Small Cell Lung Cancer Cohort Research Articles

Abstract 5260: Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice

Abstract Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling activity. In the previous meeting (AACR2022, 2023), we reported that ERI and liposomal formulation of ERI (ERI-LF) also have immunomodulatory activity that induces CD8+ T cells via its vascular remodeling activity and ERI-LF showed more potent immune modulation and combination activities with anti-PD-1 antibody (PD-1 Ab) than ERI in syngeneic mice models and humanized mice models. Although immune-checkpoint inhibitors (ICI) are using as a key drug for various types of cancers in clinical setting, several clinical questions regarding suitable therapies after ICI therapy and efficacy of ICI rechallenge are remaining. In this study, we evaluated anti-tumor activities of combination of ERI-LF and PD-1 Ab in two syngeneic transplantation models using mouse non-small lung cancer cells, P-glycoprotein-knockout (Pgp-KO) KLN205 cells and Pgp-KO LL2 cells. As a result, combination of 1mg/kg ERI-LF (Q7D×2) with PD-1 Ab (200 ug/head, twice a week ×2 weeks) showed significant stronger antitumor activity compared with each monotherapy in only Pgp-KO KLN205 model, in which ERI-LF increased intratumoral microvascular density as a vascular remodeling activity, not in Pgp-KO LL2 model. We next conducted continuous treatment of PD-1 Ab in Pgp-KO KLN205 model to investigate tumor regrowth during treatment of PD-1 Ab. In this model, tumor growth was inhibited by PD-1 Ab until about two weeks after initiation of the treatment and then this inhibitory activity disappeared after two weeks even by continuous treatment of PD-1 Ab. We performed flow cytometry analysis (FCM) for tumor-infiltrating immune cells and RNAseq analysis using regrowing tumors compared with non-treatment tumors. Expressions of mRNA of several immune inhibitory receptors were upregulated in tumors with regrowth, although CD4+ cells and CD8+ cells were also increased in FCM using tumor samples. Furthermore, we investigated anti-tumor activity of combination of ERI-LF and PD-1 Ab against tumors which changed from inhibitory phase to regrowth phase during PD-1 Ab treatment in Pgp-KO KLN205 model. The combination of ERI-LF at 1mg/kg (Q7D×3) and PD-1 Ab (200 ug/head, twice a week ×3 weeks) also showed potent anti-tumor activity against tumors with regrowth by prior PD-1 Ab treatment as well as PD-1 Ab-naïve tumor, suggesting that this combination therapy might be effective after prior ICI therapy. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancers (NCT04078295) is underway. Patients with or without prior ICI therapy were enrolled in a small cell lung cancer cohort of this clinical study. Our preclinical results might provide a scientific rationale for a uniqueness of ERI-LF as a post ICI therapy. Citation Format: Moe Tamura, Yuki Niwa, Taro Semba. Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5260.

Systemic immune index predicts tumor-infiltrating lymphocyte intensity and immunotherapy response in small cell lung cancer.

Despite recent progresses in immune checkpoint blockade (ICB) in small-cell lung cancer (SCLC), a lack of understanding regarding the systemic tumor immune environment (STIE) and local tumor immune microenvironment (TIME) makes it difficult to accurately predict clinical outcomes and identify potential beneficiaries from ICB therapy. We enrolled 191 patients with stage I-III SCLC and comprehensively evaluated the prognostic role of STIE by several quantitative measurements, and further integrate it with a local immune score system (LISS) established by eXtreme Gradient Boosting (XGBoost) machine learning algorithm. We also test the value of STIE in beneficiary selection in our independent advanced SCLC cohort receiving programmed cell death 1 ligand 1 (PD-L1) blockade therapy. Among several systemic immune markers, the STIE as assessed by prognostic nutritional index (PNI) was correlated with disease-free survival (DFS) and overall survival (OS), and remained as an independent prognostic factor for SCLC patients [hazard ratio (HR): 0.473, 95% confidence interval (CI): 0.241-0.929, P=0.030]. Higher PNI score was closely associated with inflamed SCLC molecular subtype and local tumor-infiltrating lymphocytes (TILs). We further constructed a LISS which combined top three important local immune biomarkers (CD8+ T-cell count, PD-L1 expression on CD8+ T-cell and CD4+ T-cell count) and integrated it with the PNI score. The final integrated immune risk system was an independent prognostic factor and achieved better predictive performance than Tumor Node Metastasis (TNM) stages and single immune biomarker. Furthermore, PNI-high extensive-stage SCLC patients achieved better clinical response and longer progression-free survival (PFS) (11.8 vs. 5.9 months, P=0.012) from PD-L1 blockade therapy. This study provides a method to investigate the prognostic value of overall immune status by combining the PNI with local immune biomarkers in SCLC. The promising clinical application of PNI in efficacy prediction and beneficiary selection for SCLC immunotherapy is also highlighted.

