Untreated Extensive-stage Small-cell Lung Cancer Research Articles

Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small–cell lung cancer (ES-SCLC): a phase II trial

This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored. Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100mg/m2, D1-3, Q3W and cisplatin, 75mg/m2, D1, Q3W or carboplatin, AUC=5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30Gy in 10 fractions or≥50Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337. From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P=0.071; ctDNA, P=0.060) and OS (tissue, P=0.032; ctDNA, P=0.031). Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

A Clinical Analysis of Anti-Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint Inhibitor Treatments Combined with Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25-8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12-17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level).

Atezolizumab Plus Carboplatin and Etoposide in Patients with Untreated Extensive-Stage Small-Cell Lung Cancer: Interim Results of the MAURIS Phase IIIb Trial.

MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation. Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction. At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response. Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice. Eudract No. 2019-001146-17, NCT04028050.

Phase 1 study of pembrolizumab plus chemotherapy in Japanese patients with extensive-stage small-cell lung cancer

SummaryBackgroundPart E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).MethodsPatients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).ResultsFifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).ConclusionPembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.Trial RegistrationClinicalTrials.gov, NCT01840579.

Drug Pricing of Domestic Anti-PD-L1 Antibody Adebrelimab: Cost-Effectiveness Analysis of the First-Line ES-SCLC Treatment in China.

The market price of adebrelimab, the first Chinese-developed anti-PD-L1 antibody used as a first-line treatment for extensive stage-small-cell lung cancer (ES-SCLC), has garnered significant public attention. This study sought to investigate the affordable price of adebrelimab for Chinese patients with untreated ES-SCLC through a cost-effectiveness analysis. We conducted a cost-effectiveness analysis using a Markov model, incorporating a what-if scenario of adding adebrelimab to first-line etoposide/platinum (EP) chemotherapy is cost-effective for ES-SCLC patients from the perspective of the Chinese healthcare system. The model included three mutually exclusive health states, with transition probabilities derived from the CAPSTONE-1 trial. Health state utilities and costs were acquired from a myriad of authoritative sources. We compared the incremental cost-effectiveness ratios (ICERs) for adebrelimab plus EP chemotherapy (AEP) versus EP with a willingness-to-pay threshold of $37,654 per quality-adjusted life-years (QALYs) to estimate the affordable price ceiling of the upcoming adebrelimab. For the entire ES-SCLC population, the estimated price ceiling of adebrelimab/mg was $0.542 (95% CI, $0.542-$0.552). Subgroup analyses found that the highest price ceiling of adebrelimab/mg was observed in ES-SCLC patients with lactate dehydrogenase concentration ≤ upper normal limit [$0.824 (95% CI, $0.815-$0.830)]; and the lowest was found in ES-SCLC patients with liver metastasis [$0.252 (95% CI, $0.250- $0.256)]. Sensitivity analysis revealed a heightened probability of cost-effectiveness for the first-line AEP as the price of adebrelimab decreased, encompassing both the entire ES-SCLC population and its subgroups. The affordable price range for adebrelimab/mg Chinese patients with untreated ES-SCLC was estimated to be between $0.252 and $0.824, with variations observed across different subgroups. In the context of universal healthcare coverage, our study provides valuable evidence to inform the implementation of a value-based pricing strategy for cancer treatment.

Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide

ObjectivesIn the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival. Materials and MethodsPatients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS. ResultsMore LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm. ConclusionThese exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.ClinicalTrial.gov Identifier: NCT02763579.

Outcomes and Prognostic Factors of Extensive Stage Small Cell Lung Cancer: A Retrospective Study

