Long-term survival and biomarkers of immunotherapy in small cell lung cancer: a systematic review

Introduction

Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by a high proliferation rate and prompt metastatic spread (1). For decades, platinum-based chemotherapy (CT) has been the standard of care for advanced stages. More recently, immune checkpoint inhibitors (ICIs) were incorporated to the treatment after the phase III trial IMpower133 demonstrated a benefit in overall survival (OS) of 2 months with the addition of atezolizumab (2). Other randomized trials have reported comparable results with different ICIs including adebrelimab, benmelstobart, durvalumab, serplulimab and tislelizumab (3-7).

Even though the magnitude of the benefit is small, a subset of patients achieve long-term survival (LTS), not previously reported in patients treated with CT alone (8,9). The underlying factors eliciting this favorable response are still unknown and, to our knowledge, no articles specifically exploring this population have been published yet. The aim of our systematic review is to summarize all available information regarding LTS in patients with SCLC, and to explore the potential biomarkers of response to ICIs that might be of use to identify those patients with higher probability of presenting LTS. We present this article in accordance with the PRISMA reporting checklist (10) (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1450/rc).

Methods

An initial selection was performed by searching the PubMed database. The following strategy was used for the search: (“lung cancer” OR “small cell” OR “small cell lung cancer” OR “SCLC”) AND (“survival” OR “long-term” OR “long responders” OR “prognosis”) AND (“immunotherapy” OR “immune-checkpoint inhibitors” OR “IO” OR “ICI”) NOT (“adenocarcinoma” OR “non-small” OR “squamous” OR “epitheloid” OR “mesothelioma” OR “large”). Full text articles published in English from 1974 to 2024 were included.

After removal of duplicates, the articles were screened independently by two researchers using Rayyan software (https://www.rayyan.ai) based on the information provided by the title or abstract. The following criteria were used for the selection: randomized clinical trials evaluating ICI in patients with SCLC regardless of the number of patients; non-randomized trials and retrospective case series with ≥25 patients with SCLC receiving ICIs; reviews explicitly addressing prognostic/predictive biomarkers in patients with SCLC; articles focused on SCLC and long-term response to ICIs. Reviews that did not include novel information were also excluded. Conflicts in screening were resolved by mutual agreement.

The following data was collected from each article: definition of “long-term survival”, biomarkers predictive of ICI efficacy for SCLC, variables associated with long-term response (Figure 1).

Figure 1 Flowchart representing the process of selection of articles for the systematic review. The full list of articles reviewed is available as https://cdn.amegroups.cn/static/public/tlcr-2025-1-1450-1.pdf. ICI, immune checkpoint inhibitor; SCLC, small cell lung cancer.

Results

The initial search identified 1,815 articles. After a selection based on the information available in the title and abstract, the number was reduced to 110 articles. These articles were subject to a thorough review, discarding 65 additional ones which did not fulfill the previously described criteria (motives enlisted in Table S1). The most common reasons for exclusion were the absence of data of predictive biomarkers, mixed cohorts of patients with different tumors and reviews with no new data reported. The remaining 45 works were evaluated and included in this systematic review.

Definition

A remarkable heterogeneity regarding the definition of LTS was observed. Three retrospective articles stablished thresholds of 24, 48 and 60 months, although the cohorts combined patients with localized and advanced disease and none of the patients had received ICI as the approval of these drugs was posterior (11-13). A study in patients with extensive-stage SCLC treated with CT without ICI also considered LTS beyond 24 months (14).

Some recent publications have focused on patients with SCLC treated with ICI. In a presentation at ESMO Congress 2020, a threshold of progression-free survival (PFS) ≥12 months was used to identify patients with LTS from the CASPIAN trial (15). At the European Lung Cancer Congress 2022, patients from this very trial were considered long-term survivors if they were alive at the data cutoff with a median follow-up of 39.4 months (16). A work including 20 patients with SCLC treated with CT combined with ICI presented at ESMO Congress 2022 defined durable clinical response as a PFS >200 days (17). Finally, preliminary results of the IMbrella A trial, with a cohort of patients from the phase III IMPower133, were communicated at the World Conference on Lung Cancer (WCLC) 2023. The authors considered LTS if patients with advanced disease were alive after 5 years (18).