Small Cell Lung Cancer and Pleural Effusion: An Analysis from a District General Hospital.

The incidence of malignant pleural effusion (MPE) in patients with small cell lung cancer (SCLC) in an American population is approximately 11%, and overall survival in that group is 3 months (compared to 7 months without an effusion. To our knowledge, no study has been done in the United Kindgom and we thus sought to determine the characteristics of the local population. All patients coded as having small cell lung cancer from Somerset register from January 2012-September 2021 were reviewed. We excluded those with indeterminate pathology reports, carcinoid or large cell neuroendocrine cancers. Basic demographics, presence of an MPE and any interventions and outcomes were collected for descriptive analysis. Continuous variables are presented as mean (±) range, median (± IQR) when outliers were present and categorical variables as percentages where appropriate. Caldicott reference C3905. Four hundred one patients with SCLC were identified (11% of all patients, median time to death from presentation 208days, IQR 304 [many outliers); 224 (55.9%) were female, 177 male [median age 75years, IQR 13]. One hundred seven (27%) presented with an effusion: 23 were sampled, 10 had positive cytology, all were exudates, 8 required chest drainage, the mean performance status (PS) was 2 (range 1-4) and the median time to death 142days, IQR 45. Of the 294 with no initial effusions, 70 (24%) developed a pleural effusion with progressive disease (mean PS 1, median age 71.5years, IQR 14, median to death 327days, IQR 395, 1 outlier); 224 patients never had a MPE with a median time to death of 212 days, IQR 305, multiple outliers and, when compared to those with a MPE at any point, median time to death was 211days, IQR 295.5 (multiple outliers). Meaningful analysis was difficult because of the presence of multiple outliers in values collected and not correcting for stage at presentation or treatment modalities and previous studies did not correct for those either. Those presenting with an MPE had a poorer prognosis, probably signifying advanced disease and the presence of MPE in our SCLC cohort seems higher. Large prospective databases for this are required.

Phase 2 small cell lung cancer (SCLC) cohort of a phase 1b/2 trial of a liposomal formulation of eribulin in combination with nivolumab.

8593 Background: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin. Combining E7389-LF with an immune checkpoint inhibitor (ICI; eg, nivolumab) may improve antitumor response via vascular remodeling. The phase 1b part of the open-label Study 120 evaluated the dosing and safety of E7389-LF in combination with nivolumab in patients (pts) with solid tumors. The phase 2 part assessed efficacy and safety in disease cohorts; herein, we report results from the SCLC cohort. Methods: Pts with unresectable and measurable SCLC who had progression during or after 1st-line (1L) platinum-based chemotherapy with/without an ICI were enrolled to the SCLC cohort of the phase 2 part of Study 120. Pts received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg IV Q3W. The primary objective of the phase 2 part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory objectives included the disease control rate (DCR), overall survival (OS), and biomarker analysis. Tumor response was assessed by investigators per RECIST v1.1 Q6W. All adverse events (AEs) were monitored and recorded. Results: In the SCLC cohort, 34 pts were enrolled; the median age was 66.0 years (range 46–81). At data cutoff (May 31, 2022), 5 pts (14.7%) were undergoing treatment. Discontinuations occurred in 29 pts (85.3%)—26 (76.5%) primarily due to disease progression, 3 (8.8%) due to an AE. Efficacy analyses included 33 pts, as 1 pt had their diagnosis of SCLC changed to a different cancer type after being enrolled. Of the 33 evaluable pts, 27 (81.8%) had an ICI as part of their prior 1L therapy. The ORR of E7389-LF in combination with nivolumab was 24.2% (95% CI 11.1–42.3) in the evaluable population; the DCR was 75.8% (95% CI 57.7–88.9). Median PFS was 3.98 mos (95% CI 2.63–4.40); the 6-mo PFS rate was 27.7% (95% CI 13.0–44.6). At a median follow-up period of 10.6 mos, median OS was not reached (95% CI not estimable); the 6-mo OS rate was 90.9% (95% CI 74.4–97.0). Treatment-related, treatment-emergent (TE)AEs of any grade and of grade ≥3 severity occurred in 97.1% (n = 33) and 82.4% (n = 28) of the 34 enrolled pts, respectively; the most common treatment-related TEAE was neutropenia (any grade: 58.8% [n = 20]; grade ≥3: 52.9% [n = 18]). The neutrophil count nadir occurred around cycle 1 day 8. TEAEs led to dose reduction of E7389-LF in 19 pts (55.9%). Withdrawal of E7389-LF or nivolumab occurred in 5 pts (14.7%): acute kidney injury, cough, myocarditis, pneumonitis, and radiation pneumonitis (n = 1 each). Changes in vascular and immune-related plasma markers were observed. Conclusions: E7389-LF in combination with nivolumab showed notable antitumor activity as 2L therapy in pts with SCLC, as evidenced by the notable ORR of 24.2%. No new safety signals were observed for this combination. Clinical trial information: NCT04078295 .

Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results.

3027 Background: Mirzotamab clezutoclax (ABBV-155; Mirzo-C) is a first-in-class antibody-drug conjugate with three components: an anti–B7-H3 monoclonal antibody, a solubilizing linker, and a BCL-XL inhibitor payload. By specific targeting of BCL-XL, synergy with other anticancer agents was observed in preclinical models. When combined with a taxane, clinical antitumor activity was reported in relapsed and/or refractory (R/R) solid tumors during the dose escalation phase of an ongoing Phase 1, open-label study (NCT03595059). Methods: In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C was administered at the recommended Phase 2 dose determined at dose escalation. Primary objectives were safety and overall response rate (ORR). Results: As of November 18, 2022, 78 patients were enrolled (SCLC n=14; NSCLC n=36; BrCa n=28). The median (range) follow-up was 2.0 (0.6–9.1) months for the SCLC cohort, 4.9 (0.6–8.5) for NSCLC, and 10.4 (0.8–13.3) for BrCa. The median number of prior lines of systemic therapy was 2 in the SCLC cohort, 2 in NSCLC, and 6 in BrCa. Prior taxane therapy was received by 7% of patients in the SCLC cohort, 36% in NSCLC, and 64% in BrCa. The most common adverse events (AEs) in SCLC were fatigue, increased aspartate aminotransferase, diarrhea, and headache (21%, n=3 for each AE); fatigue was the most common AE in NSCLC (58%, n=21; Grade 3/4: 3%, n=1) and in BrCa (61%, n=17). Thrombocytopenia, a result of the systemic effects of BCL-XL inhibitors, was not observed in the Mirzo-C monotherapy cohort. Neutropenia/decreased neutrophil count was not observed in the SCLC monotherapy cohort but was common with BrCa paclitaxel combo (64%, n=18; Grade 3/4: 29%, n=8) and NSCLC docetaxel combo (53%, n=19; Grade 3/4: 44%, n=16); 5 patients in the NSCLC cohort (14%) and 1 in BrCa (4%) had febrile neutropenia. Confirmed ORR was 0% in the SCLC cohort, 11% in NSCLC, and 18% in BrCa. Conclusions: Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC. Combination treatments were active with high best overall response (BOR) and disease control rates in heavily pretreated NSCLC and BrCa patients, where Grade 3/4 neutropenia was observed. It is unknown if Mirzo-C exacerbated the neutropenia risk associated with taxanes. Clinical trial information: NCT03595059 . [Table: see text]

Abstract CT218: A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas

Abstract Objectives: Small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas (NECs) share many clinical features, including limited response to immune checkpoint inhibitors (ICIs). However, preclinical data suggest synergistic response with combined ICI and poly (ADP-ribose) polymerase inhibitors (PARPi) in SCLC models. This single-institution, phase II trial (NCT04701307) assessed the efficacy of a combination of the anti-PD-1 monoclonal antibody, dostarlimab, with the selective PARPi, niraparib, in patients with relapsed SCLC or NECs. Methods: Eligible patients with SCLC (Cohort 1) or NECs (Cohort 2) had received at least one prior line of therapy and were treated with niraparib 300 mg (or 200 mg if <77kg or platelets < 150,000/µL) PO daily, and dostarlimab 500 mg IV q21d (1000mg IV q42d starting with Cycle 5). Co-primary endpoints were objective response rate (ORR) by RECISTv1.1 and 6-month progression free-survival (PFS6). Using a Bayesian Optimal Phase 2 (BOP2) design, interim futility analyses were planned after enrolling up to 15 SCLC and 9 NEC patients (NEC), respectively. Adverse events (AE) were monitored continuously. Patients underwent biopsies, if feasible, at Cycle 1 and Cycle 3, as well as longitudinal plasma collection for translational studies. Results: From Feb 2021 to Aug 2021, 14 and 9 patients enrolled with SCLC and NEC, respectively. NECs included tumors from gynecological, head/neck, and gastrointestinal sites. In Cohort 1 (SCLC), 12 of 14 patients were evaluable by RECISTv1.1, including 1 complete response (CR), while 4 patients not achieving partial response (PR) had minor responses (-2%, -14%, -19%, and -24% from baseline). Only 1 patient in this cohort achieved PFS6, though 2 additional patients progressed between 5 and 6 months. In Cohort 2 (NEC), 6 of 9 patients were evaluable by RECISTv1.1 and no CR/PRs were observed. One patient did experience durable minor response (-21%), but no patients achieved PFS6. Dose-limiting, niraparib-related hematological AEs, typically thrombocytopenia, occurred in 12 of 23 patients. Non-hematological, treatment-related serious AEs occurred in only 1 patient (Grade 3 inflammatory arthritis), while 1 additional patient experienced brief dose-interruption due to Grade 2 pneumonitis. Preliminary translational data, including bulk and single-cell RNAseq, indicate molecular features, such as transcriptional subtype, are shared across SCLC and NECs and may predict response to this combination. Conclusions: In heavily pre-treated patients across SCLC and NEC cohorts, combined niraparib and dostarlimab failed to exceed interim futility criteria. However, multiple SCLC patients experienced durable disease control, including one patient with sustained CR and associated translational studies point to potential biomarker-driven approaches in the future. Trial supported by GlaxoSmithKline. Citation Format: Carl M. Gay, C. Allison Stewart, Michael Frumovitz, Junya Fujimoto, Yuann xi, Qi Wang, Runsheng Wang, Veronica Novegil, Mehmet Altan, Tina Cascone, Arvind Dasari, Yasir Y. Elamin, Frank V. Fossella, Bonnie S. Glisson, Charles S. Lu, Marcelo V. Negrao, Ferdinandos Skoulidis, Natalie Vokes, Robert J. Cardnell, Ignacio I. Wistuba, Jing Wang, John V. Heymach, Lauren A. Byers. A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas [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 CT218.

