Atezolizumab plus platinum-based chemotherapy and etoposide as first-line treatment for metastatic small cell lung cancer: A retrospective multicenter observational study.

Atezolizumab plus platinum-based chemotherapy and etoposide as first-line treatment for metastatic small cell lung cancer: a retrospective multicenter observational study.

Background: ZL-1310, a novel antibody-drug conjugate (ADC) targeting delta-like protein 3 (DLL3) with a camptothecin derivative as its payload via a protease-cleavable linker, employs TMALIN® (Tumor Microenvironment Activable LINker-payload) ADC technology platform. DLL3, an inhibitory Notch pathway ligand and a validated target for directed therapy, is highly expressed in more than 80% of patients with small cell lung cancer (SCLC) and also has variable expression in other neuroendocrine (NE) tumors. There remains an unmet medical need for 2nd-line SCLC, as the standard of care chemotherapy has a modest response rate of ~25%. ZL-1310 is designed to minimize payload toxicity and improve anti-tumor effectiveness. Methods: This is an open-label, multiple-dose, phase 1 study of ZL-1310 administered to subjects with relapsed/refractory (r/r) metastatic SCLC who have progressed after at least one platinum-based chemotherapy regimen. The study consists of two parts: Part 1 (dose escalation) and Part 2 (dose expansion). In Part 1, the Bayesian optimal interval (BOIN) design is employed for dose escalation, while in Part 2, patients will be randomized into two cohorts with different doses of ZL-1310 to further define safety and preliminary antitumor activity. The major inclusion criteria are as follows: (1) Subjects must have histologically or cytologically confirmed metastatic or extensive-stage SCLC with no more than 3 prior regimens in the r/r setting. (2) Subjects must have at least one measurable target lesion as defined by RECIST v1.1. (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The major exclusion criteria include: (1) Prior exposure to DLL3-targeted therapy. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections.Part 1 Dose Escalation is recruiting subjects in the US and China. Citation Format: Afshin Dowlati, Alexander Spira, Xiaodong Shen, Yinjia Fu, Yiyuan Pan, Linda Liu, Renke Zhou, Yi-Long Wu. Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT155.

Nivolumab showed durable responses in patients with small cell lung cancer (SCLC). A randomized phase II study investigating nivolumab plus cisplatin/carboplatin and etoposide (PE) versus PE for patients with untreated extensive-stage (ES) SCLC was conducted. Patients with untreated ES-SCLC, Eastern Cooperative Oncology Group performance status 0-1, were randomized 1:1 to nivolumab 360 mg intravenously (IV) plus cisplatin 75 mg/m2 or carboplatin area under the curve 5 on day 1 and etoposide 100 mg/m2 (PE) on days 1-3 every 21 days for four cycles followed by nivolumab 240 mg intravenously (arm A) every 2 weeks on a 6-week cycle for up to 2 years or PE alone (Arm B) for 4 cycles followed by observation. The primary endpoint was progression-free survival (PFS). The primary comparison of PFS used a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Overall, 160 patients were enrolled; 144 patients were treated and constituted the primary analysis. The median PFS was 5.5 months (95% confidence interval [CI], 4.3-5.9 months) on arm A, and 4.9 months (95% CI, 4.5-5.7 months) on arm B (hazard ratio, 0.78; p=.083). The estimated median OS was 11.2 months (95% CI, 8.8-14.2 months) on arm A and 8.1 months (95% CI, 7.2-9.6 months) on arm B (hazard ratio, 0.71; p=.059). The combination of PE and nivolumab improves both PFS and OS for patients with ES-SCLC. No new safety signals were observed.

Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Extensive-stage small cell lung cancer (ES-SCLC) in older adults is associated with poor outcomes, and optimal management in this population remains challenging. This study aimed to identify clinical and treatment-related factors associated with survival in patients aged ≥70 years with ES-SCLC. A retrospective multicenter cohort study included 135 older adults (aged ≥70 years) diagnosed with ES-SCLC across 3 tertiary centers. All patients received at least 1 cycle of platinum–etoposide–based chemotherapy. Demographic, clinical, and treatment variables – including metastatic sites, number of chemotherapy cycles, thoracic radiotherapy (TRT), prophylactic cranial irradiation, and palliative radiotherapy to extracranial metastases – were collected. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors for progression-free survival and overall survival (OS) were evaluated using Cox proportional hazards regression models. The median age was 73.2 years; 88.1% of patients were male. The objective response rate was 69.9%. Median progression-free survival and OS were 7.1 and 8.3 months, respectively (95% CI: 6.09–8.17 and 7.67–8.93). In multivariate analysis, Eastern Cooperative Oncology Group performance status ≥2 (P <.001), liver metastases (P = .006), fewer than 4 chemotherapy cycles (P <.001), absence of prophylactic cranial irradiation (P = .028), and lack of palliative radiotherapy to extracranial metastases (P <.001) were independently associated with shorter OS. TRT did not retain statistical significance in multivariate analysis. Only 34.1% of patients received second-line therapy. The 1-year and 2-year OS rates were 33% and 12%, respectively. Fit older adults (Eastern Cooperative Oncology Group performance status 0–1) may derive meaningful survival benefit from multimodal treatment strategies. Treatment decisions should be individualized based on functional status rather than chronological age alone. Prospective studies incorporating comprehensive geriatric assessment are warranted.

Real-world effectiveness and safety of atezolizumab-carboplatin-etoposide regimen in extensive-stage small-cell lung cancer.

Translated article] Real-world effectiveness and safety of atezolizumab-carboplatin-etoposide regimen in extensive-stage small-cell lung cancer.

The current standard of care for the treatment of small cell lung cancer (SCLC) is concurrent chemoradiation for patients with limited-stage SCLC (LS-SCLC) and chemoimmunotherapy for extensive-stage SCLC (ES-SCLC). The backbone of chemotherapy regimens in both is a platinum-etoposide doublet: cisplatin is traditionally the preferred platinum agent in the curative intent setting, whereas carboplatin is preferred in ES-SCLC because of its favorable toxicity profile. To determine whether cisplatin is associated with better survival outcomes than carboplatin in treating LS-SCLC and ES-SCLC. In this cohort study, data were compiled from the National Veterans Affairs Central Cancer Registry for patients with SCLC who received platinum-based multiagent chemotherapy between 2000 and 2020 for ES-SCLC and 2000 and 2021 for LS-SCLC. Only patients with pathologically confirmed cases of LS-SCLC who received concurrent chemoradiation and ES-SCLC who received chemotherapy were included. The primary end point was overall survival (OS). The secondary end points included OS by Eastern Cooperative Oncology Group performance status, age, and laterality. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median OS and hazard ratios (HRs), respectively. Survival curves were compared by a Wald test. A total of 4408 SCLC cases were studied. Most patients were White (3589 patients [81.4%]), male (4252 [96.5%]), and non-Hispanic (4142 [94.0%]); 2262 patients (51.3%) were 60 to 69 years old, followed by 1476 patients (33.5%) aged 70 years or older, 631 patients (14.3%) aged 50 to 59 years, and 39 patients (0.9%) aged 30 to 49 years. Among 2652 patients with ES-SCLC, 2032 were treated with carboplatin-based therapy and 660 received cisplatin; the median OS was 8.45 months (95% CI, 7.75-9.20 months) for cisplatin and 8.51 months (95% CI, 8.07-8.97 months) for carboplatin (HR, 1.01; 95% CI, 0.91-1.12; P = .90). Subset analysis showed no survival difference between the 2 agents in different age or performance status groups except for patients aged 70 years and older, for whom the median OS was 6.36 months (95% CI, 5.31-7.56 months) for cisplatin and 8.47 months (95% CI, 7.79-9.19 months) for carboplatin (HR, 0.77; 95% CI, 0.61-0.96; P = .02). Multivariable analysis of performance status and age did not show a significant difference in survival between the 2 groups (HR, 0.96; 95% CI, 0.83-1.10; P = .54). Of 1756 patients with LS-SCLC, 801 received carboplatin, and 1018 received cisplatin. The median OS was 26.92 months (95% CI, 25.03-28.81 months) for cisplatin and 25.58 months (95% CI, 23.64-27.72 months) for carboplatin (HR, 1.04; 95% CI, 0.94-1.16; P = .46). The median OS was not significantly different between 2 agents according to cancer stage (I-III), performance status, and age groups. A multivariable analysis of factors associated with OS accounting for stage (I-III), performance status, and age did not demonstrate a significant difference in survival between carboplatin and cisplatin in patients with LS-SCLC (HR, 0.995; 95% CI, 0.86-1.15; P = .95). Cisplatin is not associated with a survival advantage over carboplatin among patients with either ES-SCLC or LS-SCLC, irrespective of performance status and age. The favorable toxicity profile of carboplatin and comparable OS support its use in both LS-SCLC and ES-SCLC in clinical practice and may allow more room for combination with novel treatment strategies in clinical trials.

