Extensive-stage Small Cell Lung Cancer Research Articles

BEAT-SC: A randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC).

8001 Background: Atezolizumab combined with carboplatin and etoposide is approved as first-line treatment for patients with ES-SCLC, based on results from the Phase I/III IMpower133 trial (NCT02763579). The VEGF inhibitor bevacizumab (bev) is approved for the treatment of many tumor types and has synergistic effects when combined with atezolizumab, as demonstrated by the Phase III IMpower150 study (NCT02366143) in non-small cell lung cancer. BEAT-SC (jRCT2080224946) is evaluating the efficacy and safety of bev combined with atezolizumab and platinum-based chemotherapy in patients with ES-SCLC from Japan and China. Here, we report the primary analysis for progression-free survival (PFS) and the first interim analysis for overall survival (OS) from BEAT-SC. Methods: Eligible patients had measurable ES-SCLC, were aged ≥20 y (≥18 y for patients from China), had an ECOG performance status of 0 or 1 and had no prior systemic treatment for ES-SCLC. Patients were randomized 1:1 to receive 4 cycles (21 days/cycle) of induction therapy with bev combined with atezolizumab + cisplatin or carboplatin + etoposide (ACE) or placebo combined with ACE, followed by maintenance therapy with bev + atezolizumab or placebo + atezolizumab, respectively. The primary endpoint was investigator-assessed PFS (INV-PFS). Key secondary endpoints included OS and safety. Results: The ITT population comprised 333 patients with a median age of 65.0 y; 82.6% of the patients were male, 57.7% were from China, 91.8% received carboplatin and 87.6% were current or former smokers. At data cutoff (June 30, 2023; median follow-up, 10.2 mo), median INV-PFS was 5.7 mo for bev + ACE vs 4.4 mo for placebo + ACE (HR, 0.70; 95% CI: 0.54, 0.90; P=0.0060; 2-sided α boundary=0.05). Median OS was 13.0 mo for bev + ACE vs 16.6 mo for placebo + ACE (HR, 1.22; 95% CI: 0.89, 1.67; P=0.2212; 2-sided α boundary=0.0079). Among the safety analysis population (n=330), bev + ACE was well-tolerated and treatment-related adverse events (TRAEs) were generally similar between treatment arms (Table). Conclusions: BEAT-SC met its primary endpoint, demonstrating that the addition of bev to ACE significantly increased PFS vs placebo + ACE. OS data were immature at the first interim OS analysis, and the numerical OS improvement of bev + ACE was not shown vs placebo + ACE; OS follow-up will continue. No new safety signals were observed. Clinical trial information: jRCT2080224946 . [Table: see text]

DAREON-8: A phase I, open-label, dose escalation/expansion trial of the DLL3-targeting T-cell engager, BI 764532, combined with first-line (1L) standard of care (platinum, etoposide, and anti-PD-L1 antibody) in patients (pts) with extensive-stage small cell lung carcinoma (ES-SCLC).

TPS8127 Background: Platinum/etoposide chemotherapy in combination with anti-PD-L1 antibodies is the 1L standard of care (SoC) for pts with ES-SCLC. However, most pts relapse and subsequent treatment (Tx) options are limited. Hence, outcomes are poor with a 5-year survival rate of < 7%. Delta-like ligand 3 (DLL3) is a Notch receptor ligand expressed on tumor cells but not on normal cells. BI 764532 is an IgG-like T-cell engager (TcE) that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in selective, T-cell mediated tumor cell lysis. An ongoing Phase I trial of BI 764532 (NCT04429087) in pts with pretreated DLL3-positive tumors demonstrated an overall response rate of 28%, a disease control rate of 54%, and a manageable safety profile. Here, we describe DAREON-8 (NCT06077500), a Phase I open-label dose escalation/expansion trial of BI 764532 plus SoC as a 1L Tx for pts with ES-SCLC. Methods: Pts will be recruited from ~20 sites into this two-part trial. In Part A (dose escalation), ~30 pts will receive escalating doses of intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide + atezolizumab. Dose escalation will be guided by a Bayesian logistic regression model with overdose control. Tx with BI 764532 will continue for 36 months, withdrawal or progressive disease (PD). The primary objective is to determine the maximum tolerated dose (MTD) of BI 764532 and/or the recommended dose for expansion (RDE)/recommended Phase II dose (RP2D) for BI 764532 plus SoC. Safety, efficacy and/or PK assessments will guide the RDE/RP2D. The primary endpoint focuses on the occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation period. In Part B (dose expansion), ~30 pts will receive BI 764532 at the RDE/RP2D determined in Part A for 36 months, withdrawal or PD and platinum/etoposide + either atezolizumab or durvalumab. The primary objective of Part B is to confirm the safety and tolerability of BI 764532 at the RDE/RP2D plus SoC Tx as measured by the occurrence of DLTs during the on-Tx period. Key inclusion criteria include confirmed ES-SCLC; no prior systemic treatment for ES-SCLC; and eligibility to receive platinum/etoposide chemotherapy + anti-PD-L1 antibodies. Key exclusion criteria include previous Tx with DLL3-targeting TcEs; persistent, unresolved toxicity from previous Txs; immunodeficiency, or systemic steroid or other immunosuppressive therapy ≤7 days prior to first dose of BI 764532; and significant cardio/cerebrovascular disease. Clinical trial information: NCT06077500 .

