VSports注册入口 - Toripalimab for extensive-stage small cell lung cancer: insights and future directions

"VSports" Introduction

Extensive-stage small cell lung cancer (ES-SCLC) has long been a challenging disease with historically poor outcomes. For decades, the standard first-line therapy was limited to platinum-etoposide chemotherapy, which provided only modest survival benefits V体育安卓版. Practice changed in 2018, when the addition of checkpoint inhibitors to chemotherapy first showed improved survival in ES-SCLC (1). The approval of atezolizumab and durvalumab in the first-line setting marked the beginning of chemo-immunotherapy as a new standard of care (2,3). Multiple other drugs targeting the programmed cell death protein-1/programmed death receptor ligand 1 (PD-1/PD-L1) axis have since been investigated, most recently toripalimab (4). Yet despite improvements, long-term outcomes remain poor, response rates to immunotherapy are low, and toxicity can be devastating. This commentary provides perspective on the latest advances and discusses how better patient selection may improve outcomes further in future.

Toripalimab: a new first-line option

Toripalimab, a PD-1 inhibitor, is the latest immunotherapy to demonstrate efficacy in first-line ES-SCLC. The randomised, double-blind phase III EXTENTORCH trial evaluated toripalimab plus platinum-etoposide vs V体育ios版. chemotherapy alone, and reported a significant improvement in progression-free survival (PFS) and overall survival (OS) (4). Specifically, toripalimab prolonged median OS to 14. 6 months compared to 13. 3 months with chemotherapy alone [hazard ratio (HR) 0. 80, P=0. 03]. While the absolute OS gain was around 1. 3 months, there was substantial variation between patients with some showing much longer responses. Importantly, toripalimab plus chemotherapy had a tolerable safety profile without new safety signals. Based on these data, toripalimab represents a promising addition to first-line treatment options, broadening the range of checkpoint inhibitors available to patients and clinicians.

First-line chemo-immunotherapy trials in ES-SCLC: key results

To put toripalimab’s results in context, Table 1 summarizes eight randomized phase III trials of PD-1/PD-L1 inhibitors added to first-line chemotherapy in ES-SCLC. These include global trials with atezolizumab (1) and durvalumab (6) that established immunotherapy as standard care, trials of pembrolizumab (7) and nivolumab (8) which missed their OS endpoints, and several recent trials in predominantly Chinese populations with adebrelimab (9), serplulimab (10), tislelizumab (11), and toripalimab (4). All trials used a backbone of etoposide-platinum doublet chemotherapy, with immunotherapy or placebo added in the experimental vs VSports最新版本. control arms. While no direct head-to-head comparisons exist, the table allows a side-by-side view of efficacy outcomes.

In all trials except KEYNOTE-604 and CheckMate-451, adding a PD-1 or PD-L1 inhibitor to chemotherapy significantly improved OS. IMpower133 first showed a survival benefit with atezolizumab (median OS 12. 3 vs. 10. 3 months) (1), and CASPIAN confirmed a similar benefit with durvalumab (OS 13. 0 vs. 10. 3 months) (6). Pembrolizumab also prolonged survival (OS 10. 8 vs. 9. 7 months, HR 0. 80), as did nivolumab (OS 10. 4 vs. 9. 6 months) but the result did not reach the pre-specified significance threshold (7). Interestingly the CheckMate-451 study included an arm of dual PD-1/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with nivolumab and ipilimumab, which performed worse than nivolumab alone (median OS 9. 2 vs. 9. 6 months in placebo arm) VSports注册入口. Notably, several China-led trials reported longer survival times. For example, serplulimab achieved a median OS of 15. 4 months (10), and tislelizumab and adebrelimab both showed median OS beyond 15 months in the immunotherapy arms (5,11). These outcomes are encouraging and underscore that multiple agents can improve survival when combined with first-line chemotherapy. At the same time, cross-trial comparisons should be made cautiously, as differences in trial design and patient populations may influence results.

Trial differences and cross-trial considerations

While the efficacy of first-line chemo-immunotherapy is a consistent finding across recent trials, there are notable differences between them. Trial designs varied: some were double-blind placebo-controlled (IMpower133, KEYNOTE-604, ASTRUM-005, etc. ), while others like CASPIAN were open-label. The chemotherapy backbone was platinum (carboplatin or cisplatin) plus etoposide in all cases, but CASPIAN allowed up to 6 cycles of chemotherapy and optional prophylactic cranial irradiation in the control arm, whereas most other trials used 4 cycles and no routine radiation (6). Demographic differences also played a role: global trials enrolled patients from Europe and North America (with ~15–20% Asian patients), whereas Chinese trials predominantly involved East Asian patients. These variations likely contributed to differences in median survival of control arms (e. g V体育官网入口. , ~10. 3 months in IMpower133 and CASPIAN vs. 13+ months in some recent Chinese trials, Table 1).

Crucially, while all four recent positive trials in ES-SCLC were conducted in China, including three with PD-1 checkpoint inhibitors, studies involving pembrolizumab and nivolumab in a global population did not meet the statistical OS benefit. This discrepancy underscores the importance of testing these promising Chinese PD-1 agents, such as toripalimab, in global populations to confirm their efficacy. While the results from Chinese trials are promising, they may be influenced by factors such as genetic differences, environmental factors, and healthcare infrastructure that differ from those in non-Chinese populations. Therefore, repeating these trials in global cohorts is essential to determine if these agents hold the same potential for improving outcomes in ES-SCLC across diverse populations. Furthermore, no head-to-head comparisons have been conducted between the various PD-1/PD-L1 inhibitors, which makes it challenging to definitely determine whether one agent is definitely superior over others. However, the hazard ratios for OS across trials are generally in a similar range (approximately 0 VSports在线直播. 63–0. 84), suggesting a class effect. In sum, each of these trials reinforces the benefit of immunotherapy in ES-SCLC, even as their specific outcomes vary. Understanding why recent Chinese trials demonstrated larger benefits than others remains an important question that must be addressed by conducting similar trials in the global population.