e20574 Background: For a small subset of patients, immune checkpoint blockade heralds a promising strategy for achieving disease control in small cell lung cancer (SCLC). Nivolumab or pembrolizumab monotherapy has been granted accelerated approval for treatment of patients with extensive-stage SCLC with disease progression after platinum-based chemotherapy and at least one other line of therapy. Moreover, Based on IMpower133 and CASPIAN data, addition of PD-L1 antibody such as atezolizumab or durvalumab to first-line platinum-based chemotherapy prolongs overall survival over chemotherapy alone. However, it remains exclusive that whether PD-1/PD-L1 antibody combined with chemotherapy is effective against extensive-stage SCLC when progressed on previous chemotherapy. Methods: We reviewed patients with extensive-stage SCLC who have failed in first-line or beyond chemotherapy and received PD-1/PD-L1 antibodies with chemotherapy in a single institute. The efficacy and safety were evaluated. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 11 patients were included in this retrospective cohort study. The median age was 46 years (range from 29 to 62). Seven patients were male. Four were current or former smokers. Six received two prior therapies. Nine had previously received radiation therapy. PD-1 and PD-L1 inhibitors were administrated in 5 and 6 patients, respectively. No patient had a complete response. 2 patients had a partial response, and the objective response rate was 18.2%. 5 patients were evaluated as stable disease with a disease control rate of 63.6%. The median overall survival and progression-free survival was 3.0 months and 2.3 months, respectively. A patient with partial response had a long duration of response of 5.2 months. The most common grade 3 or 4 treatment-related were neutropenia, anemia, and decreased neutrophil count. Most immune-related adverse events were grade 1 or 2, with rash, pruritus and hypothyroidism being the most common, and 1 patient had grade 3 pneumonia. Conclusions: Immunotherapy plus chemotherapy could be beneficial for a subgroup of extensive-stage SCLC patients who have progressed after previous chemotherapy. Further prospective, randomized studies are warranted.

A Phase II Trial of Carboplatin and Weekly Topotecan in the First-Line Treatment of Patients with Extensive Stage Small Cell Lung Cancer

