consolidating the standard position of PD-1/PD-L1 in the first-line treatment of extensive-stage SCLC.
Concurrent chemoradiotherapy is currently the standard treatment for limited-stage SCLC, and with the breakthrough of immunotherapy in the first-line treatment of extensive-stage small cell lung cancer, researchers also pin their hopes on immunotherapy to improve the treatment status of limited-stage small cell lung cancer. The treatment of immunotherapy in limited-stage SCLC includes two exploratory modes, one is immune consolidation therapy after induction chemoradiotherapy, and the other is initiation of intervention at the time of induction chemoradiotherapy. The Phase II study, the STIMALI study, is an early attempt at immunotherapy in limited-stage SCLC and explores the efficacy and safety of nivolumab in combination with ipilimumab (O+Y) as consolidation therapy after standard concurrent chemoradiotherapy (cCRT) and prophylactic cranial irradiation (PCI) for limited-stage SCLC. The investigators found that "O+Y" consolidation therapy after induction chemoradiotherapy failed to significantly improve PFS and OS. Due to the early start of this study, the study protocol selected a more toxic regimen, and there was a significant increase in AEs and treatment termination events due to AEs in the "O+Y" treatment group compared with the observation group, which may be one of the factors affecting the efficacy of immunotherapy10.
Uninterrupted learning: durvalumab ushers in a new era of limited-stage SCLC therapy
Past failures have not stopped researchers from exploring. Based on the favorable benefits of durvalumab in the CASPIAN study and the success of the PACIFIC study, the investigators conducted a randomized, double-blind, placebo-controlled, phase III ADRIATIC study to explore the safety and efficacy of durvalumab with or without tremelimumab as consolidation therapy for patients with stable limited-stage SCLC after cCRT therapy. Participants were randomly divided into three groups to receive durvalumab, durvalumab + tremelimumab, or placebo consolidation11. PFS (RECIST v1.1) and OS as assessed by an independent review committee (BIRC) were the primary endpoints of this study, while ORR, 24-month OS rate, and 18-month PFS rate were secondary endpoints.
Figure 1. ADRIATIC Study Design
In this ADRIATIC study, PFS and OS crossed the "finish line", making durvalumab the world's first and only PD-L1 inhibitor to demonstrate survival benefit in the global phase III clinical study of limited-stage SCLC, and strongly confirmed the effectiveness of durvalumab as a consolidation treatment for patients with limited-stage SCLC with stable disease after cCRT with solid evidence-based medical evidence, breaking the "passive waiting" after cCRT in patients with limited-stage SCLC The treatment pattern has promoted the further expansion and exploration of PD-L1 inhibitors in limited-stage SCLC. While achieving both mPFS and mOS benefits, durvalumab demonstrated a consistent safety profile as in previous studies12. In addition, the results of durvalumab plus tremelimumab have not been unblinded.
With the success of the ADRIATIC study, durvalumab has achieved full "flowering" of SCLC, becoming the only PD-L1 inhibitor to achieve positive results in both limited-stage SCLC and extensive-stage SCLC. As a clinician, I not only look forward to the "appearance" of the ADRIATIC study results at the recent international academic conference, but also hope that durvalumab will be approved for relevant indications in the near future, injecting new vitality into the treatment of patients with limited-stage SCLC.
In addition to SCLC, durvalumab has also made many achievements in the field of non-small cell lung cancer (NSCLC), providing more treatment options for patients with early- to mid-stage NSCLC. For example, the PACIFIC study pioneered the consolidation of PD-L1 inhibitors after radical cCRT in inoperable stage III NSCLC, significantly improving the survival benefit in this patient population13. In addition, the AEGEAN study announced results from durvalumab "sandwich" in patients with resectable stage II.A-III.B(N2) NSCLC without EGFR and ALK mutations (neoadjuvant immunization + surgery + adjuvant immunity), providing a solution for further benefit in patients with operable NSCLC.14 Durvalumab has comprehensive benefits in the field of SCLC and NSCLC, which has further promoted the survival benefit of lung cancer patients to a new level and helped realize the "Healthy China 2030" plan.
bibliography
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12.https://www.astrazeneca.com/media-centre/press-releases/2024/imfinzi-improved-os-and-pfs-in-limited-stage-sclc.html
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14. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023; 389(18):1672-1684.
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