aNSCLC Patients Research Articles

Abstract A025: Tumor fraction (TF) is associated with real-world progression-free survival (rwPFS) in advanced non-small-cell lung cancer (aNSCLC) patients treated with chemotherapy (chemo)

Abstract Background: Genomic ctDNA molecular response (gMR) predicts clinical benefit from immune checkpoint inhibitors, but associations with benefit from chemo are inconsistent. gMR may predict benefit from chemo after filtering to tissue-confirmed somatic variants, suggesting interference from clonal hematopoiesis (CH) mutations. Using methylation tumor fraction (TF) for MR assessment may mitigate the risk of CH interference without tissue and with higher sensitivity. Here, we report a retrospective study assessing the feasibility of using methylation- based TF from the Guardant Infinity platform to predict clinical benefit from chemo in a real- world cohort of patients (pts) with aNSCLC. Methods: Plasma samples were analyzed from pts (n=67) with aNSCLC, undergoing treatment with chemo only in 1st line or later setting, who had serial methylation TF results from tissue-free genomic and epigenomic ctDNA NGS. The present analysis included 27 pts with a baseline sample (T1) within 105 days prior to treatment start and an on-treatment timepoint (T2) 2-15 weeks after treatment start and >10 days prior to treatment end. gMR was based on the % change in mean variant allele fraction (VAF) T2/T1. TF % change was defined as TF (T2) / TF (T1). Relationships between time-to-next- treatment (TTNT; proxy for progression-free survival) and gMR or TF % change from T1 to T2 were explored using Cox proportional hazards (CPH) analysis. Multiple cutpoints were evaluated to label pts as molecular responders or non-responders for outcomes analysis. Gender, age, and therapy line were included as covariates for all analyses. Results: A ctDNA change from T1 to T2 was quantifiable in 85% of pts (18/27) by TF change versus 67% of pts by gMR due to improved limit of quantification for TF relative to somatic variants. CPH revealed that gMR defined by any ctDNA % change threshold was not associated with TTNT (p=(0.182- 0.862)). However, pts with a ≥95% decrease in TF from T1 to T2 had a significant association with improved TTNT (HR 0.14; 95% CI (0.03, 0.80); p=0.027). Furthermore, molecular responders defined by any decrease cutpoint >70% were significantly associated with improved TTNT (p≤0.033). Conclusions: A decrease in TF >70% early during chemotherapy was significantly associated with improved TTNT, even in this small cohort. The change in ctDNA was quantifiable in more patients by TF change than by gMR and included patients with no somatic variants detected. In contrast, gMR defined by any ctDNA % change threshold was not associated with TTNT. These results demonstrate feasibility of methylation-based TF to predict benefit from chemo in aNSCLC patients without tissue and with higher sensitivity than gMR, laying groundwork for future studies to address validity of serial TF monitoring in this patient population. Citation Format: Jing Wang, Sean Gordon, Errin Lagow, Tara Dinman, Carin Espenschied, Shile Zhang, Kimberly Banks. Tumor fraction (TF) is associated with real-world progression-free survival (rwPFS) in advanced non-small-cell lung cancer (aNSCLC) patients treated with chemotherapy (chemo) [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A025.

Real-world clinical outcomes among patients with non-squamous advanced non-small cell lung cancer (aNSCLC) treated with docetaxel-based regimens post initial standard of care (SOC) in the United States.

