Anlotinib plus oral fluoropyrimidine S-1 in refractory or relapsed small-cell lung cancer (SALTER TRIAL): a multicenter, single-arm, phase II trial.

BACKGROUND: Patients with small-cell lung cancer (SCLC) have few treatment options and dismal overall survival (OS) after failed platinum-based chemotherapy. METHODS: The eligibility criteria of this phase II clinical trial included patients with measurable disease, age of 18 to 75 years, a confirmed diagnosis of disease progression or recurrence after prior platinum-based chemotherapy with a pathologically proven diagnosis of SCLC. Patients were treated with anlotinib at a dosage of 12 mg once daily (QD) and S-1 at 60 mg twice daily (BID) for 2 weeks, followed by a 1-week treatment-free interval. After six cycles of the above treatment, patients continued the maintenance therapy using S-1 monotherapy at 60 mg/ BID for 2 weeks, followed by a 1-week treatment-free interval until disease progression. RESULTS: From March 2019 to June 2020, a total of 71 patients were initially assessed for eligibility in this study. Out of these, 52 patients who met the inclusion criteria were enrolled, and 48 patients received at least two doses of the study drug. The median follow-up time was 25.1 months. The ORR was seen in 21 patients (43.8%). The median PFS was 4.5 months (95% CI, 3.5-5.5 months), and the median OS was 5.9 months (95% CI, 4.6-7.3 months). The most common grade 3-4 treatment-related adverse events were thrombocytopenia (16.7%), anemia (14.6%), neutropenia (14.6%), and hypertension (10.4%). No treatment-related death occurred. CONCLUSIONS: The combination of anlotinib with oral fluoropyrimidine S-1 demonstrated notable activity in relapsed or refractory SCLC, showing a favorable ORR and an acceptable, manageable safety profile. TRIAL REGISTRATION: This trial was registered with ClinicalTrial.gov (NCT03823118) on 3 January 2019.

Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 68Ga-SSO120 PET with immunohistochemistry and survival.

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.

[Molecular Subtype of Small Cell Lung Cancer: 
Challenge for Transforming into Clinical Practice].

Small cell lung cancer (SCLC), one of the histological subtypes of lung cancer, is characterized by high proliferation, early metastasis, susceptibility to drug resistance and recurrence. For several years, SCLC has always been regarded as a homogeneous disease, treated with a unified radiotherapy and chemotherapy strategy. Despite significant early therapeutic effects, drug resistance and recurrence occur quickly, and there is a lack of satisfactory treatment results, which may be due to insufficient understanding of the tumor heterogeneity of SCLC at present. Recently, the concept of SCLC molecular subtype based on the definition of relatively high expression of lineage transcription factors has been proposed in preclinical studies. This article mainly elaborates on the current status and latest findings of SCLC molecular subtype, emphasizing the potential problems that molecular typing may encounter in clinical practice, aiming to promote understanding of the research progress of molecular subtype in SCLC.
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Serum uric acid level can predict asymptomatic brain metastasis at diagnosis in patients with small cell lung cancer.

BACKGROUND: The aim of this study was to determine the relationship between serum uric acid level at diagnosis and asymptomatic brain metastasis in patients with extensive-stage small cell lung cancer. METHODS: A total of 69 patients with extensive-stage small cell lung cancer without symptomatic brain metastases, whose serum uric acid level was measured at the time of diagnosis, were included in this retrospective cross-sectional study. The patients were divided into two groups as those with and without asymptomatic brain metastases. The Mann-Whitney U test was used for comparison between groups, and Spearman's correlation test was used for correlation analysis. The cut-off level of serum uric acid level was analyzed, and sensitivity, specificity, and accuracy rates were determined for brain metastasis. Independent factors affecting asymptomatic brain metastasis were determined by multivariate Cox regression analysis. RESULTS: The median serum uric acid level of all patients was 6.9 mg/dL. Twenty-two percent of patients had asymptomatic brain metastases, and serum uric acid levels were significantly higher in these patients (P = 0.0014). The cut-off value for serum uric acid level was calculated as 6.2 mg/dL. The sensitivity, specificity, and accuracy of this value for brain metastasis were 84%, 76%, and 78%, respectively. High serum uric acid level was an independent risk factor for asymptomatic brain metastasis (OR 3.446 95% CI 1.337-5.480; P = 0.005). CONCLUSION: In conclusion, a serum uric acid level of 6.2 mg/dL and above at the time of diagnosis may predict asymptomatic brain metastasis in patients.