149P A phase Ⅰb/Ⅱ trial of surufatinib plus toripalimab and etoposide (E) combined with cisplatin (P) in patients (pts) with untreated advanced small cell lung cancer (SCLC)

Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in an SCLC cohort in a trial evaluating S + T in pts with selected solid tumors. This study is assessing the safety, tolerability, and preliminary efficacy of S+ T+ chemotherapy (EP) as first-line regimen for SCLC pts. Here, we report the preliminary efficacy results.

Immunogenomic correlates of immune-related adverse events for anti-programmed cell death 1 therapy.

Despite impressive antitumor efficacy of programmed cell death 1 (PD-1) inhibitors, this inhibition can induce mild to severe autoimmune toxicities, termed immune-related adverse events (irAEs). Yet, predictive pretreatment biomarkers for irAEs development across cancer types remain elusive. We first assessed cellular and molecular factors. To determine factors predicting the risk of irAEs for anti-PD-1 immunotherapy across multiple cancer types, an integrative analysis of cellular and molecular factors from 9104 patients across 21 cancer types and 4865522 postmarketing adverse event reports retrieved from adverse event reporting system was then performed. Accuracy of predictions was quantified as Pearson correlation coefficient determined using leave-one-out cross-validation. Independent validation sets included small cell lung cancer and melanoma cohorts. Out of 4865522 eligible adverse events reports, 10412 cases received anti-PD-1 monotherapy, of which, 2997 (28.78%) exhibited at least one irAE. Among established immunogenomic factors, dendritic cells (DC) abundance showed the strongest correlation with irAEs risk, followed by tumor mutational burden (TMB). Further predictive accuracy was achieved by DC and TMB in combination with CD4+ naive T-cells abundance, and then validated in the small cell lung cancer cohort. Additionally, global screening of multiomics data identified 11 novel predictors of irAEs. Of these, IRF4 showed the highest correlation. Best predictive performance was observed in the IRF4 - TCL1A - SHC-pY317 trivariate model. Associations of IRF4 and TCL1A expression with irAEs development were verified in the melanoma cohort receiving immune checkpoint inhibitors. Collectively, pretreatment cellular and molecular irAEs-associated features as well as their combinations are identified regardless of cancer types. These findings may deepen our knowledge of irAEs pathogenesis and, ultimately, aid in early detection of high-risk patients and management of irAEs.

Molecular subtyping of small-cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies.

Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.

Mutational landscape of homologous recombination-related genes in small-cell lung cancer.

Homologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression. Next-generation sequencing (NGS)-based target capture sequencing of 543 cancer-related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD-L1 expression was evaluated in 90 out of 133 patients using the SP142 PD-L1 immunohistochemistry assay. Among the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR-Mut) and without HRR mutations (HRR-WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK-RAS pathway occurred more frequently in the HRR-Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p=0.048), but there was no correlation of HRR gene mutation status with PD-L1 expression. We exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma

PurposeLurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet. Patients and methodsClinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples. ResultsA total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4–3.0), and median overall survival was 7.0 months (95% CI: 4.7–not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4–4.2), and median overall survival was 7.2 months (95% CI: 5.9–not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes. ConclusionLurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations.