392 Background: Immunotherapy (IO) or targeted therapy used separately or in combination with platinum-based chemotherapy (PBC) are SOC among treatment naïve aNSCLC patients. After progression on SOC, patients have limited treatment options. Previous US-based real-world studies have shown docetaxel ± ramucirumab as the most used line of treatment (LOT) post-SOC. This study sought to assess clinical outcomes associated with docetaxel+ramucirumab (DTX-R) or docetaxel monotherapy (DTX) received post SOC among patients with non-squamous aNSCLC independent of genomic alteration status. Methods: This retrospective study, using electronic medical record data from the ConcertAI Patient360 NSCLC data product (01/2015–09/2022), included adult patients (≥18 years) with stage IIIB-IV non-squamous aNSCLC who received docetaxel-based regimens (DTX-R or DTX) as subsequent LOT (index LOT) after discontinuation of the prior qualifying SOC LOT (IO + PBC or targeted therapy + PBC). Kaplan-Meier analysis was used to estimate median time to discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS) on docetaxel-based index regimens. Results: Out of 656 non-squamous aNSCLC patients which discontinued prior SOC therapy, 165 (25.2%) received a docetaxel-based regimen (n = 96 [DTX-R]; 69 [DTX]) which was the most commonly received index regimen. Other patients received a variety of other treatments, most commonly, pembrolizumab monotherapy (11.4%), pemetrexed + pembrolizumab (8.4%), pemetrexed monotherapy (4.4%), carboplatin + pemetrexed (4.1%), and osimertinib (3.8%). Among patients with index DTX-R and DTX, median age was 66 and 65 years; 36.5% and 60.9% were female; 74.0% and 63.8% were White; 86.5% and 75.4% received care in community setting; 15.1% and 31.8% had brain metastasis; 63.6% and 65.2% had ECOG 0-1; 1 and 2 median prior LOT; and median follow-up from index was 10 and 11 months, respectively. Median TTD, TTNT, rwPFS, and rwOS for docetaxel-based regimens are reported in the table. Conclusions: Docetaxel ± ramucirumab is the most used regimen in a fragmented treatment landscape post SOC therapy among patients with non-squamous aNSCLC. Observed rwOS, rwPFS, and treatment durations on docetaxel-based regimens in this real-world setting suggested the limited clinical benefit associated with these therapies. Overall, there is a need for more effective treatment options post SOC therapies. Real-world outcomes for DTX-R and DTX treated patients post SOC. Outcome, months (median, 95% CI) Docetaxel+Ramucirumab Docetaxel Monotherapy rwOS 6.37 (4.4, 9.3) 4.73 (2.3, 7.8) rwPFS 3.88 (2.8, 6.0) 3.22 (2.0, 5.7) TTD 3.06 (2.4, 3.5) 1.71 (1.7, 2.4) TTNT 3.45 (2.9, 4.5) 3.02 (1.9, 4.6)

1853P Risk model for overall survival (OS) based on composite patient-reported outcomes (PROs) in aNSCLC patients treated with first-line (1L) cemiplimab-based therapy

1853P Risk model for overall survival (OS) based on composite patient-reported outcomes (PROs) in aNSCLC patients treated with first-line (1L) cemiplimab-based therapy

Two nomograms constructed for predicting the efficacy and prognosis of advanced non‑small cell lung cancer patients treated with anti‑PD‑1 inhibitors based on the absolute counts of lymphocyte subsets

BackgroundPatients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors.MethodsThis retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve.ResultIn training cohort, lower baseline absolute counts of CD3+ (P < 0.001) and CD4+ (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3+ (P < 0.001), CD4+ (P < 0.001), CD8+ (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation.ConclusionWe constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.

Effectiveness of standard treatments in non-small-cell lung cancer with METexon14 skipping mutation: a real-world study.

Aim: To assess real-world clinical outcomes with standard therapies for advanced non-small-cell lung cancer (aNSCLC) with METexon14 skipping mutation (METex14).Methods: In an oncologists-led retrospective review of medical records, data were abstracted and analyzed for patients initiating first-line (1L) systemic therapy after 1 January 2017.Results: In total 287 aNSCLC patients with METex14, the real-world best overall response rate was 73.4% for capmatinib (n=146), 68.8% for immunotherapy (IO) monotherapy (n=48), 52.0% for chemotherapy (CT, n=30), and 54.8% for IO+CT (n=63). As compared with capmatinib, patients receiving IO (hazard ratio [HR]: 1.57; 95% CI: 0.77-3.20;p=0.220), CT (HR: 2.41; 95% CI: 1.19-4.85;p=0.014) and IO+CT (HR: 2.33; 95% CI: 1.35-4.04;p=0.003) had higher rates of progression. Further, patients receiving CT (HR: 4.43; 95% CI: 1.54-12.75;p=0.006) and IO+CT (HR: 3.53, 95% CI: 1.41-8.85;p=0.007) had higher rates of mortality than patients receiving capmatinib.Conclusion: The study showed better clinical outcomes with capmatinib than other standard therapies in 1L setting for aNSCLC harboring METex14.

Abstract 2546: Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s)

