Highlight
• NEJ045A demonstrates that first‑line durvalumab combined with carboplatin and etoposide is feasible in treatment‑naive extensive‑stage small‑cell lung cancer (ES‑SCLC) patients with poor performance status (PS 2–3), with induction completion rates exceeding pre‑specified thresholds.
• One‑year survival was 43.4% overall (50% for PS2 and 18.2% for PS3), suggesting a clinically meaningful benefit compared with historical expectations for poor‑PS cohorts.
• High rates of grade ≥3 adverse events (93% of patients) and treatment discontinuations (21%) highlight the need for careful patient selection, dose individualization, and intensive supportive care.
Background: clinical need and rationale
Extensive‑stage small‑cell lung cancer (ES‑SCLC) is an aggressive neuroendocrine lung cancer subtype with early metastatic dissemination and high chemo‑sensitivity but short median survival. Immune checkpoint inhibitors (ICIs) added to platinum–etoposide improved survival in randomized trials of fit patients (WHO/ECOG PS 0–1), establishing durvalumab plus platinum–etoposide as a first‑line option (CASPIAN). However, many patients present with poor performance status (PS 2 or 3) because of disease burden, comorbidity, or age; these patients are often excluded from pivotal trials and routinely underrepresented in evidence guiding treatment. There is an important unmet need for prospective data to inform the safety and efficacy of chemo‑immunotherapy in this frail population.
Study design and population (NEJ045A)
Design and objectives
NEJ045A was an open‑label, single‑arm, phase 2 trial conducted in Japan enrolling treatment‑naive patients with ES‑SCLC and poor performance status (PS 2 or 3). The primary endpoint was tolerability, operationalized as the proportion of patients completing the induction phase (four cycles) of durvalumab plus carboplatin and etoposide. A principal secondary endpoint was 1‑year survival rate. The study used a pragmatic dose‑adjustment strategy: starting doses of carboplatin–etoposide were reduced for frailty, with preplanned escalation based on tolerability and adverse events.
Population
Fifty‑seven patients were enrolled between April 8, 2021, and Oct 3, 2023 (median age 73.5 years, IQR 69.0–77.5). Forty‑three patients (75%) had PS 2 and 14 (25%) had PS 3. The cohort was predominantly male (79% of 56 evaluable patients).
Treatment
Patients received four cycles of durvalumab plus carboplatin and etoposide followed by maintenance durvalumab. Dosing began at reduced carboplatin–etoposide levels with prospective adjustments based on toxicity, permitting escalation in patients who tolerated initial dosing.
Key results
Tolerability and induction completion
Completion of the four‑cycle induction regimen exceeded the pre‑specified thresholds. Among patients with PS 2, 26 of 39 evaluable patients (67%; 80% CI 55.2–76.7; p<0.0001) completed induction. Among those with PS 3, 5 of 10 evaluable patients (50%; 80% CI 26.7–73.3; p=0.0088) completed induction. These results met the study’s primary tolerability endpoint and suggest that a structured dose‑modification strategy can permit many frail patients to receive full induction chemo‑immunotherapy.
Safety
High rates of treatment‑emergent toxicity were observed, consistent with combined platinum‑etoposide cytotoxicity in a frail population. Grade 3 or higher adverse events occurred in 52 of 56 patients (93%). Treatment discontinuation due to adverse events occurred in 12 of 56 patients (21%). The trial report emphasizes the need for vigilant monitoring, prompt supportive measures, and individualized dose modifications when treating poor‑PS patients with combination regimens. Immune‑related adverse events (imAEs) were not detailed in the summary provided, but given prior durvalumab experience, clinicians should anticipate endocrine, hepatic, pulmonary, and dermatologic imAEs and manage according to established guidelines.
Survival outcomes
The 1‑year survival rate was 43.4% overall (80% CI 34.1–53.1; p<0.0001). Stratified by performance status, 1‑year survival was 50.0% (80% CI 39.1–60.9; p<0.0001) for PS 2 and 18.2% (80% CI 5.0–41.5) for PS 3. Although a median overall survival (mOS) was not reported in the abstracted summary, the 1‑year survival signal in PS 2 patients compares favorably to historical controls for poor‑PS cohorts and suggests clinical activity beyond what would be expected from best supportive care or chemotherapy alone in this population.
Comparison with prior durvalumab studies
NEJ045A addresses a patient subgroup largely excluded from CASPIAN (randomized durvalumab plus platinum–etoposide vs platinum–etoposide in PS 0–1). CASPIAN demonstrated an overall survival benefit with durvalumab: median OS 13.0 months versus 10.3 months in the control arm (HR 0.73; 95% CI 0.59–0.91), and acceptable safety in fit patients. The CANTABRICO single‑arm study (allowing up to 30% PS 2) reported grade ≥3 AEs in 76.2% and a median OS of 9.6 months (95% CI 7.8–11.3), with 12‑ and 24‑month OS rates of approximately 41% and 25% respectively. NEJ045A complements these data by focusing explicitly on PS 2–3, showing that many PS2 patients can complete induction and have a substantial 1‑year survival, though PS3 outcomes remain poor.