Abstract 3396: Identification of small cell lung cancer stage-specific DNA methylation in patients using liquid biopsies

Abstract Introduction: Small cell lung cancer (SCLC) is a deadly disease and patients often suffer from recurrent disease. Biologic mechanisms of recurrence are unclear. Epigenetic mechanisms, like DNA methylation, may be operant. SCLC is rarely resected; therefore, the SCLC methylome is understudied due to scarce tumor tissue. Methods: In this study, we examined the pre-treatment methylome of 72 SCLC patients at our institution through cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) on plasma cell-free DNA (cfDNA) and on sheared genomic DNA from paired peripheral blood leukocytes (PBLs) (n = 72) to increase tumor signal specificity. cfMeDIP-seq was also performed on an independent cohort of healthy non-cancer controls (n = 20) and on tumors from circulating tumor cell-derived xenograft (CDX) models (n = 12 CDXs of 72 patients). cfMeDIP-seq libraries were sequenced at a depth of 100 million reads, paired-end, on the NovaSeq 6000. For all bioinformatic analyses, chromosomes 1-22 were binned into 300-bp windows (n = 9.6e6 genome-wide windows); reads from cfMeDIP-seq were tallied per bin. To filter out noise from non-tumor cells, ENCODE blacklist regions (n = 1e6 windows) were removed and CG-rich (>5 CGs per window), PBL-associated windows with MeDEStrand-converted beta-values < 0.2 were kept (n = 190,769 windows). Subsequent cfDNA analyses were performed using these 190,769 windows. Results: 33 (45.8%) and 39 (54.2%) of the 72 patients had limited-stage (LS) and extensive-stage (ES) SCLC, respectively. Most were current or former smokers (65/72, 90.3%). Using filtered windows (n = 190,769), methylated cfDNA from SCLC were distinguished from healthy controls: SCLC cfDNA was enriched for hypermethylated CpG islands and shore regions, whereas controls had more methylated open-sea regions. SCLC cohort by consensus clustering of the top 5000 most variant windows revealed two distinct cfDNA methylation patterns. Cluster A (9 ES, 22 LS) and Cluster B (33 ES, 11 LS) were significantly different by stage (X2(1) = 13.79, p < 0.001). There was no significant difference in sex (p = 0.81). Patients in Cluster A had a lower concentration of cfDNA (median = 7.2ng/ml) compared to Cluster B (median = 15.9ng/ml) but not statistically significant (p = 0.33). High concordance between genome-wide methylome profiles was found between paired patient cfDNA and CDX tumor, demonstrating that cfDNA is representative of tumor methylation (Pearson's correlation median r = 0.86). Conclusion: We identified stage-specific methylation patterns in the plasma of SCLC patients using the cfMeDIP-seq assay that may reveal novel epigenetic and biologic mechanisms of SCLC disease progression. Moreover, CDXs recapitulate the methylome of SCLC cell-free patient samples highlighting their utility in future work as representative models for methylome analysis. Citation Format: Sami Ul Haq, Sabine Schmid, Mansi K. Aparnathi, Katrina Hueniken, Luna J. Zhan, Danielle Sacdalan, Janice J.N. Li, Devalben Patel, Dangxiao Cheng, Vivek Philip, Geoffrey Liu, Scott V. Bratman, Benjamin H. Lok. Identification of small cell lung cancer stage-specific DNA methylation in patients using liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3396.

Clinical characteristics and outcomes of extrapulmonary small cell cancer: A retrospective analysis of the SEER database.

e20616 Background: Extrapulmonary small cell cancer (EPSCC) accounts for only 5-10% of small cell carcinoma, with the rest consisting of small cell lung cancer (SCLC). The incidence of this entity has been rising due to better diagnosis, however it is not well described and data is limited. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis to further characterize the biology and clinical aspects of this entity, in comparison to SCLC. Methods: The Surveillance, Epidemiology and End Results (SEER) 18 database was used to obtain data on age, gender, ethnicity, survival, and tumor characteristics of n = 9,712 US patients diagnosed with EPSCC between 2000-2018 and these were compared to n = 118,514 patients with SCLC diagnosed during the same period. Results: Among the EPSCC cohort 58.1 % were males while in the SCLC cohort 50.3% were males. Median age of diagnosis was 65.50 years for EPSCC and 66.81years for SCLC. Among the EPSCC patients, 75.9 % were Caucasians, 9.2 % were African-Americans, and 8.8% were Hispanics. Amongst SCLC patients, Caucasians made up 83.1% of the patients, while African-Americans made up 8.6% and Hispanics made up 4.5 % of the patients. Most common sites for EPSCC were urinary bladder (20.2%), prostate (7%), cervix uteri (6.2%), pancreas (4.5%), rectum (3%), and ovaries (2.6%). Median OS for EPSCC was 8 months (95% CI: 8 - 8), while median overall survival for SCLC was 7 month (95% CI: 7 - 7). Hazard ratio for death for EPSCC: 0.77 (95% CI: 0.75 - 0.79), p < 0.001. The survival at 12 months, 24 months and 60 months was 36%, 22%, and 13 % for EPSCC and 29%, 13%, and 5% for SCLC. There were no significant gender or racial differences in overall survival (OS). Conclusions: EPSCC has better overall and 5-year survival as compared to SCLC. There are no significant differences in survival outcomes in EPSCC patients based on location of primary, gender or race.