Abstract Background: ICIs, either alone or in combination with chemotherapy, have become the primary treatment options for aNSCLC patients without any targetable mutations. However, not all patients benefit similarly from these therapies even after selection based on the currently approved biomarker PD-L1 expression. Previous studies have shown that mutations in certain genes like STK11 and KEAP1 may predict non-response to these therapies. Mutations in STK11 occur in 25-30% of aNSCLC patients. We have used a real-world clinico-genomics dataset to investigate how this STK11+ aNSCLC patient population responds to ICIs in the context of other underlying co-mutations and whether some beneficial co-mutations may help patients overcome resistance due to their STK11 status. Methods: The ConcertAI Genome360TM NSCLC dataset (N=14193) was used in this retrospective study. aNSCLC patients who tested positive for STK11 mutations and received ICIs were considered (N=377). Based on their response to ICIs, the patients were divided into responder (N= 192) and non-responder (N=185) cohorts. Other genes with pathogenic mutations, fusions, and copy number changes were identified in both cohorts, and enrichment analysis was performed to identify co-mutations significantly enriched in one cohort vs the other. Once significant co-mutations were identified, pathway analysis was performed, taking into account the immune signaling network to help rationalise and validate the results. Results: One potential mechanism by which STK11 mutations influence the response to ICIs is through downregulation of the cGas-Sting pathway, which has been shown to play an important role in ICI response. Our co-mutational analysis also strongly supported this theory. We found that additional mutations that can nullify the effect of STK11 mutations on the cGas-Sting pathway led to a positive response (p=0.002) within the STK11+ cohort. Two such co-mutational signatures in responder patients identified were co-mutations in STK11/SMARCA4/TP53 (no KEAP1) (p-value = 0.003) and SKT11/KRAS/RBM10 (p-value = 0.04). Additionally, co-mutations in the DNA damage pathway genes (ATM, BRCA1, BRIP1, PALB2, STAG2) (p-value = 0.001) were also predictive of response to ICIs in the STK11+ cohort. Conclusion: By leveraging a real-world clinico-genomics dataset linking the tumor genomic profiles with patient response to ICIs, we have been able to perform a comprehensive co-mutational analysis of STK11+ aNSCLC patients to tease out the interplay of various biomarkers and signaling pathways that determine response to ICIs. Even though 25-30% aNSCLC patients are STK11+, we find that ~23% of these patients could still benefit from ICI treatment due to the presence of other co-mutations. Citation Format: Neeraj Singh, Smita Agrawal. Identifying co-mutational signatures in STK11 mutated advanced non-small cell lung cancer (aNSCLC) patients that help overcome poor response to immune checkpoint inhibitors (ICI’s) [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 2546.

High-Throughput Antigen Microarray Identifies Longitudinal Prognostic Autoantibody for Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer

Chemoimmunotherapy has evolved as a standard treatment for advanced non-small cell lung cancer (aNSCLC). However, inevitable drug resistance has limited its efficacy, highlighting the urgent need for biomarkers of chemoimmunotherapy. A three-phase strategy to discover, verify, and validate longitudinal predictive autoantibodies (AAbs) for aNSCLC before and after chemoimmunotherapy was employed. A total of 528 plasma samples from 267 aNSCLC patients before and after anti-PD1 immunotherapy were collected, plus 30 independent formalin-fixed paraffin-embedded samples. Candidate AAbs were firstly selected using a HuProt high-density microarray containing 21,000 proteins in the discovery phase, followed by validation using an aNSCLC-focused microarray. Longitudinal predictive AAbs were chosen for ELISA based on responders versus non-responders comparison and progression-free survival (PFS) survival analysis. Prognostic markers were also validated using immunohistochemistry and publicly available immunotherapy datasets. We identified and validated a panel of two AAbs (MAX and DHX29) as pre-treatment biomarkers and another panel of two AAbs (MAX and TAPBP) as on-treatment predictive markers in aNSCLC patients undergoing chemoimmunotherapy. All three AAbs exhibited a positive correlation with early responses and PFS (p < 0.05). The kinetics of MAX AAb showed an increasing trend in responders (p < 0.05) and a tendency to initially increase and then decrease in non-responders (p < 0.05). Importantly, MAX protein and mRNA levels effectively discriminated PFS (p < 0.05) in aNSCLC patients treated with immunotherapy. Our results present a longitudinal analysis of changes in prognostic AAbs in aNSCLC patients undergoing chemoimmunotherapy.

CD34 as a potential prognostic indicator for camrelizumab response in advanced non-small-cell lung cancer: insights from digital spatial profiling.

Given that only a small subset of patients with advanced non-small-cell lung cancer (aNSCLC) benefit from immune checkpoint inhibitors (ICIs), the effectiveness of ICIs is often compromised by the complex interplay within the tumor microenvironment (TME). To identify predictive biomarkers associated with ICI resistance at a multi-omics spatial level. A total of eight aNSCLC patients who received first-line anti-programmed cell death protein-1 (PD-1) monoclonal antibody camrelizumab at Shandong Cancer Hospital and Institute between 2021 and 2022 were included in the discovery cohort. An additional validation cohort of 45 samples from camrelizumab-treated aNSCLC patients was also enrolled. NanoString GeoMx® digital spatial profiling was conducted at the transcriptomic and proteomic level within pan-cytokeratin (panCK+), CD45+, and CD68+ compartments. For validation, multiplex immunofluorescence (mIF) staining was performed. Distinct spatial expression patterns and levels of immune infiltration were observed between tumor and leukocyte compartments. Higher CD34 expression in the macrophage compartment correlated with poorer prognosis and response to camrelizumab (p < 0.05). mIF validation confirmed the association of elevated CD34 expression level with reduced progression-free survival (PFS; hazard ratio (HR) = 5.011, 95% confidence interval: 1.057-23.752, p = 0.042), outperforming traditional tumor markers in predictive accuracy. Our findings identify CD34 as a novel spatial biomarker for anti-PD-1 therapy efficacy, potentially guiding the selection of aNSCLC patients who are more likely to benefit from ICI treatment. ChiCTR2000040416.

