Precision de-escalation of immunotherapy in extensive-stage small cell lung cancer: a case report on ctDNA-guided management in a long-term survivor

Introduction

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy comprising 10–15% of all lung cancers (1). It is characterized by rapid proliferation and early hematogenous dissemination, with the majority of patients presenting with extensive-stage disease at diagnosis. Although SCLC is initially sensitive to chemotherapy and radiotherapy, relapse is common and leads to poor overall survival (2). In recent years, circulating tumor DNA (ctDNA) analysis has demonstrated significant potential in the management of lung cancer (3-8). Evidence indicates that ctDNA-based detection of minimal residual disease (MRD) can precede radiographic recurrence by several months, providing a crucial window for early therapeutic intervention (3). Furthermore, MRD status has been shown to correlate strongly with patient outcomes (9). While ctDNA-MRD monitoring has been proven valuable in guiding de-escalation treatment in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) (10), its utility in guiding immunotherapy for SCLC remains unexplored. Here, we present a case of immunotherapy de-escalation in extensive-stage SCLC (ES-SCLC), guided by longitudinal ctDNA-MRD surveillance. We present this article in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0594/rc).

Case presentation

A 64-year-old female never-smoker presented with a persistent cough and chest pain. A chest computed tomography (CT) scan revealed a mass in the right middle lobe, pleural nodules, and a massive pleural effusion. Enlarged lymph nodes were noted in stations 2, 4R, and 10R. Serum neuron-specific enolase (NSE) was elevated at 42.7 ng/mL. A CT-guided percutaneous lung biopsy of the mass pathologically confirmed the diagnosis of SCLC. Clinical staging was T3N2M1a according to the American Joint Committee on Cancer (AJCC) 8^th edition staging system. Immunohistochemistry analysis was positive for AE1/AE3 (2+) and INSM1 (1+), with a Ki-67 proliferation index of 60%, while TTF-1, synaptophysin, chromogranin A, and P40 were negative.

In December 2022, the patient commenced first-line therapy with intravenous etoposide (100 mg/m² on days 1–3) plus cisplatin (75 mg/m² on day 1) and durvalumab (1,500 mg on day 1), administered every 21 days. The best response, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (11), was a partial response (PR). After four cycles of this combination therapy, she began maintenance treatment with durvalumab monotherapy every 28 days in March 2023. Concurrently, she underwent radiotherapy targeting the primary lung lesion (45 Gy in 15 fractions of 3 Gy per fraction) and the involved lymph nodes in stations 2, 4R, and 10R in March 2023, followed by prophylactic cranial irradiation (25 Gy in 10 fractions of 2.5 Gy per fraction) in May 2023. Tumor assessments with CT scans every eight weeks consistently confirmed a maintained PR. After 9 months of maintenance, we initiated dynamic peripheral blood ctDNA-MRD monitoring every 2 to 3 months and all subsequent tests remained negative for ctDNA. ctDNA-MRD was evaluated by the Huajianwei bespoke MRD assay based on Signatera as previously described (12). Based on the sustained durable PR, persistent serum tumor markers and ctDNA negativity, treatment was electively discontinued following the 22^nd maintenance cycle. Then, we conducted CT, tumor marker and MRD tests on this patient every 3 months. Whole-exome sequencing (WES) revealed heterogeneous tumor-core gene alterations, including a pathogenic KIT mutation, CCND1 amplification, and TP53/RYR2/MAP4K3/SLC34A2 variants [variant allele frequency (VAF) 14.53–41.08%]. Until the last follow-up in April 2026, she had achieved a progression-free survival (PFS) of over 40 months and a treatment-free interval exceeding 17 months (Figure 1). All procedures performed in this case were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Clinical timeline. Baseline CT scan after pleural effusion drainage revealed a primary lesion measuring 110 mm × 91 mm in the right middle lobe (pink arrowheads), a pleura metastatic lesion measuring 35 mm × 28 mm (blue arrowheads), and enlarged lymph nodes in mediastinal stations 2, 4R, and 10R (yellow arrowheads). On the latest CT scan, both the primary and metastatic lesions showed significant shrinkage. This patient underwent a total of 11 ctDNA-MRD tests, all of which yielded negative results. CT, computed tomography; ctDNA, circulating tumor DNA; Dur, durvalumab; EP, etoposide plus cisplatin; ES-SCLC, extensive-stage small cell lung cancer; MRD, minimal residual disease; PR, partial response.