Considering that the different thresholds have been selected arbitrarily and might not reflect a particular biology of the tumors, the “plateau” in the survival curves present in most clinical trials evaluating chemoimmunotherapy as frontline treatment for patients with SCLC could be of help. A “plateau” was observed after a PFS >12 months or an OS >24 months in the CASPIAN trial with durvalumab and tremelimumab (15), after an OS >24 months in the CAPSTONE-1 trial with adebrelimab (7), after a PFS >12 months in the ASTRUM-005 trial with serplulimab (3), after a PFS of 9 months or an OS of 20 months in the IMPower 133 trial (8), after a PFS of 9 months or an OS of 24 months in the KEYNOTE-604 trial with pembrolizumab (19). Even in trials evaluating ICI in patients that have relapsed after platinum-based CT, the plateau in OS was equally observed after 24 months (20,21). And even though the roughly 20% of patients that are included by these thresholds clearly overestimates the actual incidence of LTS that is observed in clinical practice, it could be an adequate starting point as the majority of patients with worse prognosis are already excluded.

Factors associated with LTS

In patients with long-term response to ICI from the CASPIAN trial, as defined by PFS ≥12 months, and compared with the rest of patients, a lesser percentage had a performance status (PS) of 1 or greater (52% vs. 64%), were male (63% vs. 75%) or Asian (9% vs. 17%). However, PS of 1 or greater was also less frequent (58% vs. 67%) in patients with PFS ≥12 months treated with CT (15). When the definition for LTS was being alive at a median follow-up of 39.4 months, it was more frequent when durvalumab or durvalumab + tremelimumab were added to CT (16% vs. 14% vs. 5%, respectively). Female sex remained as a factor associated with LTS (50% vs. 29%) and more patients with LTS completed the 4 cycles of CT planned (100% vs. 87%). There was also a lower prevalence of liver metastases (20% vs. 40%) and brain metastases (7% vs. 10%) among patients with LTS, although this was also observed in the CT and the durvalumab + tremelimumab + CT cohorts (16).

Only 12% of the patients enrolled in the experimental arm of the phase III IMpower133 were alive at 5 years, and 18 of them were included in the IMbrella A. Ten of them had not required a subsequent therapy for more than 24 months. In this cohort, compared with the rest of patients, there was a lower frequency of patients aged >65 years old (22.2% vs. 44.8%), PS ≥1 (33.3% vs. 63.7%) and with liver metastases (11.1% vs. 38.3%). Among the 11 patients that had completed a follow up of 5 years, 57.1% presented a transcriptional subtype SCLC-N as defined by Gay et al. (22), while the prevalence of this subtype was 22.5% among the original cohort from IMpower133 (18).

Predictive biomarkers

Different groups have explored the association between the efficacy of ICI in patients with SCLC and several biomarkers. The predictive and not prognostic value of these biomarkers is supported by independent cohorts of patients treated with CT without ICI, in which the reported association is not observed.

The retrospective study by Kanemura et al. included a cohort of 64 patients with SCLC treated with ICI combined with CT and a cohort of 71 patients receiving only CT. Patients with inflamed tumors, consisting in PD-L1 combined positive score (CPS) >1% and >85 CD8 tumor infiltrating lymphocytes (TILs) per mm3, from the CT + ICI cohort had longer PFS (10.8 vs. 5.1 months, P=0.002), while no differences were observed in the CT only cohort. The evaluation of gene expression in 50 and 39 tumors from the CT cohort and CT + ICI cohort respectively revealed that high expression of MYC was associated with lower efficacy of ICI (HR 2.18, P=0.028), with no impact on the efficacy of CT (23).

In the phase I/II CheckMate 032, patients receiving nivolumab plus ipilimumab yielded better efficacy in the group with high tumor mutational burden (TMB) (>247 mutations/Mb) compared with medium (143–247 mutations/Mb) and low TMB (<143 mutations/Mb) in terms of OS (22.0, 3.6 and 3.0 months respectively). The efficacy was also better in the cohort treated with nivolumab alone, although the magnitude of the differences was lesser. More importantly, no differences were observed in an independent cohort of patients with SCLC who did not receive ICI (24).

A retrospective multicentric study observed worse PFS (HR 3.1, P<0.01) in patients with a high total metabolic tumor volume (TMTV) evaluated by 18-FDG PET in a cohort of patients with SCLC treated with CT combined with ICIs, without differences in the CT control arm (25).