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

PurposeThe addition of immune checkpoint inhibitors to chemotherapy has improved survival outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC). However, their real-world effectiveness remains unknown. Therefore, we investigated the effectiveness of atezolizumab plus chemotherapy in ES-SCLC in actual clinical settings.Materials and MethodsIn this multicenter prospective cohort study, patients with ES-SCLC receiving or scheduled to receive atezolizumab in combination with etoposide and carboplatin were enrolled between June 2021 and August 2022. The primary outcomes were progression-free survival (PFS) and the 1-year overall survival (OS) rate.ResultsA total of 100 patients with ES-SCLC were enrolled from seven centers. Median age was 69 years, and 6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. The median PFS was 6.0 months, the 1-year OS rate was 62.2%, and the median OS was 13.5 months. An ECOG PS of 2-3 and progressive disease as the best response were poor prognostic factors for PFS, while an ECOG PS of 2-3 and brain metastasis were associated with poor prognosis for OS. In addition, consolidative thoracic radiotherapy was found to be an independent favorable prognostic factor for OS (hazard ratio, 0.336; p=0.021). Grade ≥ 3 treatment-related adverse events were observed in 7% of patients, with treatment-related deaths occurring in 2% of patients.ConclusionWe provided evidence of the favorable real-world effectiveness and safety of atezolizumab plus chemotherapy in ES-SCLC patients, including in the elderly and those with poor ECOG PS. Additional consolidative thoracic radiotherapy may also benefit ES-SCLC patients.

Phase II Trial of Irinotecan, Carboplatin, and Bevacizumab in the Treatment of Patients with Extensive-Stage Small-Cell Lung Cancer

Background: Chiauranib (CS2164) selectively inhibits multiple kinase targets, including Aurora B, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, c-Kit and colony stimulating factor 1 receptor. Phase 1 studies showed that chiauranib 50mg once daily was well tolerated. Here we report results from an exploratory phase 2 study of chiauranib monotherapy for small cell lung cancer (SCLC) conducted in China (NCT03216343). Methods: This single arm phase 2 study involved SCLC patients with progression after platinum-based regimen and at least one other chemotherapy therapy. Patients received chiauranib 50 mg once daily orally until disease progression or unacceptable toxicity. Tumor assessments were conducted at baseline, 4 weeks for the first time and every 8 weeks thereafter. The primary endpoint of this study was objective response rate (ORR) by investigator assessment per the Response Evaluation Criteria in Solid Tumors, version 1.1. Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were evaluated as secondary endpoints. Results: Between November 21, 2017 and March 21, 2019, 28 patients were enrolled in six study sites in China. The median age was 55.5 (range 32-71) years and 21 (75%) patients were male. Eastern Cooperative Oncology Group performance status was 0 in 8 (28.6%) patients and 1 in 20 (71.4%) patients. 12 (42.9%) patients were treated with two prior systemic treatment regimens, 16 (57.1%) patients were treated with three or more. At the cut-off date of Nov 15, 2020, the median follow-up duration was 25.6 (Range, 19.5-not evaluable) months. Two patients were still receiving treatment. Patients received a median of 3.5 cycles treatment. Twenty-seven patients had at least one tumor assessment and one patient died before the first assessment. The ORR and DCR were 17.9% (95% confidence interval [CI]: 6.06%-36.89%) and 64.3% (95% CI: 44.07%-81.36%), respectively. The median PFS, DOR and OS were 3.6, 8.2 and 8.4 months, respectively. The ≥ 10% adverse events (AEs) were mainly grade 1-2, and grade 3-4 AEs were hypertension (25%), hyponatremia (14.3%), fatigue (7.1%), diarrhea (3.6%), hypertriglyceridemia (3.6%), cough (3.6%) and limb pain (3.6%). No treatment related death was reported in the study. Two patients discontinued treatment due to grade 3 fatigue. Conclusions: Chiauranib exhibited impressing antitumor activity in patients with recurrent or metastatic SCLC who had undergone two or more previous lines of chemotherapy, and was well tolerated. Further clinical studies are in plan to verify the findings from the current report. Citation Format: Yuankai Shi, Jian Fang, Xingya Li, Yutao Liu, Zhendong Chen, Zhiyong Ma, Tao Sun. An exploratory phase 2 study of chiauranib monotherapy for small cell lung cancer after two or more lines of previous therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT157.

First-line durvalumab plus platinum-etoposide in Japanese patients with extensive-stage small-cell lung cancer.