Efficacy and safety of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer: Preliminary results of a phase 1 study.

8580 Background: Lurbinectedin (Zepzelca), a selective inhibitor of oncogenic transcription, was granted accelerated approval on June 15, 2020, by the FDA for adult patients (pts) with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy, based on the results from SCLC cohort in PM1183-B-005-14 trial. Here we report the preliminary results of a phase 1 study (LY01017/CT-CHN-101) which aimed to evaluate the safety, tolerability, pharmacokinetics (PK) characters and preliminary efficacy of lurbinectedin in Chinese pts with advanced solid tumors including relapsed SCLC. Methods: In the dose-escalation stage, 10 pts with advanced solid tumors received lurbinectedin (2.5-3.2 mg/m2) as 1-hour i.v. infusion q3wk in a classical 3+3 design, without primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during Cycle 1. In the dose-expansion stage, 22 pts with relapsed SCLC after first-line platinum-based chemotherapy were treated with single-agent lurbinectedin at the recommended dose (RD) defined in the dose-escalation stage, with or without G-CSF support. Endpoints included safety (CTCAE v5.0), tolerability, PK, and confirmed objective response rate (ORR; RECIST v1.1). The data cutoff was January 13, 2022. Results: No dose-limiting toxicity (DLT) was observed in the first 3 pts treated at 2.5 mg/m2, while 1/7 pts treated at 3.2 mg/m2 had DLT (grade 4 neutropenia lasting ≥3 days) in Cycle 1, thus 3.2mg/m2 without G-CSF prophylaxis was defined as the RD of the dose-expansion stage. At cutoff, 22 SCLC pts treated in the dose-expansion stage were still ongoing, with 21 and 22 pts evaluable for efficacy and safety, respectively. The investigator-assessed confirmed ORR was 42.9% (9/21, partial responses). The duration of response (DOR) is pending. The most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (16 [72.7%]), leukopenia (13 [59.1%]), thrombocytopenia (9 [40.9%]), increased ALT (4 [18.2%]), anemia (3 [13.6%]), and increased AST (2 [9.1%]). Serious treatment-related adverse events, including neutropenia (5 [22.7%]), leukopenia (4 [18.2%]), thrombocytopenia (3 [13.6%]), increased ALT (2 [9.1%]), increased AST (2 [9.1%]), vomiting (2 [9.1%]), febrile neutropenia (1 [4.5%]), and edema (1 [4.5%]), were reported in 10 pts (45.5%). No cases of infection, sepsis and Hy’s law were reported. A total of 40.9% (9/22) had dose delay and 31.8% (7/22) had dose reduction, mainly attributed to hematological toxicities. No discontinuations occurred due to AEs. No treatment-related deaths were reported. Conclusions: Lurbinectedin at the RD (3.2mg/m2) shows promising efficacy as second-line therapy in Chinese pts with SCLC, with acceptable tolerability and manageable safety profile. Clinical trial information: NCT04638491.

Efficacy of lurbinectedin in a clinical trial versus other standard of care in a real-world comparator arm in relapsed/refractory small cell lung cancer patients.

e20619 Background: Lurbinectedin monotherapy is currently approved for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a single-arm phase 2 basket trial. The current study established real-world comparator arms (RWCAs) to enable retrospective comparison of the efficacy of lurbinectedin from the trial, notably overall survival (OS) and overall response rate (ORR), to other standard of care treatments. Methods: This exploratory study consisted of two arms, where the 1st arm was the lurbinectedin trial arm (LTA) comprised of data from the SCLC cohort of the trial (NCT02454972) and the 2nd arm was an RWCA sourced from ConcertAI electronic medical records in the US (2010 to 2019). Relevant inclusion and exclusion criteria from the trial were applied to the RWCA to ensure comparability at baseline. Given the absence of Eastern Cooperative Oncology Group performance status (ECOG) for a sizable portion of patients in the RWCA, two RWCA groups were studied, one that excluded patients with reported ECOG > 2 (RWCA1) and the other that excluded patients with reported ECOG > 2 and missing ECOG (RWCA2). Propensity score (PS) weighting was used to further balance measured baseline characteristics between LTA and each RWCA. OS was defined as the time from treatment initiation to death. Weighted cox regression was used to compare OS. ORR was defined as the percentage of patients with a complete or partial response. A weighted two-sample test of proportions was used to compare ORR. Results: This study included 105 patients in LTA and 121 in RWCA1 (74 in RWCA2). After PS weighting, baseline characteristics were mostly similar between LTA and each RWCA. ECOG was balanced between RWCA2 and LTA but was different between RWCA1 and LTA. A numerical median OS benefit of 3.8 and 4.7 months was observed in LTA, compared to RWCA1 and RWCA2, respectively (see table). Probability of survival was greater in LTA compared to RWCAs at 3 and 6 months. ORR was two-fold higher in LTA compared to RWCA1. Consistent findings were seen for LTA compared to RWCA2. Conclusions: Lurbinectedin monotherapy demonstrated improved median OS, lower risk of death at 3 and 6 months, and higher response rate compared to other standard of care treatments in relapsed/refractory SCLC. Future studies with larger sample size powered to detect statistical differences in OS are warranted.[Table: see text]