J-TAIL-2: A prospective, observational study of atezolizumab (atezo) combined with carboplatin and etoposide (CE) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) in Japan.

8092 Background: Atezo + CE is approved for the first-line treatment of ES-SCLC based on IMpower133 (IMp133; NCT02763579). Due to the limited data available in Japanese pts, J-TAIL-2 (NCT04501497) is evaluating the efficacy and safety of atezo + CE in Japanese pts in the clinical setting. Methods: Pts from Japan had ES-SCLC, were aged ≥20 y and were scheduled to start atezo + CE in clinical practice. The primary endpoint was 12-mo OS rate. Secondary endpoints included OS, PFS and safety. Efficacy and safety were evaluated in these subgroups: IMp133-unlike (e.g., ECOG PS 2-4, CNS metastases, history/complication of autoimmune or interstitial lung disease, previous treatment for ES-SCLC) vs IMp133-like (met IMp133 eligibility criteria), age <70 vs ≥70 y and geriatric score (G8) < median vs ≥ median. G8 was assessed in pts aged ≥70 y at baseline, with lower vs higher scores indicating poorer health status. Results: From Aug 21, 2020, to data cutoff (Feb 3, 2023), 403 pts were enrolled from 150 sites. Baseline characteristics are shown in the Table. In the efficacy analysis population (n=399), the 12-mo OS rate was 63.7% (95% CI: 58.6, 68.3), median OS (mOS) was 16.5 mo and mPFS was 5.1 mo. In the IMp133-unlike vs -like groups, mOS was 15.5 vs 19.1 mo (HR, 1.32; 95% CI: 0.98, 1.77) and mPFS was 4.8 vs 5.4 mo (HR, 1.14; 95% CI: 0.90, 1.45). In pts aged <70 vs ≥70 y, mOS was 17.9 vs 16.4 mo (HR, 1.18; 95% CI: 0.90, 1.55) and PFS was 5.1 vs 5.1 mo (HR, 1.07; 95% CI: 0.86, 1.33). The median G8 score was 12; in pts with a G8 score < median vs ≥ median, mOS was 11.1 vs 18.4 mo (HR, 1.95; 95% CI: 1.38, 2.77) and mPFS was 4.8 vs 5.2 mo (HR, 1.25; 95% CI: 0.94, 1.67). In the safety analysis population (n=400), treatment-related AEs occurred in 36.0% of pts, Grade (Gr) ≥3 AEs in 66.3% and Gr 5 AEs in 2.8%. Safety outcomes were similar for the IMp133-unlike vs -like and age <70 vs ≥70 y groups. In pts with a G8 score < median vs ≥ median, Gr ≥3 AEs occurred in 70.8% vs 63.5% of pts and Gr 5 AEs occurred in 5.2% vs 0.8% of pts. Conclusions: The efficacy and safety of atezo + CE in Japanese pts treated in clinical practice were consistent with those seen in IMp133. Subgroup analyses support the use of atezo + CE in pts who would have been ineligible for IMp133, although clinical outcomes favored the IMp133-like group. Efficacy and safety were similar for pts aged <70 vs ≥70 y but were worse for those with lower vs higher G8 scores, suggesting that this assessment may be a useful tool for therapeutic strategies. These data support the use of atezo + CE in Japanese pts with ES-SCLC, including in subgroups excluded from IMp133. Clinical trial information: NCT04501497 . [Table: see text]

Efficacy and safety of CalliSpheres drug-eluting beads for bronchial arterial chemoembolization combined with intravenous chemotherapy for extensive-stage small cell lung cancer.

e20137 Background: We aim to explore the efficacy and tolerability of Drug-Eluting Bead Bronchial Arterial Chemotherapy Embolization (DEB-BACE) combined with intravenous chemotherapy in the treatment of patients with initially diagnosed extensive-stage small cell lung cancer (SCLC). Methods: We collected data from 24 patients with extensive-stage small cell lung cancer who received DEB-BACE combined with intravenous chemotherapy (DEB-BACE-V) and initially diagnosed at our hospital between 2013 and 2022. Among them, nine patients received BACE combined with intravenous chemotherapy from the first-line (first-line DEB-BACE-V), ten patients from the third-line (third -line DEB-BACE-V), and five patients from the second-line (second -line DEB-BACE-V). Then, the treatment response (objective response rate and rate of cancer regression) and tumor marker levels were evaluated at the first month and third month after treatment. The quality of life was assessed using the EORTC QLQ-C30 scale. Overall survival (OS) was also evaluated. First, compare the first-line DEB-BACE-V group with the second-line DEB-BACE-V group. Then, compare the first-line DEB-BACE-V group with third-line DEB-BACE-V group. Lastly, compare the second-line DEB-BACE-V group with the third-line DEB-BACE-V group. Results: In initially diagnosed extensive-stage SCLC patients treated with DEB-BACE combined with intravenous chemotherapy, first and third month post treatment, the objective response rates were 58.33% and 79.17%, respectively; and the rates of cancer regression were 75% and 91.67%, respectively. In addition, the neuron-specific enolase (NSE) and progastrin-releasing peptide levels were reduced at the third and sixth month. Quality of life assessed by EORTC QLQ-C30 scale, which included subscales of general health status, functional domains, symptom domains, and single domains except for financial difficulty, was markedly improved in first and third month of post treatment. Adverse reactions were mild and manageable, the most common being chest pain and low fever. Median values of OS in first-line DEB-BACE-V, second -line DEB-BACE-V and third -line DEB-BACE-V were 15.7 (95% CI: 9.1595-20.759) months, 29.63 (95% CI: 20.5684-36.268) months 16.92 (95% CI: 10.4044-21.871) months, and respectively. Conclusions: Due to its favorable therapeutic response, quality of life, survival benefits, and safety profile, DEB-BACE combined with intravenous chemotherapy may become a treatment option for patients with extensive-stage SCLC, particularly as second-line therapy.