The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma.

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component-by-component next-generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double-positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1-dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3-dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic-like expression. Among the combined SCLCs with component-specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic-like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'.

Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial.

There is still room for improvement in first-line treatment of advanced small cell lung cancer (SCLC). This trial firstly investigated efficacy and safety of antiangiogenic therapy (surufatinib) (200 mg, qd, po) plus anti-PD-1 treatment (toripalimab) (240 mg, d1, ivdrip) combined with etoposide (100 mg/m², d1-d3, iv, drip) and cisplatin (25 mg/m², d1-d3, ivdrip) for advanced SCLC as first-line treatment, which has been registered on ClinicalTrials.gov under the identifier NCT04996771. The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab. The primary endpoint was progression-free survival (PFS). The secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. All of the 38 patients were enrolled for safety analysis, while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment. After a median follow-up of 21.3 months, the ORR was 97.1% (34/35), and the DCR and the tumor shrinkage rate were both 100% (35/35). The median PFS was 6.9 months (95% CI: 4.6 m-9.2 m) and the median OS was 21.1 months (95% CI: 12.1 m-30.1 m). The 12-month, 18-month, and 24-month OS rates were 66.94%, 51.39% and 38.54%. The occurrence rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 63.2% (24/38), including neutrophil count decreased (31.6%, 12/38), white blood cell count decreased (23.7%, 9/38) and platelet count decreased (10.5%, 4/38). No unexpected adverse events occurred. This novel four-drug regimen (surufatinib, toripalimab, etoposide plus cisplatin) revealed impressive therapeutic efficacy and tolerable toxicities.

ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer.

Patients with small-cell lung cancer (SCLC) have poor prognosis and typically experience only transient benefits from combined immune checkpoint blockade (ICB) and chemotherapy. Here, we show that inhibition of ataxia telangiectasia and rad3 related (ATR), the primary replication stress response activator, induces DNA damage-mediated micronuclei formation in SCLC models. ATR inhibition in SCLC activates the stimulator of interferon genes (STING)-mediated interferon signaling, recruits T cells, and augments the antitumor immune response of programmed death-ligand 1 (PD-L1) blockade in mouse models. We demonstrate that combined ATR and PD-L1 inhibition causes improved antitumor response than PD-L1 alone as the second-line treatment in SCLC. This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling-mediated immunogenicity in SCLC.

A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited-disease small cell lung cancer: insights from two institutions and review of the literature.

BACKGROUND: The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. PATIENTS AND METHODS: From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. RESULTS: A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. CONCLUSIONS: Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group.

Risk factors and nomograms for diagnosis and early death in patients with combined small cell lung cancer with distant metastasis: a population-based study.

OBJECTIVE: Combined small cell lung cancer (CSCLC) with distant metastasis (DM) is an aggressive disease with a poor prognosis. Effective nomograms are needed to predict DM and early death in patients with CSCLC and DM. METHODS: This retrospective study included patients with CSCLC from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Risk factors for DM and early death were analyzed by univariate and multivariate logistic regression. Nomograms were constructed based on the results in a training cohort and confirmed in a validation cohort, and their performances were assessed by concordance index (C-index), receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 788 patients with CSCLC were selected, including 364 patients with metastatic CSCLC. Sex, tumor site, T stage, and N stage were independent risk factors for DM, while age, surgery, chemotherapy, and liver metastasis were independent risk factors for early death. C-index, ROC, calibration, and DCA curve analyses all showed good predictive performances for both nomograms. CONCLUSIONS: These nomograms could reliably predict DM risk in CSCLC patients and early death in CSCLC patients with DM, and may thus help clinicians to assess these risks and implement individualized therapies.