Circulating Levels of the Cardiovascular Biomarkers ST2 and Adrenomedullin Predict Outcome within a Randomized Phase III Lung Cancer Trial (RASTEN).

Simple SummaryCardiovascular disease is common in patients with small cell lung cancer, partly reflecting its high correlation with smoking. Cardiovascular comorbidities may limit patient tolerance to cytotoxic drugs, thereby influencing the choice and intensity of treatment and, ultimately, patient survival. In light of the challenges relating to assessing cardiovascular status clinically in newly diagnosed lung cancer, objective biomarkers of cardiovascular vulnerability are warranted. Here, we show that circulating levels of ST2, an established biomarker in heart failure, and adrenomedullin, a vasodilator peptide known to reflect several aspects of cardiovascular status, strongly correlate with survival in small cell lung cancer. Our data, which are based on a large, randomized trial cohort, suggest the potential use of cardiovascular biomarkers in guiding clinicians in making individualized treatment decisions.Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44–3.98; p = 0.001) and 2.18 (95% CI 1.35–3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73–6.79; p < 0.001) and 3.49 (95% CI 1.84–6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions.

Effect of systemic inflammation biomarkers on overall survival after lung cancer radiotherapy: a single-center large-cohort study

Introduction Recent studies suggest that immune-related cells can be recruited for anti-tumor functions as well as tumor progression and the interplay between systemic inflammation and local immune response may play a major role in the development and progression of various cancers including lung cancer. Inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) can be used as surrogate biomarkers of host immune status. In this work, associations between neutrophils, lymphocytes, platelets, NLR, PLR, SII and overall survival (OS) are investigated in two cohorts of non-small cell lung cancer (NSCLC) patients treated with fractionated radiotherapy (RT) and stereotactic body radiation therapy (SBRT) and a cohort of small cell lung cancer (SCLC) patients treated with fractionated RT. Material and Methods Data from 2513 lung cancer patients were retrospectively analyzed. Baseline NLR, PLR, and SII (NLR × platelet count) were calculated from full blood test prior to RT initiation. Cox proportional hazards regression analyses were used to evaluate the association between systemic inflammation markers and known clinical factors with OS. Results The two-year OS was 42%, 63%, and 62% in the NSCLC fractionated RT, SBRT, and SCLC cohort. NLR (per 1 unit: hazard ratio [HR]: 1.04, p < 0.05) and SII (per 100 × 109/L: HR: 1.01, p < 0.05) remained the strongest independent factors of OS in multivariable Cox analyses, correcting for clinical factors in early-stage and locally advanced NSCLC and SCLC patients treated with RT. Discussion This single-center large-cohort study suggests that baseline NLR and SII are independent prognostic biomarkers associated with OS in locally advanced and early-stage NSCLC patients treated with either curative-intent fractionated RT or SBRT and SCLC patients treated with curative-intent fractionated RT. External validation is warranted to evaluate the utility of these biomarkers for patients’ stratification and adapting new treatment approaches.

157P Surufatinib plus toripalimab in patients with advanced small cell lung cancer (SCLC) after failure of first-line systemic chemotherapy

Patients (pts) with advanced SCLC have a rapid relapse after 1L treatment, and only one approved agent (topotecan) for 2L treatment. Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in a neuroendocrine carcinoma cohort in a trial evaluating S + T in pts with selected solid tumors. Here, we report the safety and efficacy results in the SCLC cohort.