Real world outcomes of patients with small cell lung cancer (SCLC) presenting with brain metastasis at diagnosis in a single institution health system.

e20136 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive lung cancer subtype with high propensity for brain metastases (mets). Despite this, there is no consensus on the treatment of brain mets especially in the setting of frontline chemoimmunotherapy and advanced radiation techniques like Gamma Knife radiosurgery (GKRS). Methods: In this single-institution retrospective study, we queried the Yale Tumor registry for all patients diagnosed with ES-SCLC in 1/2016-4/2023. Patients with brain mets at the time of presentation were identified and underwent manual chart review for abstraction of clinical information specifically pertaining to brain mets and treatment modalities. Survival outcomes including median progression free survival (mPFS), median central nervous system-progression free survival (mcPFS) and median overall survival (mOS) measured in months were also captured. Results: 423 ES-SCLC patients were identified. Of those, 92 (22%) had brain mets at initial presentation and were reviewed. 44 (48%) of patients with brain mets were treated with frontline chemotherapy (platinum doublet) while 42 (46%) were treated with chemoimmunotherapy (platinum doublet with atezolizumab or durvalumab). Patients treated with upfront chemotherapy had mPFS 6.4 (95% CI -1.2, 14.1), mcPFS 7.7 (95% CI -1.2, 17.1), and mOS 9.3 (95% CI -13.7, 36.4), compared to patients treated with chemoimmunotherapy, who had mPFS 4.9 (p=0.23; 95% CI -3.5, 15.4), mcPFS 6.7 (p=0.99; 95% CI 3.3, 20.8), and mOS 7.7 (p=0.89; 95% CI -11.4, 33.9). 63 (68%) of patients underwent upfront brain radiation. 44 (48%) had whole brain radiation (WBRT) while 19 (30%) underwent GKRS. Of the patients undergoing GKRS, 8 (42%) were symptomatic. 7 patients (37%) presented with 1 brain met, and 12 (63%) patients presented with 2-5 brain mets. For patients treated with GKRS, mPFS 6.8 (95% CI 2.3, 10.4), mcPFS 7.2 (95% CI 2.9, 12.6), and mOS 11.1 (95% CI -13.0, 40.9). For patients undergoing WBRT, mPFS 6.5 (p = 1.0; 95% CI -4.5, 20.2), mcPFS 6.5 (p = 0.96; 95% CI -3.9, 21.6), and mOS 8.6 (p = 0.21; 95% CI -17.7, 39.9). Conclusions: GKRS is a viable option for SCLC patients presenting with brain metastases, especially in those with a low number of mets. Further studies are required to determine the optimal ES-SCLC candidates for upfront GKRS. [Table: see text]

Overall survival of adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line treatment for extensive-stage small cell lung cancer.

8014 Background: The phase 3 trial (CAPSTONE-1) showed that adebrelimab (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival (OS) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC). Previous studies have shown that radiotherapy can enhance the immunogenicity of tumors, indicating the great potential of combining radiotherapy with immunotherapy. The purpose of this study was to explore the efficacy and safety of adebrelimab combined with chemotherapy and sequential thoracic radiotherapy (TRT) as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts 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). Pts with response sequentially received adebrelimab combined with consolidate TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation). Pts then entered the maintenance treatment stage with adebrelimab until disease progression or intolerable side effects. The primary endpoint was OS. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to April 2023, 67 pts with ES-SCLC were enrolled. Most patients were male (83.6%), current or former smokers (65.7%) with an ECOG performance status of 1 (95.5%). 22 (32.8%) patients were diagnosed with brain metastasis and 21 (31.3%) patients had liver metastasis at baseline. 45 patients received sequential TRT as planned. All patients were included in the safety and efficacy analysis population. At data cutoff (December 22, 2023), the median follow-up duration was 17.7 months. The median OS was 21.4 months (95% CI: 17.2–not reached months). 1-year and 2-year OS rate were 74.1% (95% CI: 63.6-86.4%) and 39.7% (95% CI: 25.5-61.9%). The median PFS was 10.1 months (95% CI: 6.9–15.5 months). The confirmed ORR was 71.6% (95% CI: 59.3-82.0%) and DCR was 89.6% (95% CI: 79.7-95.7%). The most common grade 3 or higher treatment-related adverse events included neutrophil count decreased (41.8%), white blood cell count decreased (19.4%) and lymphocyte count decreased (13.4%). No unexpected adverse events were observed. Conclusions: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Clinical trial information: NCT04562337 .