Introduction Small cell lung cancer (SCLC) represents about 15% of all lung cancers. Extensive stage (ES) SCLC represents around 60% of diagnosed SCLC cancers. The median survival in untreated ES SCLC is 2 to 4 months and that of treated cases is 8 to 13 months. Aim and Objectives This retrospective analysis aims to find out the clinical outcome of patients with ES SCLC and the prognostic factors affecting their survival. Methods Details of patients registered in the department of radiation oncology from January 1, 2010 to September 30, 2019 were retrieved from the hospital records. This includes the demographic characteristics, treatment received, toxicity, and follow-up details. Results Two-hundred eighty-three patients were included. Median age of presentation was 62 years. Around 97.5% of patients were men. Smokers constitute 94% of all cases. About 86.9% (246 patients) of cases were not alive at the end of the study period. The median estimated overall survival (OS) was 7 months ± 0.47 (95% confidence interval [CI]: 6.026–7.974) and progression-free survival (PFS) was 5 months ± 0.535 (95% CI: 3.952–6.048). Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), hyponatremia, number of chemotherapy cycles, consolidative radiotherapy (RT) and prophylactic cranial irradiation (PCI) were found to have prognostic effect on OS. Smoking, ECOG PS, number of chemotherapy cycles, consolidative RT, and PCI were found to have prognostic effects on PFS. Conclusion There is a difference in OS and PFS patterns of ES SCLC patients among various Indian studies even though the available data is scarce. Our study shows that the OS and PFS of our study population are comparable to other South Indian studies available. PS, serum sodium level, number of chemotherapy cycles, consolidative RT, and PCI were found to be independent prognostic factors for survival of ES SCLC. The identification of these factors will help physicians to tailor treatment.

Abstract CT219: Efficacy and safety of Low dose radiotherapy (LDRT) concurrent Atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: Primary analysis of Phase II MATCH study

Abstract Background: The IMpower133 represented the current standard of care in the 1L setting for patients (pts) with ES-SCLC (extensive-stage small cell lung cancer). However, there are still unmet needs for ES-SCLC treatment. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. The interim analysis of MATCH study after stage I showed promising benefit and tolerability of combination of Atezo + chemotherapy + LDRT in pts with ES-SCLC. Here we report the primary efficacy and safety results of this study. Methods: The MATCH study was a single-arm phase II trial conducted in 8 centers across China. Previously untreated ES-SCLC pts with measureable disease per RECIST v1.1 at baseline, age≥18, ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with a complete response or partial response on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. A Simon’s minimax 2-stage design was adopted. Results: As the cutoff date of 30th Nov. 2022, 56 pts have been enrolled. 49 (87.5%) were males; mean age was 58.9 years with 78.6% pts had ECOG PS of 1. 80.4% pts had smoking history. Most pts were staged T4 (n = 33, 58.9%), N3 (n = 37, 66.1%) and M1(n = 40, 71.4%). Median follow-up was 14.8 months (range: 11.6-17.8 m). The confirmed ORR was 87.5% (95% CI: 75.9%-94.8%), all partial response. DCR was 94.6% (95% CI: 85.1%-98.9%). Median PFS was 6.9 m (95% CI: 5.4-9.3 m). The 6-month and 12-month PFS rate were 56.5% and 27.7%. Median OS was not reached (NR, 95% CI: 13.3m, NR). The 12-month OS rate was 71.9%. The safety profile, analyzed in all 56 pts, was consistent with the previous reports. Neutrophil count decreased (60.7%), white blood cell count decreased (58.9%) and platelet count decreased (23.2%) were the most common grade (G) 3-4 adverse events (AE). G5 AE occurred in 1 pt (pneumonia and pulmonary embolism). 4 pts experienced AEs leading to treatment discontinuation. IrAEs were reported in 21 (37.5%) pts, most common irAEs were hyperthyroidism (5.4%) and rash (5.4%). Radiation pneumonitis (G1) was observed in 1 pt. Conclusions: Adding LDRT to Atezo + chemotherapy shows impressive antitumor activity, potential survival benefit and well tolerability in 1L treatment of ES-SCLC. Clinical registration: NCT04622228. Citation Format: Lin Zhou, Jianguo Sun, Conghua Xie, Youling Gong, Meijuan Huang, Zhiyong Yuan, Lin Wu, Hui Wang, Nan Bi, Yaping Xu, Jiang Zhu, Yongmei Liu, Yan Zhang, Min Fan, Bingwen Zou, Min Yu, Yanying Li, Feifei Na, Weigang Xiu, Yong Xu, Jin Wang, Xuanwei Zhang, Jianxin Xue, You Lu. Efficacy and safety of Low dose radiotherapy (LDRT) concurrent Atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: Primary analysis of Phase II MATCH study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT219.