Immune Checkpoint Inhibitors and the Risk of Cardiovascular Adverse Events: A Pooled Clinical Trial Database Analysis

Introduction Immune checkpoint inhibitors (ICIs) are a highly effective class of cancer immunotherapy, but their use has been limited by immune-related adverse events (irAEs) affecting various organ systems. Recent real-world studies have shown higher incidence rates of cardiovascular (CV) events in patients with cancer who are treated with ICIs compared to those treated with conventional chemotherapy (Laenens et al, J Clin Oncol 2022). Studies suggest that the underlying mechanism involves a pro-inflammatory response causing unintended vascular compromise, but there have been limited data on ICI-related cardiotoxicity across pooled datasets. Given that ICIs have been applied to lung cancer treatment in recent years, we use it as an example indication to study clinical trial (CT) patients with advanced non-small cell lung cancer (aNSCLC) randomized to either a first-line (1L) ICI-containing regimen or to 1L chemotherapy alone (chemo) to evaluate for potential differential rates of CV events. Methods We pooled patient-level, phase 3 CT data on aNSCLC patients treated with ICI or chemo from the Medidata Enterprise Data Store. Treatment assignment was the main variable of interest. The primary outcome was a composite CV event (acute coronary syndrome, heart failure, stroke, transient ischemic attack), occurring between the start of study treatment (index date) and 30 days following the last dose of study treatment. Incidence rates and the relative hazard of a CV event by treatment assignment were estimated. Additionally, the risk of CV event with non-CV death treated as a competing risk was estimated using the Fine-Gray model. In a post-hoc subgroup analysis we explored the impact of treatment assignment on overall survival (OS) among patients with and without baseline vascular disease. OS was defined as the time from the index date until the date of death (all-cause). Patients alive at the end of CT follow-up were censored. Results A total of 1862 patients were included in this analysis, with 1128 (60.6%) randomized to ICI and 734 (39.4%) to chemo. Baseline demographics and comorbidities were balanced across treatment groups. Forty-six (2.5%) patients experienced at least 1 CV event. The incidence rate of CV events was 2.48 times (95% CI: 1.10, 6.57) higher among patients treated with ICI compared to chemo. The unadjusted hazard of composite CV event, estimated using Kaplan-Meier, differed significantly by treatment assignment (p= 0.008) ( Figure 1). After adjusting for baseline demographics and comorbidities, the hazard of a composite CV event remained higher for patients treated with ICI compared to chemo (aHR 2.68, 95% CI: 1.19-6.06) ( Table 1). Baseline vascular disease history (N=359; 19.3%) was also associated with an increased hazard of a CV event (aHR: 2.40; 95% CI: 1.25-4.60). Similar results were found in the competing risk analysis. In the subgroup analysis, patients without baseline vascular disease history had a significant OS benefit from an ICI compared to chemo (aHR 0.84, 95% CI: 0.75-0.95), whereas patients with baseline vascular disease did not (aHR 1.00, 95% CI: 0.78-1.27). Conclusion Though ICIs enhance the body's immune responses against cancer, it is important to study the associated effect of irAEs on off-target tissues. These analyses of historical CT data suggest a positive association between 1L treatment of aNSCLC with ICI and subsequent composite CV events compared with chemo alone. Given the high prevalence of morbidity among patients with lung cancer, the use of concomitant cardioprotective therapies may be an important consideration when treating cancer populations with ICIs. Pooling CT data increases the power to detect clinically important differences in rare toxicities and may inform future research and patient-physician decision-making regarding the suitability of ICI use in aNSCLC treatment. Furthermore, this research highlights the potential clinical utility of drug repurposing: expanding the use of drugs approved to treat CV events and exploring their use in patients with vascular disease who are also being treated with ICIs. As cell-mediated immune responses play a key role in the potential CV effects of ICI treatments, future studies are needed to define the underlying mechanisms of ICI-related dysregulation of the immune system to better monitor patients and improve clinical outcomes in the context of immunotherapy for aNSCLC and other cancer types.