Surufatinib plus PD-1/L1 inhibitors as maintenance therapy following first line (1L) platinum-based chemotherapy combined with PD-1/L1 inhibitors in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC).

e15109 Background: Pts with ES-SCLC have a poor prognosis. PD-1/L1 inhibitors combined with chemotherapy as 1L treatment has been demonstrated to improve the survival. Yet, pts are prone to progression after chemo-immunotherapy followed by anti-PD-1/L1 monotherapy. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) combined with PD-1/L1 inhibitors in pts with ES-SCLC as 1L maintenance therapy. Methods: Key inclusion criteria were cytologically or pathologically confirmed ES-SCLC, ECOG PS 0-1, no disease progression after 4-6 cycles platinum-based chemotherapy combined with PD-1/L1 inhibitors. Enrolled pts received surufatinib (250mg, po, QD) plus PD-1/L1 inhibitors (same as that in prior 1L therapy: Durvalumab, Sintilimab, Toripalimab or Serplulimab) until disease progression or intolerable toxicity. The primary endpoint is progression free survival (PFS) per RECIST 1.1 by investigator. Results: From Sept 2022 to July 2023, 21 pts were enrolled. The median age was 62 years. 90.5% were male, 85.7% were former and current smokers and 52.4% had ECOG PS of 0, 11 pts completed 6 cycles of platinum-based chemotherapy combined with PD-1/L1 inhibitors, and 12 pts received durvalumab in 1L therapy. As of 20 Nov, 2023, the median follow-up duration was 9.2 months. Objective response rate (ORR) was 14.3% and DCR (disease control rate) was 71.4%. The mPFS of 1L maintenance therapy was 4.0 months (95%CI: 2.0-5.6). The mPFS from 1L treatment to disease progression was 8.7 months. mOS was not reached, with 3 mo- , 6 mo- and 9 mo- OS rate was 100%, 94.4% and 75.6%, respectively. 21 (100%) pts experienced treatment-emergent adverse events (TEAEs), and 8 (38.1%) pts experienced grade ≥3 TEAEs, most commonly with platelet count decreased, neutrophil count decreased and pneumonia. There was no treatment-related death. Conclusions: Surufatinib combined with PD-1/L1 inhibitors showed encouraging efficacy and tolerable safety profile as 1L maintenance therapy. Further OS follow-up is warranted. Clinical trial information: NCT05509699 .

Outcome of chemo-immunotherapy for extensive-stage small-cell lung cancer according to potential clinical trial eligibility: 3-year outcomes from prospective cohort study.

8087 Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small-cell lung cancer (ES-SCLC). Our large previous real-world prospective analysis showed outcomes of chemo-immunotherapy for these patients according to potential clinical trial eligibility with a minimum follow-up period of 1 year. However, long-term outcomes have not been studied in the real-world setting. Methods: We conducted a 32-hospital prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered “trial-eligible.” We present 3-year outcomes from this study. Results: In total, 207 patients with ES-SCLC were analyzed. The median (range) time from the start of treatment to data cutoff (September 30, 2023) was 42.2 (35.8.-48.2) months. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) were categorized as trial-eligible patients. The 3-year PFS and OS probability of all patients was 6.1 % (95%CI:3.5-10.4%) and 20.9 % (95%CI:15.6-27.3%), respectively. Patients achieving 3-year OS included significantly higher proportions of trial-eligible patients (30 out of 132 versus 5 out of 75, respectively; p = 0.002). Kaplan-Meier estimates of the 3-year OS rate were 26.7% for the trial-eligible group and 9.5 % for the trial-ineligible group. Conclusions: This is the first real-world study to show the long-term efficacy of chemo-immunotherapy for ES-SCLC by using the largest prospective cohort of its kind. Additionally, this study demonstrated that trial eligibility was associated with long-term efficacy. Our study suggests that long-term clinical outcomes among trial-eligible patients may not translate to ineligible patients.

Serplulimab vs. placebo combined with chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: Extended follow-up results and patient-reported outcomes from the international phase 3 ASTRUM-005 study.

8100 Background: ASTRUM-005 is a randomized, double-blind, phase 3 trial comparing efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus chemotherapy (chemo) vs. placebo plus chemo as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). Interim analysis presented at 2022 ASCO Annual Meeting showed significantly prolonged overall survival (OS) in the serplulimab arm. Continuing improvements were seen in all efficacy endpoints in an updated analysis reported at ESMO Asia Congress 2022. Here we present the updated results with an extended follow-up duration of 31.6 months and the previously undisclosed patient-reported outcomes (PROs). Methods: 585 patients with ES-SCLC who had not received prior systemic therapy were randomized 2:1 (serplulimab arm, n = 389; placebo arm, n = 196) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received up to 4 cycles of intravenous carboplatin and etoposide every 3 weeks. Stratification factors were PD-L1 expression level, brain metastases, and age. The primary endpoint was OS. PROs were assessed using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires. Results: By the data cutoff of June 13, 2023, 267 (68.6%) patients in the serplulimab arm and 160 (81.6%) in the placebo arm had died. Median OS was markedly longer in the serplulimab arm than that in the placebo arm (15.8 vs.11.1 months; stratified HR 0.61, 95% CI 0.50–0.74). Subgroup analysis by race showed similar trends of a prolonged median OS in Asians (unstratified HR 0.61, 95% CI 0.48–0.77) and non-Asians (all were White; unstratified HR 0.57, 95% CI 0.39–0.83). Estimated OS rate at 3 years was 24.6% (95% CI 19.5–30.1) and 9.8% (95% CI 5.6–15.4) in the respective arms. By-visit longitudinal changes in all domains of the 3 questionnaires were comparable between arms. Least square mean (LSM) changes from baseline to week 18 in QLQ-C30 functional and symptom domains, QLQ-LC13 symptom domains, and EQ-5D-5L VAS were similar and generally improved in both arms, with more pronounced and persistent amelioration in “pain in other parts” symptom domain for the serplulimab arm (difference in LSM change, −6.37 [95% CI −11.59 to −1.15], p = 0.0170). Time to deterioration was similar between arms: median, not reached (NR) vs. NR for global health status/quality of life (HR 0.90, 95% CI 0.59–1.39), physical functioning (HR 1.01, 95% CI 0.61–1.65), and role functioning (HR 1.17, 95% CI 0.74–1.87). Conclusions: With extended follow-up, the survival benefits brought by the addition of serplulimab were maintained in the first-line therapy of ES-SCLC. PROs were not adversely impacted, and pain in other parts was significantly improved. All these results support serplulimab plus chemo as a promising first-line treatment option for ES-SCLC. Clinical trial information: NCT04063163 .