Impact of thoracic radiotherapy on first-line treatment outcomes in ES-SCLC patients.

BACKGROUND: The therapeutic advantage of thoracic radiotherapy (tRT) as an adjunct to first-line immunotherapy and chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC) remains unclear. We sought to elucidate this in a retrospective cohort study comparing the effectiveness and safety of tRT in combination with first-line immunotherapy and chemotherapy. METHODS: Our retrospective study included patients with ES-SCLC, treated at the West China Hospital between January 2019 and December 2022. They received first-line immunotherapy and chemotherapy and were categorized into two cohorts based on the administration of tRT. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Cox regression analysis was utilized to identify potential independent predictors of prognosis and to compare the treatment outcomes across various patient subgroups. Treatment-related toxicities across both cohorts were compared using the Chi-squared test. RESULTS: A total of 99patients were eligible for the study, out of which 55 received tRT. The medianduration of follow-up was 39 months. Remarkably, patients who received tRTdemonstrated superior OS and PFS in comparison to those who did not (P < 0.05). Subgroup analysis further confirmed these findings. Multivariate analysisidentified treatment group and liver metastasis as independent prognosticfactors (P < 0.05). The incidence of grade 3-4 adverse events showed nostatistically significant difference between the two cohorts. CONCLUSIONS: Thus, weconfirmed that the addition of tRT to the conventional regimen of first-linechemotherapy and immunotherapy yields better survival outcomes without asignificant increase in toxicity.

Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial.

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7-78.9%) and the DCR was 76% (95% CI: 54.9-90.6%). The mPFS was 6.0 months (95% CI: 5.4-9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

BUB1 induces AKT/mTOR pathway activity to promote EMT induction in human small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive tumor. Abnormal expression of BUB1 has been reported in several cancer types, wherein it plays a range of functional roles. This work aimed to elucidate the functional significance and molecular impacts of BUB1 in SCLC. It was found that SCLC cell lines exhibited significant BUB1 upregulation relative to control bronchial cells using data from the Gene Expression Omnibus (GEO) database and verified by immunohistochemical staining. BUB1 was also found to promote the proliferative, migratory, invasive activity of SCLC cells, as shown by CCK-8, 3D migration wound-healing, and Transwell assays, as well as flow cytometry. Additionally, it was found that BUB1 silencing enhanced E-cadherin expression while suppressing N-cadherin, Vimentin, ZEB-1, and Snail levels, as shown by Western immunoblotting. The loss of BUB1 also reduced p-AKT and p-mTOR levels without altering total AKT or mTOR protein levels. In conclusion, BUB1 functions as an oncogenic promoter in SCLC, potentially regulating the epithelial-mesenchymal transition by activation of AKT/mTOR signaling.

Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review.

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023.

Serum tumor markers: potential indicators for occult lymph node metastasis in clinical T1 - 2N0M0 small cell lung cancer patients.

In their letter-to-the-editor entitled "Letter to the Editor: Incidence rate of occult lymph node metastasis in clinical T1 - 2N0M0 small cell lung cancer patients and radiomic prediction based on contrast-enhanced CT imaging: a multicenter study", Prof. Chen et al. provided insightful comments and suggestions on our original study. We appreciate the authors' feedback and have conducted a preliminary exploration of the predictive value of serum tumor markers (TMs) for occult lymph node metastasis (OLM) in clinical T1 - 2N0M0 (cT1 - 2N0M0) small cell lung cancer (SCLC) patients. The results indicate that neuron-specific enolase (NSE), carbohydrate antigen 125 (CA125), and squamous cell carcinoma antigen (SCC) have potential predictive value for detecting OLM in cT1 - 2N0M0 SCLC patients. Additionally, further exploration and confirmation through prospective, large-scale studies with robust external validation are needed.