Regarding circulating biomarkers, a retrospective study including a cohort of patients with SCLC treated with ipilimumab plus CT and another with only CT found that elevated baseline IL-6 and TNF-α were associated with shorter median OS (mOS) (9.5 vs. 18.5 months, P=0.026 and 7.8 vs. 18.5 months, P=0.004, respectively) only in the ICI cohort. Moreover, the increase in IL-2 and IL-4 was also associated with the efficacy of ipilimumab. On the other hand, high baseline IL-8 was an adverse prognostic factor in both cohorts (26). To conclude, a post-hoc analysis of the KEYNOTE-604 trial found that patients with low levels of circulating monocytic myeloid-derived suppressor cells (MDSCs) had a benefit in PFS from the addition of pembrolizumab to CT, while the patients with low levels of circulating granulocytic MDSCs had a benefit in OS (27).

Prognostic biomarkers

Other studies have evaluated additional biomarkers, including factors related to the patient, the treatment or the tumor microenvironment, and their association with survival in patients with SCLC treated with ICIs. However, as they do not include a CT-only cohort, whether these are related to the efficacy of ICI or merely with the prognosis of SCLC cannot be concluded (Table 1).

Clinical biomarkers

It has been stablished that the metastatic spread of the malignancy, and particularly presence of liver or brain metastases, is associated with lack of efficacy of ICI, although whether in some cases this is just a reflection of the worse prognosis of these patients is under debate (48,49). Two retrospective studies found an association between high tumor burden and worse PFS and OS (35,37).

Regarding liver metastases, regardless their presence patients included in trials CASPIAN, CAPSTONE-1 and CheckMate 032 benefited from the ICI plus CT (5,7,19). However, several retrospective trials found an independent association between liver metastases and worse PFS and OS in patients with SCLC treated with ICI plus CT (36,38-40). Accordingly, in the CheckMate 331 trial comparing nivolumab with topotecan or amrubicin after progression to platinum-based CT, a multivariate analysis revealed that nivolumab was more effective than CT only in patients without liver metastases (21). To conclude, two meta-analysis including patients with SCLC and liver metastases showed that the addition of ICI to CT improved OS (50,51), but a more recent one with 3,501 patients from 6 clinical trials did not find any benefit (52).

With respect to brain metastases, most of the main clinical trials evaluating the benefit of ICI combined with CT as frontline therapy for SCLC did not detect any benefit (2,19). Surprisingly, in the phase III CASPIAN the patients with brain metastases did obtain a benefit in OS from the addition of durvalumab, and a clear trend was observed in the randomized trial ASTRUM-005 with serplulimab (3,5). It should be noted that, unlike in IMPower 133 and KEYNOTE-604, prophylactic cranial irradiation (PCI) was not allowed in the experimental arm of CASPIAN trial, while it was not specified in the protocol from ASTRUM-005. A detrimental effect of the combination of PCI with chemo-immunotherapy could be an explanation for this lack of consistency.

The five meta-analysis published up to date including several thousand patients have not detected any improvement from the addition of ICI to CT in patients with brain metastases (50,51,53-55), and neither a real-world study conducted in China (56). Two retrospective studies, including the study IFCT-1905 CLINATEZO, found worse PFS in patients with brain metastases (28,32).

An independent association between bone metastases and worse survival has been also described although only in two retrospective Asian studies (32,38).

The radiological characteristics of the response might also be a tool to predict the efficacy of ICIs. A retrospective trial including 104 patients studied the association between the efficacy of ICI plus CT as first line treatment and the percentage change in tumor volume per month. A decrease <34.3% was associated with shorter PFS and OS. More importantly this was also true when evaluating only responders, which reinforces that not only the radiological response but also its magnitude is associated with better outcomes (35).

Regarding treatment-related toxicity, different articles have described greater efficacy in patients that present immune-related adverse events (IRAEs) in terms of PFS and OS, including not only a retrospective study but also a phase II trial with CT, camrelizumab and apatinib, in which longer PFS was observed in the subgroup of patients who presented irAEs (32,33). These findings are line with what has been previously described for other tumor types, although it should be taken into account that a longer exposure to ICIs is directly associated with the incidence of irAEs (57). A retrospective multicentric study that included patients treated with anti-PD1/PD-L1 alone or in combination with anti-CTLA4 observed that patients that experienced IRAEs had tumors with higher TMB, and presented better overall response rate (ORR), median PFS (mPFS) and mOS. This effect was not dependent on the severity of the adverse event (34). In a retrospective cohort of 42 patients treated with CT plus ipilimumab, positivity for antinuclear antibodies (ANA) was associated with longer mPFS but not with OS (58).