A phase II exploratory trial of adebrelimab in combination with chemotherapy and concurrent radiotherapy as a first-line treatment for oligo-metastatic extensive-stage small-cell lung cancer.

TPS8131 Background: Oligometastasis of extensive-stage small-cell lung cancer (ES-SCLC) is an intermediate state between local and extensive metastasis, characterized by reduced metastatic potential and a limited number of metastatic sites, which makes local treatment of each lesion possible. Multiple clinical studies have shown that adding local therapy to standard systemic therapy can improve the prognosis of patients with oligometastatic disease. The PD-L1 inhibitor adebrelimab combined with chemotherapy has become one of the standard regimens for first-line treatment of ES-SCLC. Based on these, we hypothesize that in patients with oligometastatic ES-SCLC at risk of early progression, the early addition of chest radiotherapy and stereotactic radiotherapy (SBRT) for metastatic lesions to first-line treatment with adebrelimab combined with chemotherapy may be expected to achieve local control, thereby improving survival benefits. Methods: This is a prospective, single-arm, multicenter, phase II exploratory trial. Patients will be eligible if they are 18 to 75 years of age; have histopathologically or cytologically confirmed ES-SCLC with the number of metastatic lesions of ≤ 5 and organ metastasis of ≤ 3 (i.e. oligometastases); have an ECOG PS of 0-1; and have no previous systemic treatment. The treatment period in this trial is subdivided into induction therapy, concurrent chemoradiotherapy, and consolidation and maintenance therapy. In the induction setting, patients will receive two 3-week cycles of adebrelimab (20 mg/kg on day 1), carboplatin (AUC of 5 mg/mL per min on day 1)/cisplatin (75 mg/m2 on day 1), and etoposide (100 mg/m2 on days 1-3). Patients who achieve partial response or stable disease after induction therapy will then receive concurrent chemoradiotherapy, of which chemotherapy regimen is the same as the induction setting. Radical IMRT radiotherapy (2.5-3 Gy/f, total dose 45-55 Gy) will be performed for the primary tumor in the chest and lymph node region, and SBRT radiotherapy will be given to metastatic lesions. Prophylactic cranial irradiation is optional. After the end of chemoradiotherapy, patients will receive 1-2 cycles of consolidation treatment with the same regimen as induction treatment, followed by adebrelimab monotherapy (20 mg/kg on day 1, q3w) as maintenance treatment until disease progression, intolerance toxicity, or up to 2 years of adebrelimab. The total cycle number of chemotherapy is 4-6. The primary endpoint is progression-free survival (PFS), and secondary endpoints are objective response rate, duration of response, overall survival (OS), 6-month and 1-year PFS rates, 1-year and 2-year OS rates, and safety. The trial is under recruitment, and a total of 62 patients are planned to be enrolled. Clinical trial information: NCT06177925 .

First-line sintilimab combined with platinum-based chemotherapy in extensive stage small cell lung cancer: A phase II study and post-hoc biomarker analysis.

e20127 Background: Immune checkpoint inhibitors (ICIs) combined with etoposide and platinum-based chemotherapy improves prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC). However, nearly 40% of patients do not benefit from Immunochemotherapy. Herein, this phase II study of first-line immunochemotherapy was conducted aiming to investigate potential biomarkers associated with therapeutic efficacy. Methods: A multi-center, single-arm, prospective phase II trial (ChiCTR2000038354) was designed and conducted to evaluate the efficacy and safety of sintilimab combined with platinum-based chemotherapy in patients with ES-SCLC who had not previously received treatment. The primary endpoint of this study is progression-free survival (PFS), with patients being defined as disease progression according to RECIST 1.1. Pre-treatment FFPE samples were analyzed using whole exome sequencing (WES) and whole transcriptome sequencing (WTS) to investigate biomarkers. Results: A total of 44 patients were included in the study, with a median follow-up of 10 months and a median PFS of 7.57 months. 8 patients with a PFS greater than 6 months were defined as the responder group (R group) and 5 patients with a PFS less than 6 months belonged to the non-responder group (NR group). WES and WTS were performed on the pre-treatment samples of these 13 patients. WES results revealed mutation frequencies of TP53 (69%), RB1 (31%) and FAT1 (31%) aligning with prior research. Significantly, ZFHX4 mutations correlated with R group (p = 0.05). Genomic instability, as defined by Homologous Recombination Deficiency (HRD) scores, displayed higher scores in NR group than in R group (p = 0.023), which suggests potential benefits of PARP inhibition in the NR group. WTS data revealed that higher M2/M1 macrophage ratio (p = 0.028) in NR group. Additionally, the NR group demonstrated significant VEGFA overexpression. Besides, NOTCH-signaling (p = 0.034), KRAS-signaling-DN (p<0.001), Angiogenesis (p<0.001) and EMT (p<0.001) pathway were also enriched in NR group. Conversely, M1 macrophages (p = 0.079), CD4+T cells (p = 0.093), Mast cells (p = 0.045), NK cells (p = 0.045) and neutrophils (p = 0.06) was higher in R group. Conclusions: This study highlights genomic instability as well as activation of cancer hallmarks such as angiogenesis, EMT may result the resistance to immunotherapy in ES-SCLC patients. These findings may shed light on combinational strategy overcoming therapeutic resistance. Clinical trial information: ChiCTR2000038354.