Human leukocyte antigen (HLA) haplotypes and genetic biomarkers: explaining differences?

One intriguing finding emerging from the toripalimab EXTENTORCH trial is the potential role of host genetics—specifically HLA haplotypes—in modulating immunotherapy benefit. An exploratory whole-exome analysis found that patients with the HLA-A11 positive/HLA-B62 negative genotype had significantly better PFS and OS on toripalimab (4). This HLA profile may enhance immune recognition of tumors, perhaps by presenting immunogenic peptides more effectively, thereby improving response to PD-1 blockade. Notably, the HLA-A11 allele is common in Chinese populations, whereas the HLA-B62 serotype is relatively less prevalent (12) V体育2025版. As a result, a larger proportion of Chinese patients may carry the favourable HLA-A11+/B62– immunogenetic signature. This raises the hypothesis that population genetics could partly explain why trials conducted in Chinese cohorts (e. g. , serplulimab’s ASTRUM-005) reported deeper survival improvements; the patient populations in those trials might have been inherently more primed to benefit from immunotherapy due to genetic makeup. While this idea remains speculative, it underscores the importance of biomarker research considering host factors, as well as tumour factors. If HLA type indeed correlates with benefit, it could serve as a biomarker to identify which patients are most likely to respond. This finding also highlights that ethnicity-related genomic differences deserve careful study; what holds true in one population may differ in another. Future trials might incorporate HLA typing or stratify by such genetic factors to further validate their impact.

Towards robust predictive biomarkers for immunotherapy (V体育官网入口)

Predicting immunotherapy response in small cell lung cancer (SCLC), and other cancers, is an area of active research. To date, no validated biomarker has been adopted in clinical practice for ES-SCLC unlike for non-small cell lung cancer (NSCLC). PD-L1 expression, a useful marker in some non-small cell lung cancers, has not been sufficiently predictive in SCLC for clinical use. Most SCLC tumors have low or no PD-L1 expression, and even PD-L1-negative SCLC can respond to checkpoint inhibitors. Tumor mutational burden (TMB) was explored in trials like IMpower133 and EXTENTORCH, but results failed to differentiate clear responder subsets. Genomic analyses in EXTENTORCH identify inter-tumour heterogeneity as a predictor of response, and specific mutations which have either negative (KMT2D, COL4A4) or positive (CTNNA2, SCN4A) effects on outcomes. At the protein expression level, SCLC tumours have previously been classified into molecular subtypes, with an “inflamed” subtype more responsive to immunotherapy (13), though this classification has not been directly explored in the clinical trials discussed.

These findings suggest that it may be possible to develop clinically useful biomarkers, but to do so will require complex analysis of both tumour and host factors, and their interactions. Efforts such as the UK’s MANIFEST study (14)—a multi-center platform collecting tumor, blood, and stool samples from thousands of patients—aim to discover and validate biomarkers of immunotherapy response using multi-omics and machine learning. The MANIFEST program will profile tumors (e.g., whole-exome sequencing, RNA sequencing) and immune parameters (T-cell receptor repertoire, circulating DNA, microbiome) to identify signatures associated with durable benefit or resistance across multiple cancer types. Such large-scale endeavors are crucial to develop effective actionable biomarkers of immunotherapy response. Importantly, they also emphasize inclusivity of diverse patient populations, recognizing that ethnicity and genomic background may influence biomarker prevalence and performance. For example, if an HLA genotype is a key predictor in Asian patients, is it similarly relevant in non-Asian patients? Conversely, are there other HLA or immune gene variants in Caucasian or African populations that drive response? These questions remain open.

"V体育ios版" Conclusions and future directions

The introduction of checkpoint inhibitors in ES-SCLC marks a major breakthrough in a field that had seen little progress since the introduction of first-line platinum-based chemotherapy nearly four decades ago. Today, patients with extensive-stage disease have multiple first-line options that can improve survival beyond platinum-doublet chemotherapy alone, and toripalimab’s addition to the list being a welcome development. However, the variability in outcomes across different populations, particularly between the Chinese and non-Chinese patients highlights the need for continued research. Personalizing therapy for SCLC remains an important goal. Advancing research on predictive biomarkers—from HLA haplotypes to multi-omic signatures—is essential to driving progress. Initiatives like the MANIFEST platform and other translational studies including TRACERx-EVO (15) are paving the way to identify which patients are most likely to benefit from immunotherapy and why. In the short term, we hope to select patients for treatment, reducing unnecessary toxicity. In the longer term, a deeper understanding of the biology behind different response phenotypes will be crucial for developing more effective immunotherapies. Understanding why some recent Chinese trials saw larger benefits than others is an important next question, one that should be addressed by repeating these trials in the global population to confirm their efficacy with PD-1 agents. Achieving this vision will require global collaboration and the inclusion of patients from diverse populations to ensure findings are broadly applicable.

Acknowledgments

None.

"VSports注册入口" Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-48/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-48/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.

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VSports注册入口 - References

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