Durvalumab after chemoradiotherapy in limited stage small cell lung cancer. - ALBORAN

Lung cancer is a highly prevalent disease worldwide in women and men. In 2022, lung cancer stood as the most frequently diagnosed cancer with approximately 2.48 million new cases on a global scale, followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%). Lung cancer is the leading cause of cancer death worldwide according to data provided by the International Agency for Research on Cancer. In 2022 they estimated a 1.8 million deaths across the world. Specifically in Spain, from 1980 to 2022, lung cancer led to 745,182 deaths. Histologically, lung cancer (LC) can be classified into two major subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), accounting for 85% and 15% of LC patients, respectively. Smoking is the major risk factor for SCLC. There are two stages of SCLC: limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC). Limited-stage (LS) means that the cancer is located on the ipsilateral hemithorax that can be encompassed within a radiation port while extensive-stage (ES) means that the cancer has spread widely throughout the lungs, to non-regional lymph nodes or to other organs. At present, LS is identified in ~30% of patients, and ES is identified in ~70% of patients with SCLC. With a 5-year survival rate of less than 7%, SCLC is still one of the most lethal malignancies and it is also characterized by early metastatic spread. Reflecting this high metastatic capacity, two thirds of patients already have tumor cell dissemination outside the chest at the time of initial diagnosis (ES-SCLC). Therefore, the number of patients with LS-SCLC who can benefit from multimodality therapy with potentially curative intent is limited. SCLC is a highly aggressive form of LC that typically recurs and progresses rapidly despite initial response to chemotherapy and radiotherapy in patients with LS-SCLC. The etoposide/platinum (EP) combination was the standard of care (SoC) for patients with ES-SCLC until 2019, when the addition of immunotherapy to EP chemotherapy was shown to improve survival, with up to 17% of patients remaining alive at 3 years. On the other hand, the SoC for patients with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI) that remained unchanged for decades. Several studies have shown that concurrent chemoradiotherapy (cCRT) is more effective than sequential CRT (sCRT) in LS-SCLC. Nonetheless, subject to the lymph node regions involvement and treatment-related toxicities, some patients do not undergo concurrent CRT and instead receive sequential CRT. In a non-interventional, retrospective cohort study of limited-stage SCLC patients conducted in France, Italy and the UK, sequential chemoradiotherapy accounts for 37.6% of all treatment patterns while concurrent chemoradiotherapy accounts for 35.1% of the whole therapies used as first line. ADRIATIC (NCT03703297) is a phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating durvalumab ± tremelimumab as consolidation therapy for patients with LS-SCLC who have not progressed after cCRT. Positive high-level results of the ADRIATIC clinical trial showed durvalumab demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with LS-SCLC who had not progressed following cCRT compared to placebo. Durvalumab was well tolerated, and AEs were consistent with the known safety profile. These data support the consolidation of durvalumab as a new SoC for patients with LS-SCLC who have not progressed after cCRT. There is limited information on the effectiveness and safety of durvalumab in a broader patient population with LS-SCLC, including those who received sequential CRT. Therefore, there remains an unmet need for additional data to help support and inform the healthcare decisions on the use of durvalumab as consolidation treatment for patients with LS-SCLC in real-world clinical practice. In addition, ADRIATIC study did not allow to include patients with ECOG PS 2 assessed after CRT. The present phase IIIb study will assess the safety and effectiveness of durvalumab in real world like LS-SCLC population. Furthermore, this trial will focus on patient characteristics, treatment exposure, administration, quality of life (QoL), effectiveness and safety providing insights into durvalumab use.

Lung cancer is a highly prevalent disease worldwide in women and men. In 2022, lung cancer stood as the most frequently diagnosed cancer with approximately 2.48 million new cases on a global scale, followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%). Lung cancer is the leading cause of cancer death worldwide according to data provided by the International Agency for Research on Cancer. In 2022 they estimated a 1.8 million deaths across the world. Specifically in Spain, from 1980 to 2022, lung cancer led to 745,182 deaths. Histologically, lung cancer (LC) can be classified into two major subtypes: non-small cell lung cancer and small cell lung cancer (SCLC), accounting for 85% and 15% of LC patients, respectively. Smoking is the major risk factor for SCLC. Small cell lung cancer (SCLC) represents approximately 14% of all newly diagnosed lung cancers. SCLC is perhaps the most aggressive form of the disease, distinguishable from non-small-cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and early dissemination. It is strongly associated with tobacco smoking and is also associated with an extremely high mutation rate. Moreover, inactivation of TP53 and RB1 occurs frequently, and in a recent study in which sequencing of SCLC tumors was carried out, recurrent mutations were identified in the CREBBP, EP300, and MLL genes that encode histone modifiers. Furthermore, mutations in PTEN, SLIT2, and EPHA7 (as well as focal amplifications of the FGFR1 tyrosine kinase gene) were also observed. A 2-stage system dividing patients into limited and extensive disease was developed in 1973 by the United States (US) Veteran´s Administration Lung Cancer Study Group. Limited stage was defined as tumor tissue that could be encompassed in a single radiation port, and extensive-stage (ES) disease was defined as any tumor that extended beyond the boundaries of a single radiation port. At present, limited stage is identified in ~30% of patients, and ES is identified in ~70% of patients. The SoC treatment for LS-SCLC is thoracic radiotherapy (once daily with a total dose of 60 to 66 Gy or twice daily with a total dose of 45 Gy) combined with 4 cycles of either cisplatin or carboplatin and etoposide chemotherapy. In addition, data suggest that prophylactic cranial irradiation (PCI; for patients that respond to initial therapy) may increase the OS and PFS in LS-SCLC patients. Response rates for concurrent CRT in LS-SCLC are approximately 90%, but the majority of patients eventually progress, with median PFS of 10 to 15 months and median OS of 15 to 30 months. Therefore, there is still a significant unmet medical need for additional treatment options for this patient population to improve PFS and OS. Currently, the 5-year survival rate is approximately 20%–25% for LS-SCLC and barely 1%–2% for ES-SCLC, making SCLC one of the deadliest cancers. SCLC may be particularly susceptible to immune checkpoint inhibitor therapy given the high mutational burden of this disease. Several recent studies analysing data from different tumor types have demonstrated a correlation between mutational burden and response to checkpoint inhibitors targeting both PD-1 and CTLA-4. ADRIATIC (NCT03703297) is a phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating durvalumab ± tremelimumab as consolidation therapy for patients with LS-SCLC who have not progressed after cCRT. Positive high-level results of the ADRIATIC clinical trial showed durvalumab demonstrated a statistically significant and clinically meaningful improvement in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with LS-SCLC who had not progressed following cCRT compared to placebo. Durvalumab was well tolerated, and AEs were consistent with the known safety profile. These data support the consolidation of durvalumab as a new SoC for patients with LS-SCLC who have not progressed after cCRT. There is limited information on the effectiveness and safety of durvalumab in a broader patient population with LS-SCLC, including those who received sequential CRT. The present phase IIIb study will assess the safety and effectiveness of durvalumab in real world LS-SCLC population. Furthermore, the study will focus on patient characteristics, treatment exposure, administration and quality of life (QoL), among others, providing insights into durvalumab use.