Camrelizumab combined with chemotherapy followed by maintenance camrelizumab and apatinib as first-line therapy for extensive-stage small cell lung cancer: A phase II, single-arm, exploratory study.

e20107 Background: Extensive-stage small-cell lung cancer (ES-SCLC), a type of aggressive tumor known as with limited therapeutic options and poor prognosis in the past decades, had recently been proved curatively effective by the combination of immune checkpoint inhibitor and platinum-based chemotherapy. Nonetheless, it is still worthy and necessary to explore the new treatment pattern considering the rapid disease progression feature of ES-SCLC. Whereupon, this study aims to explore the effectiveness and safety of camrelizumab combined with chemotherapy followed by maintenance camrelizumab and apatinib in the first-line treatment of ES-SCLC. Methods: In this phase II study, 40 patients with pathological diagnosis of ES-SCLC and without receiving prior systemetic therapy are anticipated to be enrolled, and will be dosed camrelizumab (200 mg, iv, q3w) combined with etoposide (80-100 mg/m2, iv, q3w, 4-6 cycles) and platinum drugs (selected by the researcher accordingly, iv, q3w, 4-6 cycles), followed by maintenance with camrelizumab and apatinib (250 mg, qd). The primary endpoint is 6-month progress-free survival (6-month PFS) rate while the secondary endpoints are objective response rate (ORR), disease control rate (DCR), progression-free survival, overall survival and safety. Results: Up to January 24, 2024, 31 patients with a median age of 60 years (ranged from 38 to 75 years of age) were enrolled. Among them 28 patients out of 31 were capable for efficacy analysis, of which 23 patients achieved partial response, 3 had stable disease and 2 progressive disease. The ORR and DCR reached 82.14% and 92.86%, respectively. The 6-month PFS rate in evaluable patients was 75.44% and the median PFS was and 7.56 months. The median OS was 15.38 months. During the course of therapy, the grade 3 or worse treatment-related adverse events were hypertension (6.45%), increased ALT level(3.26%), increased AST level(3.26%), increased γ-GT(3.26%)and hypertriglyceridemia (3.26%). Common grade 1-2 adverse reactions included anemia(54.84%), nausea (54.84%), vomiting(45.16%). The treatment was well tolerated and no toxic death occurred. All the adverse events can be controlled and alleviated after symptomatic treatment. Conclusions: Camrelizumab with chemotherapy followed by maintenance camrelizumab plus apatinib showed preliminary efficacy and acceptable safety profile, and might be a promising regimen as first-line treatment in ES-SCLC. Clinical trial information: ChiCTR2000035599.

Results of a phase III clinical trial with anti-PDL1 treatment in combination with chemotherapy for extensive stage small cell lung cancer.

8095 Background: In China, small cell lung cancer (SCLC) accounts for over 15% of lung cancers. The morbidity of SCLC has been continuously increasing. SCLC is invasive, fast-growing cancer that distinctly differs from other cancers. Approximately 70% of cases present with metastasis at diagnosis and the median overall survival rate is about 8 to 11 months with a 5-year survival rate of less than 5%. Although being sensitive to chemotherapy and radiotherapy, SCLC patients are liable to relapse and often present with drug resistance. Here we study the combination of Socazolimab, an anti-PDL1 antibody, carboplatin and etoposide to treat extensive stage small cell lung cancer. Methods: The study is a randomized, double-blinded, placebo-controlled multicenter Phase III clinical trial. Patients who have extensive-stage SCLC are eligible to the trial. Patients are randomly assigned to the study group (Socazolimab + carboplatin + etoposide) or control group (placebo + carboplatin + etoposide) at 1:1 ratio, with a treatment cycle of every 3 weeks. There are 4 cycles of chemotherapy followed by Socazolimab or placebo alone until termination events occurred or for up to 2 years. The primary endpoint is overall survival (OS). The major secondary endpoint is progression free survival (PFS). Results: There were a total of 498 patients recruited for the study with average age of 61.9 amount which 449 patients were diagnosed with stage IV SCLC. All the analysis was based on intent-to-treat (ITT). The median baseline performance status score was 1.0. The median OS of study group and control group are 13.90 months (95% CI: 12.22-15.34) and 11.58 months (95% CI: 10.64-12.81) respectively, with a P-value of 0.0316. The 24 month survival rate of study group and control group are 20.7% (95% CI:14.8-27.3) and 5.9 %(95% CI: 0.8-18.9). The median PFS of the two groups are 5.55 months (95% CI:5.06-5.82) and 4.37 months (95% CI: 4.27-4.70) with a P-value < 0.0001. The treatment related adverse event were similar in both groups. Conclusions: These results show that Socazolimab plus chemotherapy continued to provide clinically meaningful improvements in OS for patients with extensive stage small cell lung cancer. Clinical trial information: NCT04878016 .