Discussion

In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for ES-SCLC, significantly improving patient median overall survival. Current guidelines advocate for continuous anti-tumor treatment until disease progression or unacceptable toxicity. This approach, however, exposes long-term responders to the risk of cumulative immune-related toxicities and a substantial financial burden. Programmed death-ligand 1 (PD-L1) expression, while a predictive biomarker for initial response to immunotherapy, lacks utility in guiding treatment de-escalation. In contrast, early ctDNA dynamics have demonstrated strong predictive value for treatment efficacy. A non-randomized trial from China validated the feasibility of a ctDNA-guided adaptive de-escalation strategy for EGFR-tyrosine kinase inhibitor (TKI) therapy in advanced NSCLC (10). However, similar evidence guiding immunotherapy de-escalation in SCLC has been lacking.

In real-world clinical practice, a subset of ES-SCLC patients achieves long-term survival and may not require indefinite treatment. Previous studies have identified an atypical SCLC subtype, often lacking RB1 or/and TP53 alterations but characterized by CCND1 or MDM2 amplifications, which may have distinct biological behavior (13,14). Furthermore, SCLC patients with wild-type RB1 status or lower RB1 loss-of-function (LOF) signature scores, as determined by transcriptomics, have exhibited better outcomes with ICI monotherapy (15). Our reported case closely resembles this molecular profile. Multimodal therapy, including chemotherapy, immunotherapy, consolidative thoracic radiotherapy, and prophylactic cranial irradiation, significantly improved outcomes for this patient. Within the context of this effective multimodal therapy, we observed a period of treatment de-escalation accompanied by persistent ctDNA negativity and continued clinical response, suggesting that longitudinal ctDNA-MRD monitoring may serve as a component tool to identify long-term responders who are candidates for a treatment de-escalation strategy. We clearly understand that this single case does not inform practice, but serves as a hypothesis-generating observation that could inform the design of future prospective studies exploring ctDNA-based strategies in SCLC.

However, a significant limitation of this report is the absence of baseline ctDNA testing; ctDNA monitoring was initiated following serial imaging confirmation of sustained PR. As a result, the consistently negative ctDNA results cannot be definitively attributed to “ctDNA clearance”. Another limitation is that we did not perform circulating tumor cell (CTC) analysis simultaneously. Specifically, we note that while ctDNA provides a snapshot of tumor genomic alterations, CTCs offer insights into cellular characteristics and metastatic potential (16,17). We acknowledge that a negative ctDNA result does not necessarily indicate the absence of CTCs. ctDNA and CTCs represent different aspects of tumor biology, and their relationship is complex. Both biomarkers can independently predict outcomes, and combining them may enhance monitoring accuracy.

Conclusions

This case report provides proof-of-concept that longitudinal ctDNA-MRD monitoring may guide an adaptive de-escalation strategy for ICIs in selected ES-SCLC patients experiencing long-term survival. However, this remains a single-case observation that does not establish causality between ctDNA dynamics and treatment de-escalation. Controlled studies with serial ctDNA sampling from baseline are needed to validate any causal role of ctDNA in guiding de-escalation.

Acknowledgments

We would like to express our sincere thanks to the patient for giving consent to the publication of this case.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0594/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0594/prf

Funding: This work was supported by the Sanming Project of Medicine in Shenzhen (Nos. SZSM202211012 and SZSM202411002).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0594/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this case were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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