Expert commentary and interpretation
NEJ045A is an important pragmatic step toward extending evidence‑based therapy to patients with poor performance status, a group with high unmet need. Key interpretive points include:
- Feasibility: The induction completion rates show that a majority of PS2 patients can receive four cycles of chemo‑immunotherapy when dosing and escalation are individualized. This challenges the notion that PS2 should uniformly preclude standard first‑line treatment with ICIs plus platinum‑etoposide.
- PS stratification matters: Outcomes for PS3 patients were substantially worse than for PS2, with only 18% alive at 1 year. PS3 likely represents a heterogeneous group—some with reversible, disease‑related debility who may benefit from therapy, and others with irreversible comorbidity‑related frailty where harms may outweigh benefits. Careful clinical assessment to identify potentially reversible contributors to poor PS (e.g., untreated infection, obstructive symptoms, nutrition) is essential prior to initiating combination therapy.
- Safety and resource needs: The very high rate of grade ≥3 AEs mandates robust supportive care infrastructure: prompt access to hospitalization, growth factors where appropriate, aggressive symptom control, and early recognition/management of immune‑related toxicity.
- Generalisability: NEJ045A was conducted in a Japanese population at a single study group; while biologic rationale for benefit is broad, external validation in diverse populations would strengthen confidence in widespread adoption.
- Evidence hierarchy: As a single‑arm phase 2 study, NEJ045A provides important hypothesis‑generating data but cannot replace randomized evidence. Randomized trials focused on poor‑PS populations would be ideal but are operationally challenging. Real‑world data and prospective registries will be valuable adjuncts.
Clinical implications and practical considerations
For clinicians managing poor‑PS ES‑SCLC, NEJ045A suggests the following practical approach:
- Do not reflexively deny chemo‑immunotherapy to all PS2 patients. Perform a focused assessment to determine whether poor PS is primarily disease‑related and potentially reversible.
- Consider starting at a reduced carboplatin–etoposide dose with a plan for escalation if tolerated, as implemented in NEJ045A.
- Plan for intensified monitoring during induction: early clinic review, low thresholds for lab checks, prophylaxis (antiemetics, hydration, infection prevention), and low threshold for supportive interventions (transfusion, G‑CSF where indicated).
- Discuss goals of care explicitly. For PS3 patients, have an honest shared decision‑making conversation about expected benefit, risks, and alternatives including palliative‑focused care.
- Ensure clinicians are familiar with ICI toxicity recognition and management; endocrine and pulmonary toxicities can be especially consequential in older, frail patients.
Limitations and research gaps
Key limitations of NEJ045A include single‑arm design, modest sample size (particularly for PS3 subgroup), and conduct in a single country which may limit external validity. Important unanswered questions include the optimal dosing strategy for cytotoxic agents with ICI in frail patients, the role of prophylactic measures (e.g., earlier G‑CSF), biomarker selection (PD‑L1 and tumor mutational burden are of limited utility in SCLC), and whether select PS3 patients can achieve meaningful benefit. Prospective randomized comparisons versus modified chemotherapy regimens or best supportive care would be informative but challenging; pragmatic trials or registries may be the most feasible path forward.
Conclusion
NEJ045A provides prospective evidence that durvalumab combined with carboplatin and etoposide can be delivered with tolerability and a promising 1‑year survival signal in ES‑SCLC patients with poor performance status, particularly those with PS2. High rates of grade ≥3 toxicity underscore the need for careful patient selection, individualized dosing, and comprehensive supportive care. These results support considering integrated chemo‑immunotherapy for selected frail patients after multidisciplinary assessment and shared decision making, while further validation and optimization of treatment strategies are pursued.
Funding and trial registration
NEJ045A was funded by AstraZeneca KK. The trial is registered at the Japan Registry of Clinical Trials (jRCTs031200319).
References
1. Asao T, Saida Y, Watanabe S, et al.; North East Japan Study Group. Durvalumab, carboplatin, and etoposide in patients who are treatment‑naive with extensive‑stage small‑cell lung cancer and poor performance status (NEJ045A): a single‑arm phase 2 trial. Lancet Respir Med. 2025 Dec;13(12):1057–1066. doi:10.1016/S2213-2600(25)00240-1.
2. Isla D, Zugazagoitia J, Arriola E, et al. Durvalumab plus platinum‑etoposide in the first‑line treatment of extensive‑stage small cell lung cancer (CANTABRICO): A single‑arm clinical trial. Lung Cancer. 2025 Nov;209:108763. doi:10.1016/j.lungcan.2025.108763.
3. Paz‑Ares L, Dvorkin M, Chen Y, et al.; CASPIAN investigators. Durvalumab plus platinum‑etoposide versus platinum‑etoposide in first‑line treatment of extensive‑stage small‑cell lung cancer (CASPIAN): a randomised, controlled, open‑label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929–1939. doi:10.1016/S0140-6736(19)32222-6.
4. Paz‑Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum‑etoposide in first‑line treatment of extensive‑stage small‑cell lung cancer: 3‑year overall survival update from CASPIAN. ESMO Open. 2022 Apr;7(2):100408. doi:10.1016/j.esmoop.2022.100408.