Age-Stratified Analysis of First-Line Chemoimmunotherapy for Extensive-Stage Small Cell Lung Cancer: Real-World Evidence from a Multicenter Retrospective Study.

Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung cancer were newly diagnosed at ≥75 years in Japan. Therefore, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be evaluated through real-world Japanese evidence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated with chemoimmunotherapy were divided into the non-elderly (<75 years) and elderly (≥75 years) groups, and efficacy, including PFS, OS, and post-progression survival (PPS) were evaluated. In total, 225 patients were treated with first-line therapy, and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The median PFS and OS in non-elderly and elderly were 5.1 and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate analyses revealed that age and dose reduction at the initiation of the first chemoimmunotherapy cycle were not correlated with PFS or OS. In addition, patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) = 0 who underwent second-line therapy had significantly longer PPS than those with ECOG-PS = 1 at second-line therapy initiation (p < 0.001). First-line chemoimmunotherapy had similar efficacy in elderly and non-elderly patients. Individual ECOG-PS maintenance during first-line chemoimmunotherapy is crucial for improving the PPS of patients proceeding to second-line therapy.

Chemo-Immunotherapy in First Line Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Systematic Review and Meta-Analysis.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. The standard-of-care treatment has not changed in years. Recent studies report improved progression-free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We conducted a systematic review and meta-analysis to assess the magnitude of survival benefits. We searched MEDLINE, EMBASE, and Cochrane between 1 January 2010 and 15 July 2022 and conference proceedings from 2018 to 2022, for randomised controlled trials, evaluating chemo-ICI compared with platinum-doublet chemotherapy in untreated ES-SCLC. Outcomes assessed were PFS, OS, objective response rate (ORR), duration of response (DoR), toxicity, and health-related quality of life (HRQoL). The search identified 8061 studies, with 8 (56 publications) included in the final analysis. PFS and OS were significantly improved for patients randomised to chemo-ICI (PFS hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.70-0.80) and (OS HR 0.79, 95% CI 0.73-0.85). Subgroup analysis demonstrated a differential effect between PD-1/PD-L1 and CTLA-4 inhibitors. There was no difference in ORR and DoR. All-grade adverse events (RR 1.06, 95% CI 1.00-1.12) were similar. The addition of ICI to chemotherapy in untreated ES-SCLC results in a 22% risk reduction in death, and a 25% risk reduction in disease progression with a minimal increase in toxicity. These improvements are modest but represent progress beyond the standard of care.

A phase II study of carboplatin and etoposide plus durvalumab for previously untreated extensive-stage small-cell lung cancer (ES-SCLC) patients with a poor performance status (PS): NEJ045A study protocol

BackgroundSmall-cell lung cancer (SCLC) accounts for 12–15% of lung cancers and has a limited prognosis, with approximately one-third of SCLC patients having a poor performance status (PS). Patients with extensive-stage (ES) SCLC and a poor PS have a poor prognosis. For this population, overall survival from carboplatin and etoposide treatment is 7–8 months, and treatment development is an unmet medical need. Recently, the combination of an anti-PD-L1 (a ligand for programmed cell death 1) antibody and platinum-based chemotherapy has become the standard of care for ES-SCLC patients with a good PS (PS 0–1). We hypothesized that the combination of the anti-PD-L1 antibody durvalumab with carboplatin and etoposide would be feasible and effective for such patients.MethodsWe initiated a multicenter phase II study of durvalumab combined with carboplatin and etoposide in previously untreated ES-SCLC patients with a poor PS (PS 2–3). Eligible patients will receive durvalumab plus carboplatin and etoposide every 3 to 4 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. The dosages of carboplatin and etoposide for the second and subsequent cycles will be adaptively determined based on the adverse events of the first cycle. A total of 56 patients (43 patients with a PS of 2 and 13 patients with a PS of 3) will be enrolled in this study, with a 24-month enrollment period and a 12-month follow-up. The primary endpoint is the tolerability of carboplatin and etoposide plus durvalumab in previously untreated ES-SCLC patients with a poor PS. The secondary endpoints are the 1-year survival rate, objective response rate, progression-free survival, overall survival, ratio of PS improvement, and safety.DiscussionThe results of this study are intended to establish the safety and efficacy of carboplatin and etoposide plus durvalumab in patients with ES-SCLC and a poor PS.Trial registrationJapan Registry of Clinical Trials (jRCT), jRCTs031200319. Registered 21 January 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs031200319