Patient related biomarkers

The general characteristics of the patient can have an impact on the efficacy of immunotherapy. As in most tumor types, a performance status (PS) ≥2 is associated with worse PFS and OS (28,31,32,35,38,43). When PS is ≥3 the prognosis is dismal, with HR of 21.935 for PFS and 226.829 for OS by multivariate analysis in a multicentric retrospective cohort (43).

In many malignancies, advanced age seems to limit the benefit of different therapies and it is also associated with worse quality of life (59,60). The different thresholds proposed to identify elderly patients (70, 75 or 80 years old) are arbitrary and do not reflect the general status of the individual.

Older age was not associated with worse prognosis in the trials evaluating the efficacy of CT combined with ICI in patients with SCLC (2,3,5,19,39), nor did a retrospective study using 70 years old as a threshold (29). However, a prospective trial including patients ≥70 years receiving chemo-immunotherapy as frontline treatment observed that frailty measured by G8 score ≤11 was independently associated with lower mOS, even in patients with good PS (31). However, this finding could be in relation with the worse prognosis of patients with a low G8 score, regardless of the treatment received, as no differences in PFS were detected. Shorter mOS in patients older than 65 years old was also observed in the phase II trial CLINATEZO (28).

The effect of other comorbidities has also been studied. A retrospective study observed worse PFS and OS by multivariate analysis in diabetic patients treated with chemo-immunotherapy (30).

Different treatments received by the patient could also impact in the efficacy of ICI, as it has been described in other tumors (61). In a retrospective study with 208 patients, the taking of proton-pump inhibitors was independently associated with shorter mPFS and mOS, while a dose of prednisone >10 mg per day was associated only with shorter mPFS (45). Antibiotic exposure within 2 months before or after the initiation of ICI was associated with shorter PFS and OS (30).

The association between different blood test values and ICI efficacy has been studied extensively for different tumors and treatments. Serum lactate dehydrogenase (LDH) has been previously described as a negative predictive factor of response to ICI (62,63). In the case of SCLC and ICI, several studies found an association between elevated LDH and shorter OS with CT plus atezolizumab, and also with nivolumab after progression to platinum-based CT in the randomized CheckMate331 trial (21,32,39,49). However, the benefit of chemo-immunotherapy was independent of LDH levels in the randomized trials CASPIAN and CAPSTONE-1, suggesting that serum LDH is a negative prognostic factor but does not prevent the response to ICI (7,21). Neuron-specific enolase (NSE) levels were also associated with prognosis in patients receiving ICI as frontline treatment. Patients with normal NSE had longer mPFS and OS in a retrospective real-world study (38).

The baseline nutritional status, evaluated using the prognostic nutrition index, was not a predictor of survival in a prospective cohort of 53 patients treated with CT plus atezolizumab, and neither were other scores including neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), advanced lung cancer inflammation index (ALI) or lung immune prognostic index (LIPI). In this very cohort a platelet-lymphocyte ratio (PLR) >119.23 was independently associated with shorter PFS and OS (44,64). A retrospective analysis of a group of patients with similar characteristics found an association with PFS although with the threshold of PLR >135.7 (65).

The propensity score-matched analysis by Xie et al., which compared two cohort of patients with SCLC treated with CT + ICI and with CT as frontline treatment did find a greater benefit in PFS in patients with NLR >3.1. Also, a lymphocyte/monocyte ratio >3.26 was associated with better OS, but not PFS, by multivariate analysis (40). The study by Grambow-Velilla et al. found an association between high derived NLR and worse PFS and OS in patients with SCLC treated with chemoimmunotherapy, although this was also true for the patients in the CT cohort (25). A small retrospective analysis including 41 patients with SCLC treated with ICI monotherapy as second or third-line treatment did not found any association between baseline PLR and NLR and efficacy of the treatment. However, patients with a NLR ≥5 at 6 weeks post-treatment had a longer PFS (42). The combination of NLR with serum albumin and LDH using the Gustave Roussy Immune Score (GRIm-Score) was associated with PFS an OS in a retrospective cohort of patients with SCLC treated with ICI which included a significant percentage of patients with localized disease. After adjusting with Propensity Score Matching, patients with a GRIm-Score of 0-1, who tend to have lower NLR, presented longer mPFS without differences in terms of OS (66). The most plausible interpretation from these apparently contradictory findings would be that patients high NLR yield a greater benefit from the addition of ICI to CT, although high NLR is associated with worse prognosis among patients treated with ICI plus CT.