Multi-Facility vs. Single-Facility Concurrent Chemoradiation for Lung Cancer

Coordination of definitive concurrent chemoradiotherapy (CCRT) for locally advanced lung cancer can be challenging, especially if the therapies are delivered at different facilities. We hypothesized that patients with non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) who undergo chemotherapy and radiotherapy (RT) in multiple facilities (MF) compared to a single facility (SF) will have different sociodemographic/clinical characteristics but similar overall survival (OS).We examined 2 cohorts of patients diagnosed in 2010-16 in the National Cancer Database: (1) stage III(N2+) NSCLC patients who received CCRT (60-70 Gy in 1.8-2 Gy fractions) and (2) stage III SCLC patients who received CCRT (45 Gy in 30 fractions or 60-70 Gy in 30-35 fractions). CCRT was defined as definitive multi-agent chemotherapy and external beam RT initiated within 30 days of each other. All patients received their entire course of RT at the reporting facility. Patients who received surgery or immunotherapy were excluded. We used univariable (UVA) and multivariable (MVA) analyses to assess potential associations of MF treatment with sociodemographic/clinical factors and OS. Odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) are reported. Subset analyses were performed to evaluate the impact of diagnosis year (< 2014 vs. ≥2014) and facility volume (low vs. high, defined by 75th percentile) on OS in both cohorts.Our NSCLC cohort included 9279 patients; 32.4% received MF treatment. Our SCLC cohort included 2683 patients; 31.4% received MF treatment. Characteristics significantly associated with MF treatment on MVA for both cohorts included higher median household income, earlier year of diagnosis, absence of comorbidities, treatment at a community cancer program, and treatment at a facility in the South or Midwest. NSCLC patients receiving MF treatment were less likely to travel > 20 miles for RT (OR 0.80 [CI 0.70-0.90], P < 0.001) on UVA, while no such association was found in SCLC. For NSCLC, we found no significant difference in OS between patients who received MF vs. SF treatment on UVA (23.6 [CI 22.3-24.9] vs. 23.4 [CI 22.6-24.3] months, P = 0.55) or MVA (HR 1.00 [CI 0.95-1.05], P = 0.99). For SCLC, we similarly found no significant difference in OS between patients who received MF vs. SF treatment on UVA (21.7 [CI 20.4-24.0] vs. 22.1 [CI 21.2-23.4] months, P = 0.98) or MVA (HR 0.96 [CI 0.87-1.06], P = 0.44). Subset analyses also yielded no significant differences.Receiving definitive CCRT in MF vs. SF does not appear to significantly affect OS in locally advanced NSCLC or SCLC, although NSCLC patients receiving MF care are less likely to travel farther for RT. While outcomes of local control and toxicity have yet to be explored, traveling longer distances to receive lung cancer CCRT at the same facility may not be necessary to optimize survival.

P63.01 Lurbinectedin in Pre-Treated Patients With Small Cell Lung Cancer and Malignant Pleural Mesothelioma in a Real World Setting

Lurbinectedin, a selective inhibitor of oncogenic transcription is currently being investigated in patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM) after failure of at least first-line therapy, with phase 2 studies showing promising results. In 2020, the FDA granted accelerated approval to lurbinectedin (Zepzelca®) for patients with metastatic SCLC with disease progression during or after platinum-based chemotherapy. Here, we present the first real-world data of lurbinectedin from two large heavily pre-treated patient cohorts, SCLC and MPM, treated in our tertiary referral university medical center. Lurbinectedin, a selective inhibitor of oncogenic transcription is currently being investigated in patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM) after failure of at least first-line therapy, with phase 2 studies showing promising results. In 2020, the FDA granted accelerated approval to lurbinectedin (Zepzelca®) for patients with metastatic SCLC with disease progression during or after platinum-based chemotherapy. Here, we present the first real-world data of lurbinectedin from two large heavily pre-treated patient cohorts, SCLC and MPM, treated in our tertiary referral university medical center. Between November 2019 and December 2020, a total of 95 patients (43 SCLC and 52 MM) started treatment with lurbinectedin. All patients with SCLC and 81% of MM received lurbinectedin as third or further line of therapy. The median number of cycles that was administered was 2 (range: 1-12) for SCLC and 3 (range: 1-13) for MM. After 12 weeks, in the SCLC cohort, the disease control rate (DCR) was 29% and the objective radiological response (ORR) was 17%. The median progression free survival (mPFS) was 1.5 months (95% CI: 1.4–3.0), and median overall survival (mOS) was 7.0 months (95% CI: 4.7-not reached). In the MPM cohort, the DCR after 12 weeks was 32% and no tumor responses were registered. The mPFS was 2.8 months (95% CI: 1.4–4.2), while mOS was 7.2 months (95% CI: 5.9–not reached). In general, lurbinectedin was well tolerated. Dose reductions were applied in 27% of patients, mainly because of fatigue or hematologic toxicity. Lurbinectedin appears to be a clinically meaningful therapeutic option in heavily pre-treated patients with SCLC and mesothelioma.Table 1comparison of our real-world data to the phase II clinical trialsTrigo et al. (SCLC) (n=105)Erasmus MC (SCLC) (n=43)Metaxas et al. (MPM) (n=42)Erasmus MC (MPM) (n=52)Patients number105434252Treatment line2-33-42-32-3Median follow-up17.1 months7.2 monthsNA7.3 mMedian chemotherapy-free interval3.5 months1.9 monthsNA1.6 monthsDCR 12 weeks68%29%52%32%ORR 12 weeks35%17%4%0%Median PFS3.5 months1.5 months4.1 months2.8 monthsMedian OS9.3 months7.0 months11.1 months7.2 months Open table in a new tab