LBA9 Updated results of first-line serplulimab versus placebo combined with chemotherapy in extensive-stage small cell lung cancer: An international multicentre phase III study (ASTRUM-005)

PD-L1 inhibitors have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy (chemo), marking a milestone in the management of this disease. Whether a PD-1 inhibitor provides similar or better benefits in the same patient population remains unclear. At 2022 ASCO Annual Meeting, we presented the results from the interim analysis of a phase 3 study of serplulimab, a novel anti-PD-1 antibody, in combination with chemo in previously untreated ES-SCLC patients.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. ClinicalTrials.gov Identifier: NCT04063163.

SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC).

LBA8507 Background: Atezo, in combination with CE, was the first cancer immunotherapy approved for 1L treatment of ES-SCLC. However, most pts eventually experience disease progression. TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergise with other immunotherapies, such as PD-L1/PD-1 inhibitors, and further amplify the immune response to improve clinical outcomes. SKYSCRAPER-02 (NCT04256421) evaluates whether the antitumor effect and survival benefits of the combination of atezo + CE could be enhanced by adding tira in pts with ES-SCLC. Methods: Eligible pts with untreated ES-SCLC (asymptomatic treated or untreated brain metastases [BM] permitted) were randomized 1:1 to receive induction tira 600 mg IV or placebo (pbo) combined with atezo 1200 mg IV + CE for 4 x 21-day cycles followed by maintenance tira or placebo combined with atezo every 3 weeks until disease progression or loss of clinical benefit. Stratification factors include ECOG PS (0 vs 1); presence/history of BM (yes vs no); LDH (≤upper limit of normal [ULN] vs &gt;ULN). Co-primary endpoints were investigator-assessed PFS and OS in all randomized pts without the history/presence of BM at baseline (primary analysis set [PAS]). Additional endpoints include PFS and OS in all randomized pts regardless of BM status (full analysis set [FAS]), objective response rate, duration of response, and safety. Results: A total of 490 patients were randomized (tira + atezo + CE, n=243; pbo + atezo + CE, n=247). As of 6 Feb 2022, median duration of follow-up was 13.9 months (mo); data represent final analysis for PFS and interim analysis for OS. In the PAS, no additional benefit was seen for tira + atezo + CE in PFS or OS compared with pbo + atezo + CE (Table). PFS and OS in the FAS were consistent with those observed in the PAS (Table). Grade 3/4 TRAEs occurred in 52.3% (tira + atezo + CE) and 55.7% (pbo + atezo + CE) and Grade 5 TRAEs occurred in 0.4% (tira + atezo + CE) and 2.0% (pbo + atezo + CE). TRAEs leading to any treatment discontinuation occurred in 5.0% and 5.3% with tira + atezo + CE and pbo + atezo + CE, respectively. Conclusions: The addition of tira to atezo + CE did not provide benefit over atezo + CE in pts with untreated ES-SCLC with or without BM. The combination was well tolerated, and no new safety signals were identified. The study will continue to planned final OS analysis. Clinical trial information: NCT04256421. [Table: see text]

Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: An international randomized phase 3 study.