ARTEMIS-001: Data from a phase 1a/b study of HS-20093 in patients with relapsed small cell lung cancer (SCLC).

8093 Background: SCLC is characterized by a high rate of proliferation and poor prognosis, and new therapies are urgently needed. B7-H3 is highly expressed in SCLC. HS-20093, a B7-H3-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity in advanced solid tumors in the dose escalation part of ARTEMIS-001 study (Jie Wang et al., JCO, 2023) (NCT05276609). Here, we present results on the efficacy and safety of the expansion doses in patients (pts) with SCLC from phase 1a/b. Methods: ARTEMIS-001 study consisted of dose escalation (1a) and expansion (1b) part. Pts were treated with doses of 1.0 to 16.0 mg/kg HS-20093 every 3 weeks in dose escalation, and were treated with doses at 8.0 mg/kg and 10.0 mg/kg randomly in dose expansion. Pts with SCLC were required to have received prior platinum-based standard therapy. B7-H3 expression was retrospectively evaluated by IHC. Results: As of data cutoff November 30th 2023, a total of 56 pts with extensive stage SCLC (ES-SCLC) were enrolled and received ≥1 dose of HS-20093 with doses at 8.0 mg/kg (n=31) or 10.0 mg/kg (n=25). Median prior lines of therapy was 2.0 (range: 1-6). All pts received platinum plus etoposide and 73.2% (41/56) received immunotherapy. Safety profile was consistent with previous reports. The most common grade≥3 treatment-related adverse events (≧10%) were neutropenia, leukopenia, lymphopenia, thrombocytopenia and anemia. Out of 56 pts, 52 pts were efficacy evaluable (8.0 mg/kg: 31 pts; 10.0 mg/kg: 21 pts). HS-20093 showed encouraging efficacy in relapsed ES-SCLC (Table). Tumor shrinkage in target lesions occurred in 96.2% (50/52) pts with a post-baseline scan. Deep response defined as tumor shrinkage ≥50% was obtained in 44.2% (23/52) pts. Median overall survival has not yet reached. Responses were observed regardless of B7-H3 expression. Pharmacokinetic (PK) showed approximately dose-proportional increase in exposure with a half-life of 3-7 days. PK profiles of total antibody and ADC were similar and exposure to payload was considerably low. Conclusions: HS-20093 demonstrated promising antitumor activity and manageable safety in pts with previously-treated SCLC. Phase 3 study is planned to compare the efficacy and safety of HS-20093 with standard-of-care chemotherapy in relapsed SCLC. Clinical trial information: NCT05276609 . [Table: see text]

Neoadjuvant chemoimmunotherapy in patients with limited-stage small cell lung cancer: A retrospective study.

e20002 Background: The addition of immune checkpoint inhibitors to chemotherapy significantly improves survival in extensive-stage small cell lung cancer (SCLC) and represents a promising advance in this field. However, the clinical benefit of the implementation of immunotherapy in the first-line setting for limited-stage SCLC (LS-SCLC) remains to be proven. Thus, we conducted a retrospective study to explore the efficacy of neoadjuvant chemoimmunotherapy as a first-line treatment for LS-SCLC. Methods: A retrospective study of patients with LS-SCLC who were treated with neoadjuvant PD-L1/PD-1 inhibitor combined with platinum-based chemotherapy followed by surgery between February 2020 and September 2023 was conducted. Clinical characteristics, R0 resection rate, pathologic complete response (pCR), major pathologic response (MPR), downstaging rate and disease-free survival (DFS) were evaluated. Results: As of September 30, 2023, all 21 patients (stage IIB, n = 4; stage IIIA, n = 9; stage IIIB, n = 8) received 2 to 6 cycles of neoadjuvant chemoimmunotherapy (Table 1). Nine (42.9%) patients achieved pCR and 10 (47.6%) presented an MPR (Table 2). Moreover, the R0 resection rate in total and stage III patients were 95.2% (20/21) and 94.1% (16/17), respectively. After a median follow-up of 11.2 months (range: 2.6-24.2), only two patients relapsed and the median DFS was not reached due to insufficient events. Conclusions: Neoadjuvant immune checkpoint inhibitors combined with chemotherapy demonstrated promising efficacy and feasibility, and are a potential strategy for the management of LS-SCLC. Further prospective clinical trials are necessary to clearly define the benefit of neoadjuvant chemoimmunotherapy and optimize LS-SCLC treatment. [Table: see text][Table: see text]

Survival outcomes of patients with extensive-stage small cell lung cancer who received treatment with atezolizumab in combination with carboplatin and etoposide: A propensity score adjusted cohort study.