A retrospective study including 53 patients treated with CT + ICI evaluated the prognostic value of the Pan-Immune-Inflammation Value (PIV), a biomarker derived from the product of absolute counts of neutrophils, monocytes and platelets divided by lymphocytes. PIV above the median was independently associated with worse PFS and OS (67).

To conclude, circulating immune cell subsets quantified by flow cytometry have been evaluated as biomarkers of response to immunotherapy by different groups (68). Among the advantages of this approach are the immediate accessibility of the samples without significant morbidity, the low cost and the possibility of monitoring. However, we only found the preliminary results of a study conducted by Galindo Campos MA and communicated to a scientific congress, in which a higher baseline expression of Ki67 in CD4+ CXCR5+, ICOS+ and TIM3+ cytotoxic cells was observed in patients with durable control after treatment with CT + ICI (17).

Tumor-related biomarkers

Well characterized biomarkers of response to ICI for NSCLC, including PD-L1 and TMB, do not seem to be useful for patients with SCLC.

Less than 20% of SCLC tumors express PD-L1 (69), although it might be slightly higher in infiltrating immune cells (70). Patients from IMPower 133, CASPIAN, CAPSTONE-1, ASTRUM-005 and KEYNOTE 604 benefit from the addition of ICI regardless of the expression of PD-L1 in tumor cells or in infiltrating immune cells (3,5,7,8,19). No particular benefit from Nivolumab compared with CT was detected in patients with high PD-L1 expression in CheckMate 331 (21).

However, single-arm trials studying the efficacy of ICI in clinical contexts other than frontline CT plus ICI combination have reported better efficacy in tumors with high PD-L1 expression, mostly evaluated in stromal tissue or by CPS. A phase II trial with pembrolizumab maintenance after CT reported numerically better mPFS and mOS in tumors with stromal PD-L1 expression, although only 20 patients were evaluated (71). When CPS PD-L1 expression was positive, pembrolizumab maintenance had greater mOS (72), and also a trend was observed with pembrolizumab plus amrubicin (73). A higher ORR was observed in patients with PD-L1 positive tumors in a phase II trial with camrelizumab plus apatinib as second line treatment (74).

Regarding TMB in tumor cells, exploratory analyses of IMPower133 and CASPIAN trials using different cut-offs were not predictive of a greater benefit from ICI (8,15). Comparable results were observed in the trials CheckMate 331 and KEYNOTE 604 (19,21). However, TMB did predict efficacy in other clinical contexts. In the trial CheckMate 451, when TMB was higher than 13 mut/Mb, better OS was observed with nivolumab plus ipilimumab maintenance and a trend with nivolumab. No differences were observed with a threshold of 10 mut/Mb (46). A retrospective analysis of CheckMate 032 observed better PFS and OS with ipilimumab + nivolumab when TMB was in the upper tertile (24).

Neuroendocrine markers could be associated with the efficacy of ICI. A retrospective study with 30 patients treated with ICI plus CT and 227 treated with CT alone suggested that the addition of ICI did not improve PFS when tumor cells did not express neuroendocrine markers. However, there were no differences in OS regardless the expression of neuroendocrine markers, which limits the validity of the findings (75).

TILs have been linked with better prognosis in several malignancies, and there is certain evidence of the association with better efficacy of immunotherapy mainly in breast cancer and melanoma (76). In SCLC, the number of TILs is lower compared with NSCLC (77). Nevertheless, two recent communications reported better PFS in patients with SCLC a high concentration of TILs receiving carboplatin plus etoposide plus atezolizumab (47,78). In the nivolumab cohort from the study CheckMate 032 an association was found between CD8 TIL infiltration ≥ 1% and OS (26).