8505 Background: Monoclonal antibodies against programmed death-ligand 1 (PD-L1) have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy. However, whether a programmed death 1 (PD-1) inhibitor provides similar survival benefit in this patient population remains unclear. In this study, the efficacy and safety of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, were assessed in combination with chemotherapy in previously untreated ES-SCLC patients. Methods: In this international, randomized, double-blind, multicenter, phase 3 trial (NCT04063163), patients with ES-SCLC who had not received prior systemic therapy were randomized (2:1) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Between September 12, 2019 and April 27, 2021, 585 patients were randomized (serplulimab group, n = 389; placebo group, n = 196). At interim analysis, the median follow-up duration was 12.3 months. Median OS was significantly prolonged in the serplulimab group than the placebo group (15.4 vs.10.9 months; hazard ratio [HR] 0.63, 95% CI 0.49–0.82; P &lt; 0.001). Median PFS assessed by the independent radiology review committee (IRRC) per RECIST v1.1 was significantly longer in the serplulimab group than the placebo group (5.8 vs. 4.3 months; HR 0.47, 95% CI 0.38–0.59; P &lt; 0.001). Efficacy improvements were also observed in ORR (80.2% vs. 70.4%) and DoR (5.6 vs. 3.2 months) as assessed by IRRC per RECIST v1.1. Grade ≥3 treatment-emergent adverse events (TEAEs) related to serplulimab or placebo were reported in 129 (33.2%) and 54 (27.6%) patients in the respective groups. Incidence of immune-related TEAEs was higher in the serplulimab group compared to the placebo group (37% vs. 18.4%), with the largest difference in endocrine disorders (18.3% vs. 4.6%), which are commonly reported with anti-PD-1/PD-L1 therapies. Four deaths (1 acute coronary syndrome, 1 pyrexia, and 1 platelet count decreased in the serplulimab group; 1 thrombocytopenia in the placebo group) that might be related to study drugs were reported. Conclusions: Serplulimab plus chemotherapy as first-line treatment provided significant benefits and a manageable safety profile compared with chemotherapy alone in ES-SCLC patients. For the first time, OS benefits was demonstrated with a PD-1 inhibitor in a global phase 3 study among previously untreated ES-SCLC patients. Clinical trial information: NCT04063163.

KeyVibe-008: Randomized, phase 3 study of first-line vibostolimab plus pembrolizumab plus etoposide/platinum versus atezolizumab plus EP in extensive-stage small cell lung cancer.

TPS8606 Background: Current standard of care immunotherapy plus chemotherapy options for first-line extensive-stage small-cell lung cancer (ES-SCLC) are associated with modest improvements in median OS and PFS. In the KEYNOTE-604 study, first-line pembrolizumab plus etoposide/platinum (EP) significantly improved PFS (HR 0.75; 95% CI, 0.61‒0.91; P = 0.0023) compared with placebo plus EP in ES-SCLC; OS was also longer with pembrolizumab plus EP vs placebo plus EP but did not reach statistical significance (HR 0.80; 95% CI, 0.64‒0.98; P = 0.0164). Preclinical and clinical data suggest that blocking the interaction between the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and its ligands CD112 and CD155 with the anti-TIGIT humanized monoclonal antibody vibostolimab (MK-7684) yields promising antitumor activity when combined with pembrolizumab, with or without chemotherapy, including in patients with lung cancer. The current phase 3 study, KeyVibe-008 (NCT05224141), is comparing the efficacy and safety of first-line treatment with MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, in combination with EP vs atezolizumab plus EP in patients with ES-SCLC. Methods: This multicenter, randomized, double-blind, phase 3 study is enrolling patients aged ≥18 years with histologically or cytologically confirmed, previously untreated ES-SCLC. Patients must have measurable disease per RECIST v1.1; ECOG PS of 0 or 1; no active CNS metastases/carcinomatous meningitis, autoimmune disease, neurologic paraneoplastic syndromes, pneumonitis, or interstitial lung disease; and must provide a pretreatment tumor sample. Patients are randomized 1:1 to receive up to 4 cycles of EP (cisplatin or carboplatin) in combination with MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) Q3W or atezolizumab (1200 mg) Q3W, followed by MK-7684A or atezolizumab, respectively, until disease progression, unacceptable AEs, intercurrent illness, protocol violation, or investigator/patient decision. Randomization is stratified by ECOG PS (0 vs 1), LDH (≤ULN vs &gt; ULN), liver metastases (yes vs no), and brain metastases (yes vs no). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review; safety; and patient-reported outcomes (PROs). Tumor imaging occurs at baseline, every 6 weeks until 48 weeks, and every 9 weeks thereafter until disease progression, start of new anticancer treatment, withdrawal of consent, or death. PROs are assessed using validated instruments including the EORTC quality of life and EuroQol questionnaires. AEs are graded according to NCI CTCAE v5.0. Enrollment is ongoing worldwide. Clinical trial information: NCT05224141.

First-Line Treatments for Extensive-Stage Small-Cell Lung Cancer With Immune Checkpoint Inhibitors Plus Chemotherapy: A Network Meta-Analysis and Cost-Effectiveness Analysis.