8096 Background: Small cell lung cancer (SCLC) is an aggressive type of lung cancer. Most patients (pts) are diagnosed with extensive-stage disease (ES-SCLC). The cornerstone treatment of ES-SCLC has been platinum-based chemotherapy and etoposide. Combining atezolizumab with carboplatin plus etoposide (Carbo-E) improved overall survival (OS) in ES-SCLC pts and became a new standard for first-line treatment. However, there is a paucity of real-world outcomes in ES-SCLC. Herein, we present the largest and longest follow-up retrospective study analyzing atezolizumab in combination with chemotherapy for treatment of ES-SCLC. Methods: We conducted a retrospective study and included all adult pts (≥ 18 years) with ES-SCLC treated at Cleveland Clinic between 1/2010-12/2022. ES-SCLC was defined as stage IIIB or stage IV. We collected treatment regimens and baseline characteristics including age, sex, race, smoking, alcohol intake history, and comorbidities. Responses were assessed using RECIST response criteria. Both OS and progression-free survival (PFS) were calculated from treatment initiation. We used propensity score (PS) weighting and multivariable Cox proportional hazards ratio (CPH) to adjust for baseline confounding. Results: We identified 561 ES-SCLC pts who received treatment, 375 (67%) received Carbo-E and 160 (29%) received Carbo-E + Atezolizumab (Carbo-E-Atezo). The table describes the baseline characteristics of Carbo-E and Carbo-E-Atezo groups. The median follow-up was 30 months (mo) (IQR: 14 - 59). In the Carbo-E arm, 45 patients (12%) received second-line immune therapy (nivolumab +/- ipilimumab or pembrolizumab). On PS-adjusted logistic regression, pts who received Carbo-E-Atezo had a 1.1 odds ratio (95%CI: 0.85-1.43, P>0.05) to respond compared to pts who received Carbo-E. There was no difference in PS-adjusted median OS between pts who received Carbo-E-Atezo (9.2 mo (95%CI: 8.1-11)) vs. Carbo-E (8.4 mo (95%CI: 7.7-9.0)) (log-rank P>0.05). Similarly, there was no difference in adjusted median PFS between pts who received Carbo-E-Atezo (5.9 mo (95%CI: 5.3-6.9)) vs. Carbo-E (5.5 mo (95%CI: 4.7-5.9)) (P>0.05). Using CPH model, the addition of atezolizumab to Carbo-E did not decrease mortality (Hazard Ratio: 0.84, 95%CI: 0.68-1.04, P>0.05). Male gender and increasing age were predictors of worse OS (P<0.05). Conclusions: Among pts with ES-SCLC, the addition of atezolizumab to the standard chemotherapy regimen of Carbo-E showed no significant difference in PFS or OS in our real-world study. [Table: see text]

Second-line treatment outcomes following first-line chemotherapy plus immunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC): A multicenter study.

Second-line treatment outcomes following first-line chemotherapy plus immunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC): A multicenter study.

Preliminary results of a randomized controlled, open-label, multi-center phase II study of camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy and camrelizumab consolidation therapy versus standard chemoradiotherapy as first-line treatment for limited-disease small cell lung cancer.

e20132 Background: Immune checkpoint inhibitors combined with chemotherapy have significant clinical benefits in extensive-stage small cell lung cancer (SCLC). However, for patients with limited-disease SCLC (LD-SCLC), the data on immunotherapy combined with chemoradiotherapy is insufficient. Methods: In this open-label, multi-center, phase 2 trial, we randomly 1:1 assigned patients with previously untreated LD-SCLC to receive camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy (CCRT) and camrelizumab consolidation therapy or standard chemoradiotherapy. Patients with ECOG performance status of 0 to 1, and adequate organ function were eligible. For thoracic radiation, 45 Gy in 3 weeks (1.5 Gy, BID) was given on the first day of the third cycle of chemotherapy. An etoposide plus platinum-based regimen was given 4 cycles in total. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 1-year progression-free survival rate. We assumed that the 1-year PFS rate in the experimental group was expected to reach 65% compared to chemoradiotherapy alone group 45%, and planned to enroll 112 patients with 56 in each group. Results: Up to date, we have enrolled 40 patients. The median follow-up was 10.6 months. Safety was evaluated in all treated patients. No Grade 5 adverse event was observed. Grade 3 or 4 treatment-related adverse events occurred in 58.8% of the patients in the camrelizumab plus chemoradiotherapy and in 52.9% of those in the chemoradiotherapy alone group. The most frequent grade 3 or 4 adverse events were hematologic toxicities (70.6% vs. 58.8%). Acute esophagitis and pneumonitis of grade 3 occurred in both groups were 1/17 (5.9%) and 1/17 (5.9%), respectively. In the experimental group, only one patient was developed grade 3 immune pneumonia 1/17 (5.9%). The 1-year PFS rate was 54.5% (95% confidence interval [CI] 19.5%-89.6%) with camrelizumab plus chemoradiotherapy and 44.4% (95% CI 3.9%-88.0%) with chemoradiotherapy alone. Among the 17 patients who received camrelizumab, the median PFS time was not reached, as compared with 14.35 (95% CI, 8.15-20.91) months among the 17 patients with chemoradiotherapy alone. Conclusions: In patients with LD-SCLC, the addition of camrelizumab to chemoradiotherapy did not increase the incidence of adverse events. Camrelizumab plus chemoradiotherapy resulted in an encouraging 1-year PFS rate. Larger sample sizes and longer follow-up times are required to validate our preliminary results. Clinical trial information: ChiCTR2000032275.

Correlation between multiorgan immune-related adverse events and clinical outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with chemo-immunotherapy.

Correlation between multiorgan immune-related adverse events and clinical outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with chemo-immunotherapy.

PD-(L)1 inhibitors plus anlotinib: A superior option for second-line treatment of extensive-stage small cell lung cancer.

PD-(L)1 inhibitors plus anlotinib: A superior option for second-line treatment of extensive-stage small cell lung cancer.