Impact of examined lymph node count on survival outcomes in patients with stage T1-2N0M0 small cell lung cancer undergoing surgery: A retrospective cohort study.

To explore the relationship between the count of examined lymph nodes (ELNs) and survival outcomes in patients with stage T1-2N0M0 small cell lung cancer (SCLC) after surgical treatment. We analyzed data from patients with SCLC in the Surveillance, Epidemiology, and End Results database. The study focused on examining the correlation between the ELN count and both cancer-specific survival (CSS) and overall survival (OS). This relationship was investigated using restricted cubic spline curves within the framework of multivariable Cox regression models. The cutoff value for both CSS and OS was 7 ELN counts. Patients with ELN < 7 had a median CSS of 64 months, significantly lower than 123 months of patients with ELN ≥ 7 (P = .012). Multivariable Cox regression analysis indicated that ELN ≥ 7 was an independent prognostic factor for CSS (hazard ratio = 0.50, 95% confidence interval: 0.30-0.83; P = .007). Similarly, Patients with ELN < 7 had a median OS of 41 months for patients with ELN < 7, compared to 103 months for those with ELN ≥ 7 (P = .004). Multivariable Cox regression analysis confirmed that ELN ≥ 7 was an independent prognostic factor for OS (hazard ratio = 0.54, 95% confidence interval: 0.36-0.81; P = .003). ELN ≥ 7 is recommended as the threshold for evaluating the quality of postoperative lymph node examination and for prognostic stratification in patients with stage T1-2N0M0 SCLC undergoing surgery.

A case of melanoma with atypical presentation.

Malignant melanoma, a cancer type with a high mortality rate and increasing incidence worldwide, primarily affects the skin but can also occur in various other organs and tissues, including the respiratory tract. Although primary lung malignant melanomas are rare, they are often diagnosed at advanced stages due to their asymptomatic nature, and their atypical presentations may lead to misdiagnosis as other malignancies. In this case report, a mass lesion almost completely filling the right lung initially led to the consideration of small cell lung carcinoma, but a definitive pathological diagnosis could not be obtained in subsequent studies. The diagnosis was confirmed by soft tissue biopsy taken from the anterior thoracic wall. Considering clinical, pathological, and radiological evaluations, possible diagnoses included sarcoma, small-cell lung cancer, and melanoma. The patient, diagnosed through multiple tissue sampling and detailed dermatological examination, presents an interesting atypical case. This case highlights that rare variants of melanoma can be mistaken for other cancer types, such as lung cancer, sarcoma, or lymphoma. Patients may not always present with a noticeable skin lesion; therefore, a meticulous skin examination is crucial in such cases. Malignant melanoma is a noteworthy disease, considering its increasing incidence and early diagnosis holds vital importance for appropriate treatment and management.

Phase Ib/II study on the safety, tolerability, and preliminary efficacy of pegylated irinotecan (JK1201I) as second-line monotherapy for patients with small-cell lung cancer.

PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of multiple doses of pegylated irinotecan (JK1201I) as a second-line monotherapy for treating small-cell lung cancer (SCLC) patients. METHODS: According to the "3 + 3" dose-escalation principle, patients received intravenous JK1201I at 180 or 220 mg/m2 once every 3 weeks for four cycles. Progression-free survival (PFS), overall survival (OS), median progression-free survival (mPFS), and median overall survival (mOS) were evaluated. The Kaplan-Meier method was used to analyze PFS and overall OS. Brookmeyer and Crowley's method was used for mPFS and mOS. RESULTS: This study included 29 patients with stage III-IV SCLC (stage IIIa, n = 1; stage IIIb, n = 1; and stage IV, n = 27). Of these, 26 patients were enrolled in the 180 mg/m2 dose group, and 3 patients were enrolled in the 220 mg/m2 dose group. No dose-limiting toxicity (DLT) was noted during the first 28 days of treatment. Grade 3 or higher adverse events were recorded in the 180 mg/m2 group, including diarrhea (11.5%, 3/26), neutropenia (7.7%, 2/26), and leukopenia (7.7%, 2/26). In the 220 mg/m2 group, one patient (33.3%, 1/3) experienced neutropenia or leukopenia. In the 180 mg/m2 group, 38.5% (10/26) of patients achieved an objective response rate (ORR), with a disease control rate (DCR) of 73.1% (19/26). The mPFS and mOS were 3.4 and 12.1 months, respectively. In the 220 mg/m2 group, one patient had stable disease, and one had progressive disease (PD). The ORR, DCR, mPFS, and mOS were 0% (0/3) and 33.3% (1/3), 2.7 months and 2.7 months, respectively. CONCLUSION: JK1201I exhibits promising efficacy and relatively low toxicities as a second-line monotherapy for SCLC, warranting further large-scale clinical studies to evaluate its efficacy in greater detail.

Prognostic Significance of the Advanced Lung Cancer Inflammation Index in Metastatic Small Cell Lung Cancer: A Retrospective Analysis of 96 Patients.

BACKGROUND The advanced lung cancer inflammation index (ALI) is regarded as a potential indicator of systemic inflammation. This retrospective study aimed to evaluate the prognostic role of the ALI in 96 patients with advanced small cell lung cancer (SCLC). MATERIAL AND METHODS This retrospective study included 96 patients who were diagnosed with extensive stage SCLC in a single institution between 2016 and 2022. The formula for ALI is body mass index (kg/m²)×serum albumin (g/dL)/neutrophil to lymphocyte ratio. Patients were divided into low inflammation (ALI ≥32.5) and high inflammation (ALI <32.5) groups. Kaplan-Meier analysis and Cox proportional analysis were conducted to assess the association between the ALI and patient prognosis. RESULTS Median age was 61 (range: 41-82) years. Median follow-up was 9 months, and median overall survival (OS) was 10 months (95% CI: 7.75-12.45). A lower ALI score (ALI <32.5) was correlated with a poorer OS than was a higher ALI score (median OS 7 months for ALI <32.5 95% CI: 4.6-9.3 vs 15 months for ALI ≥32.5, 95% CI: 10.6-19.3, P<0.001). In the multivariate analysis, ALI score, Eastern Cooperative Oncology Group performance status, brain metastasis, and bone metastasis were identified as independent prognostic factors. CONCLUSIONS ALI score is a substantial predictor of survival in SCLC as in other types of cancer types. Patients with a low ALI score have poorer survival. Assessment of ALI can identify lung cancer patients at high risk of poor prognosis and can be a useful prognostic marker in clinical practice.

Overcoming resistance in small-cell lung cancer.

INTRODUCTION: Small-cell lung cancer (SCLC) accounts for 15% of lung cancers and has a dismal prognosis due to early dissemination and acquired chemoresistance. The initial good response to chemotherapy is followed by refractory relapses within 1-2 years. Mechanisms leading to chemoresistance are not clear and progress is poor. AREAS COVERED: This article reviews the current evidence of the resistance of SCLCs at the cellular level including alteration of key proteins and the possible presence of cancer stem cells (CSCs). Without compelling evidence for cellular mechanisms and clinical failures of novel approaches, the study of SCLC has advanced to the role of 3D tumor cell aggregates in chemoresistance. EXPERT OPINION: The scarcity of viable tumor specimen from relapsed SCLC patients has hampered the investigations of acquired chemoresistance but a panel of nine SCLC circulating tumor cell (CTC) cell lines have revealed characteristics of SCLC in the advanced refractory states. The chemoresistance of relapsed SCLC seems to be linked to the spontaneous formation of large spheroids, termed tumorospheres, which contain resistant quiescent and hypoxic cells shielded by a physical barrier. So far, drugs to tackle large tumor spheroids are in preclinical and early clinical development.