BackgroundImmune checkpoint inhibitors (ICIs) plus chemotherapy were unlikely to be considered cost-effective compared with chemotherapy as the first-line treatment of patients with extensive-stage small-cell lung cancer (ES-SCLC) in China due to its high costs. However, the cost-effectiveness of the comparison between the regimens of ICIs plus chemotherapy were remained unclear yet. The aim of this study was to evaluate the efficacy and cost-effectiveness of ICIs plus chemotherapy as the first-line treatment for ES-SCLC from the perspective of the Chinese healthcare system.MethodsA network meta-analysis (NMA) was conducted to indirect compare the clinical benefits between the ICIs plus chemotherapy regimens. A decision-analytic model was established to evaluate the cost-effectiveness from the Chinese healthcare system, the clinical efficacy and safety data were obtained from the clinical trials and the results of NMA. Cost and utility values were gathered from the local charges and previously studies. Key outputs of the NMA were overall survival (OS) and progression-free survival (PFS). Incremental cost-effectiveness ratios (ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed to explore the robustness of the model outcomes.ResultsFive clinical trials (IMpower133, CASPIAN, KEYNOTE-604, CA184-156, and EA5161) of 1,255 patients received first-line ICIs plus chemotherapy strategies were analyzed in the NMA. NMA showed that nivolumab plus chemotherapy was ranked higher than other strategies. The cost-effectiveness analysis showed that atezolizumab plus chemotherapy achieved relatively higher health benefits and lower costs. One-way sensitivity analyses revealed that the cost of ICIs had the substantial impact on model outcomes. The probabilistic sensitivity analyses suggested that the probability of atezolizumab plus chemotherapy could be considered cost-effective was more than 50% at the willingness-to-pay (WTP) threshold of $31,313/QALY in China. In scenario analyses, when the price of nivolumab reduced 80%, the probability of nivolumab plus chemotherapy being cost-effective was more than 50%.ConclusionsThe NMA and cost-effectiveness revealed that atezolizumab plus chemotherapy is the most favorable first-line treatment for previously untreated ES-SCLC patients compared other ICIs plus chemotherapy regimens in China. The price reduction of nivolumab would make nivolumab plus chemotherapy be the most cost-effective option in future possible context.

First-Line Durvalumab in Addition to Etoposide and Platinum for Extensive-Stage Small Cell Lung Cancer: A U.S.-Based Cost-Effectiveness Analysis.

The latest published CASPIAN trial demonstrated that adding durvalumab to etoposide and platinum (EP) improved survival dramatically for patients with extensive-stage small cell lung cancer (ES-SCLC). Considering the high cost of durvalumab, this study evaluated the cost-effectiveness of durvalumab plus EP (DEP) in the first-line setting for treatment-naïve patients with ES-SCLC from the U.S. payer perspective. We developed a three-state Markov model to simulate the disease course and source consumption of ES-SCLC over a lifetime horizon. Pseudo-individual patient-level data were generated from digitized Kaplan-Meier curves. Direct medical costs, including drug and administration costs, disease management and adverse events treatment fees, best supportive care and terminal care costs were obtained from sources including the Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, and relevant literature. Health state utility values were derived from published literature. Main outcomes considered were total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). All costs were adjusted for inflation to reflect 2019 U.S. dollars. The willingness-to-pay threshold was set as $150,000/QALY. One-way and probabilistic sensitivity analyses were used to explore the uncertainty of model assumptions. Compared with EP, DEP was projected to increase life expectancy by 0.86 LYs (1.73 vs. 0.87) and 0.44 QALYs (0.93 vs. 0.49). The incremental treatment cost was $95,907, and the corresponding ICER was $216,953/QALY. The result was most sensitive to the variation of durvalumab acquisition cost. Probabilistic sensitivity analysis revealed that the probability of DEP over EP regimen to be cost-effective was 9.4% at a willingness-to-pay threshold of $150,000/QALY. In the case of reducing the price of durvalumab by 30.7%, DEP was more cost-effective than EP. From the perspective of the U.S. payer, adding durvalumab to EP is estimated to be not cost-effective compared with EP alone for patients with untreated ES-SCLC. The information provided by this analysis serves as a reference for decision makers. Lowering the price of durvalumab would be a potential measure to improve the economics of durvalumab plus etoposide and platinum (DEP), and the inclusion of durvalumab in the Medicare pharmacopeia could make DEP more economically available. These results may also guide physicians and patients to choose the most economically feasible treatment.