The identification of molecular subtypes of SCLC based on the expression of transcription factors suggested that certain subtypes could derive a greater benefit from ICI. Particularly, the retrospective analysis of tumor samples from patients enrolled in the phase III IMPower133 revealed that SCLC-I, characterized by low expression of ASCL1, NEUROD1 and POU2F3, had a longer OS compared with SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven) and SCLC-P (POU2F3-driven) in the Atezolizumab with CT arm, while no differences were detected in the control arm. However, the HR for OS was favorable to all subgroups (17). These molecular subtypes were not predictive of response in a retrospective analysis of the trial CheckMate 032 (27).

Additionally, four metabolic subtypes were identified by lipidomics and metabolomics of plasma samples from a cohort of 191 patients. 28 of them received immunotherapy, and the metabolic subtype 2, characterized by increased glucose uptake, glycolysis and lactate production (Warburg effect), had a greater benefit from ICI (41).

To conclude, it is well stablished that the detection of ctDNA is associated with tumor burden, which has clear association with the efficacy of ICI (79). A retrospective analysis the phase II IFCT-1603, evaluating ICI after progression to CT, showed that patients with detectable ctDNA had a lower disease control rate (DCR) at 6 weeks. However these differences were also present in the CT arm, suggesting that ctDNA might be a prognostic biomarker (80).

Discussion

Even though substantial progress in the treatment of SCLC has been achieved in recent years, the prognosis is still very poor. Fortunately, the main clinical trials evaluating CT + IT as frontline treatment revealed that a small subset of patients presented a LTS, warranting a profound study of their characteristics. Despite the uniformity in the therapeutic approach, the intrinsic characteristics of this neoplasm—such as a high plasticity and intratumoral heterogeneity—have hindered the identification of reliable predictive biomarkers.

A main difficulty, as our systematic review pointed out, is that only a few articles and reports specifically address LTS. Moreover, a consensus about a threshold to define this outcome is still lacking. It seems appropriate to use the timepoint were the PFS curve attains a plateau, however this value should identify patients with particular characteristics or a tumor biology that favors LTS and not merely those with better prognosis.

Regarding the biomarkers associated with the efficacy of ICI, most of the studies lack a CT-only cohort to confirm the predictive and not prognostic role, and in the vast majority of cases the data derives from a limited number of patients. We found five studies with enough evidence to support the predictive value of the biomarker described. Lymphoid driven tumor inflammation, low tumor volume evaluated by 18-FDG-PET, low baseline plasmatic levels of IL6 and TNF-α and low levels of MDSCs were reported in four works including patients treated with CT + IT. It should be noted that all of them combined suggest that a myeloid expansion hampering lymphoid activity might be a main factor driving ICI resistance. High TMB was associated with the efficacy of nivolumab plus ipilimumab.

Additionally, it is worth noting the forementioned enrichment of patients with a transcriptional subtype SCLC-N among the patients enrolled in the IMpower133 trial that were alive at 5 years, as the greater benefit from ICI is expected in SCLC-I tumors. However, unlike molecular subgroups in other tumor types, in SCLC it has been described a widespread cell plasticity and frequent overlap of transcriptional subtypes in the same tumor that advocates for a cautious interpretation of the results (81,82). In this small group of 11 patients that attained a survival of 5 years and enrolled in the IMbrella A trial, the baseline RNAseq data was available only for 7 of them. Five had already presented progressive disease and the influence of molecular subtypes on additional treatments has not been explored yet. Moreover, exploratory analysis of the whole cohort of patients included in this very trial already reported a higher proportion of patients with the subtype SCLC-I, indicating that a survival longer than 5 years is not an appropriate threshold.

With respect to the rest of biomarkers described, in which the association with efficacy of ICI has not been confirmed, most of them are reported in a limited number of studies and it is not possible to draw definitive conclusions.

There is significant consensus regarding the adverse prognosis associated with liver metastases, brain metastases and a poor general condition, and patients with these characteristics are unlikely to present a LTR, even more taking into account than in this context the potential benefit of adding ICIs to CT is dubious.

TIL tumor infiltration appears to correlate with the efficacy of ICI and has potential as a predictive biomarker, although the scarce amount of tissue usually available for the diagnosis of these patients limits the applicability.

It is unlikely the prediction of LTR to ICI will rely in a single biomarker, but rather in a combination of several ones capturing the main factors that limit the efficacy of ICIs. The CT that is usually combined with ICIs, at least when administered as frontline treatment, clearly hinders the identification of predictive biomarkers associated with LTR, and might be one of the reasons behind the lack of utility of ratios like NLR, LMR or LIPI, already validated in other neoplasms. Accordingly, well stablished biomarkers PD-L1 and TMB seem to correlate with ICI efficacy only when administered after CT, both as maintenance therapy or as a second line treatment. Moreover, the potential incorporation of lurbinectedine and atezolizumab maintenance after CT + IT induction, with an OS benefit recently reported in the phase III trial IMforte, further increases the complexities in this scenario (83).

Beyond developing the ability to predict LTR in patients with SCLC treated with ICI, the main objective would be that most of the patients truly achieve LTR. As in other tumor types, the combination of ICI with targeted therapies might entail a strong synergy that significantly improves outcomes. The S1929 trial with talazoparib and atezolizumab maintenance after CT plus atezolizumab in patients with Schlafen 11 (SLFN11)-positive SCLC reported an improvement in PFS compared with atezolizumab maintenance, confirming the potential of drugs targeting the DNA reparation pathway that previous trials suggested (84,85). Another promising target that is currently being explored in combination with ICI in clinical trials is DLL3. After having demonstrated a considerable efficacy in platinum-resistant SCLC in the trials DeLLphi-301 and DeLLphi-304 (86,87), with an unprecedented flattening of the survival curve, promising preliminary results are being reported when combined with atezolizumab maintenance, which might further increase LTR (88). Circulating biomarkers, including immune cell subpopulations or cytokines, might better reflect the deep immune suppression induced by SCLC and allow a non-invasive real-time evaluation of these aspects with the possibility of seriation. Finally, the integration of the increasingly complex multi-omic data might be capital for a better management of this disease.

Conclusions

LTS is an unfrequent and underexplored phenomenon in SCLC upon ICI treatment. The scarce number of studies specifically addressing this topic and the lack of a common definition prevent the discovery of predictive biomarkers and the underlying biological mechanisms. As reported in other tumor types, systemic inflammation, often represented by a myeloid expansion, appears to limit the efficacy of ICI. However, LTS is likely the consequence of the confluence of several factors, and further research is warranted for their identification.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1450/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1450/prf

Funding: This work was supported by the “Clínico Junior en el Territorio AECC 2023” grant from the Spanish Association against Cancer (Asociación Española Contra el Cáncer) (CLJUN234885LECU to A.L.); the Intensification Scholarship 2024 by the Health Department of Gobierno de Navarra (to H.A.); and the Spanish Association Against Cancer (Asociación Española Contra el Cáncer, AECC) with a postdoctoral fellowship (POSTD245952LABI to I.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1450/coif). I.L. received funding support from the Spanish Association Against Cancer (Asociación Española Contra el Cáncer, AECC) with a postdoctoral fellowship (POSTD245952LABI). A.L. received support from by the “Clínico Junior en el Territorio AECC 2023” (CLJUN234885LECU) grant from the Spanish Association against Cancer (Asociación Española Contra el Cáncer), and A.L. has received honoraria for speaker role from Pierre Fabre and support for attending meetings and/or travel from PharmaMar, Lilly, Merck, Seagen, Novartis and MSD. R.V. received honoraria for consultant/advisory board from Novartis, for speaker role by Roche, Amgen, Merck, MSD, Lilly, Organon, Bayer, for traveling/accommodation by MSD, Merck, Lilly and for leadership from AECC, SEOM, ECO. M.A. has received honoraria for consultant and/or advisory role from Amgen, AstraZeneca, BeiGene, Dragonfly Therapeutics, Jazz Pharmaceuticals, BMS, Novartis and MSD, and for speaker role from Astellas, AstraZeneca, BeiGene, Daiichi Sankyo, Jazz Pharmaceuticals, BMS, and MSD. H.A. received support from by the Intensification Scholarship 2024 by the Health Department of Gobierno de Navarra, and has received honoraria for consultant/advisory role from Pfizer and Roche, traveling/accommodation expenses from BMS, MSD, Roche, and speaker role from Pierre Fabre. The other 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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