Modern possibilities of immunotherapy in the treatment of extensive-stage small cell lung cancer: experience of durvalumab application. Case report

Extensive-stage small cell lung cancer (ES-SCLC) is characterized by an aggressive course, a high recurrence rate and fast progression. For a long time, the survival prognosis for the most patients suffering from this disease remained unfavorable. The situation changed with the appearance of chemoimmunotherapy in clinical practice. Chemotherapy based on durvalumab in comparison with the standard chemotherapy demonstrated the statistically and clinically significant increase in median overall survival in patients with previously untreated ES-SCLC in the CASPIAN international trial. This article deals with the case of the application of standard chemotherapy in combination with durvalumab as a first-line ES-SCLC therapy. The patient started receiving durvalumab therapy in June 2017 as a part of the CASPIAN international trial. In March 2021 the duration of therapy was 45 months, the patient had a complete regression of the disease.

P48.18 Chemo-Immunotherapy in First Line Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Systematic Review and Meta-Analysis

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. Standard of care with platinum-etoposide chemotherapy has not changed in 30 years. Immune checkpoint inhibitors (ICI) have recently demonstrated significant improvement in non-small cell lung cancer (NSCLC) patients. There is evidence for increased benefit of ICI in mutagenic cancers, such as SCLC, caused by exposure to carcinogens (i.e. smoking). There are now several studies that report improved progression free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We aimed to assess the magnitude of the survival benefit of combined chemo-ICI in the first line systemic treatment of ES-SCLC as compared to standard of care chemotherapy. MEDLINE, EMBASE and the Cochrane library were systematically searched, along with abstracts from relevant major conferences (i.e. ASCO, ESMO, WCLC). We searched databases between January 1, 2010 and June 10, 2020 and limited the search of relevant meeting and conference proceedings to 2018 to 2020. Studies were included if they met the following criteria: randomized controlled trials, patients with untreated ES-SCLC treated with combined chemo-ICI as compared to standard of care chemotherapy. Any chemo-ICI pairings were eligible including PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors, combined with platinum-etoposide or platinum-paclitaxel chemotherapy. Trials were excluded if patients were being treated in the second or further line. Relevant outcomes of interest were survival outcomes (PFS and OS), measures of response (objective response rate (ORR), duration of response (DoR)), and toxicity (Grade 1-4 toxicity, Grade 3-4 toxicity). A total of 2705 studies and abstracts were identified in our initial search, with 6 studies (33 publications) included in the final analysis. PFS was significantly improved for patients randomized to chemo-ICI compared with chemotherapy alone (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.75-0.87). Similarly, OS was significantly improved (HR 0.82, 95% CI 0.76-0.89). The between-study heterogeneity was low (I2 0%) for both outcomes. A prespecified subgroup analysis demonstrated no evidence of any significant differential effect between PD-1/PD-L1 inhibitors and CTLA-4 inhibitors. The pooled ORR as expressed as a risk ratio comparing chemo-ICI with chemotherapy alone was 1.04 (95% CI 0.98-1.10) and the pooled duration of response demonstrated a mean difference of 0.09 months (95% CI -0.13-0.32) in favor of chemo-ICI. There were no significant increases in either all grade adverse events (pooled risk ratio of 1.03, 95% CI 1.01-1.06), or grade 3-4 adverse events (risk ratio of 1.06, 95% CI 0.99-1.13). Multiple trials have assessed the efficacy of combined chemo-ICI regimens. They consistently demonstrate survival improvements in both PFS and OS with combined chemo-ICI. This review demonstrates an approximate18% risk reduction in death, and 19% risk reduction in disease progression. The pooled analysis suggests a minimal increase in toxicity with chemo-ICI regimens though clinically relevant toxicity (Grade 3-4 toxicity) crossed null. Chemo-ICI appears to offer survival benefit with potentially equivalent toxicity profile in the setting of first line ES-SCLC regardless of the class of ICI.