Evaluation of the effectiveness of a nationwide precision medicine program for patients with advanced non-small cell lung cancer in Germany: a historical cohort analysis

The national Network Genomic Medicine (nNGM) Lung Cancer provides comprehensive and high-quality multiplex molecular diagnostics and standardized personalized treatment recommendation for patients with advanced non-small cell lung cancer (aNSCLC) in Germany. The primary aim of this study was to investigate the effectiveness of the nNGM precision medicine program in terms of overall survival (OS) using real-world data (RWD). A historical nationwide cohort analysis of patients with aNSCLC and initial diagnosis between 04/2019 and 06/2020 was conducted to compare treatment and OS of patients with and without nNGM-participation. Patients participating within the nNGM (nNGM group) were selected based on a prospective nNGM database. The electronic health records (EHR) of the prospective nNGM database were case-specifically linked to claims data (AOK, German health insurance). The control group was selected from claims data of patients receiving usual care without nNGM-participation (non-nNGM group). The minimum follow-up period was six months. Overall, n=509 patients in the nNGM group and n=7213 patients in the non-nNGM group met the inclusion criteria. Patients participating in the nNGM had a significantly improved OS compared to the non-nNGM group (median OS: 10.5 months vs. 8.7 months, p=0.008, HR=0.84, 95% CI: 0.74-0.95). The 1-year survival rates were 46.8% (nNGM) and 41.3% (non-nNGM). The use of approved tyrosine kinase inhibitors (TKI) in the first-line setting was significantly higher in the nNGM group than in the non-nNGM group (nNGM: 8.4% (43/509) vs. non-nNGM: 5.1% (366/7213), p=0.001). Overall, patients receiving first-line TKI treatment had significantly higher 1-year OS rates than patients treated with PD-1/PD-L1 inhibitors and/or chemotherapy (67.2% vs. 40.2%, p<0.001). This is the first study to demonstrate a significant survival benefit and higher utilization of targeted therapies for aNSCLC patients participating within nNGM. Our data indicate that precision medicine programs can enhance collaborative personalized lung cancer care and promote the implementation of treatment innovations and the latest scientific knowledge into clinical routine care. The study was funded by the AOK Federal Association Germany.

Predicting response to immunotherapy in non-small cell lung cancer- from bench to bedside.

Immune checkpoint inhibitor (ICI) therapy is first-line treatment for many advanced non-small cell lung cancer (aNSCLC) patients. Predicting response could help guide selection of intensified or alternative anti-cancer regimens. We hypothesized that radiomics and laboratory variables predictive of ICI response in a murine model would also predict response in aNSCLC patients. Fifteen mice with lung carcinoma tumors implanted in bilateral flanks received ICI. Pre-ICI laboratory and computed tomography (CT) data were evaluated for association with systemic ICI response. Baseline clinical and CT data for 117 aNSCLC patients treated with nivolumab were correlated with overall survival (OS). Models for predicting treatment response were created and subjected to internal cross-validation, with the human model further tested on 42 aNSCLC patients who received pembrolizumab. Models incorporating baseline NLR and identical radiomics (surface-to-mass ratio, average Gray, and 2D kurtosis) predicted ICI response in mice and OS in humans with AUCs of 0.91 and 0.75, respectively. The human model successfully sorted pembrolizumab patients by longer vs. shorter predicted OS (median 35 months vs. 6 months, p=0.026 by log-rank). This study advances precision oncology by non-invasively classifying aNSCLC patients according to ICI response using pre-treatment data only. Interestingly, identical radiomics features and NLR correlated with outcomes in the preclinical study and with ICI response in 2 independent patient cohorts, suggesting translatability of the findings. Future directions include using a radiogenomic approach to optimize modeling of ICI response.

Association between treatment and improvements in overall survival of patients with advanced/metastatic non-small cell lung cancer since 2011: A study in the United States, Canada, and Germany using retrospective real-world databases.

This study aimed to describe treatment patterns and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) in three countries between 2011 and 2020. Three databases (US, Canada, Germany) were used to identify incident aNSCLC patients. OS was assessed from the date of incident aNSCLC diagnosis and, for patients who received at least a first line of therapy (1LOT), from the date of 1LOT initiation. In multivariable analyses, we analyzed the influence of index year and type of prescribed treatment on OS. We included 51,318 patients with an incident aNSCLC diagnosis. The percentage of patients treated with a 1LOT differed substantially between countries, whereas the number of patients receiving immunotherapies/targeted treatments increased over time in all three countries. Median OS from the date of incident diagnosis was 9.9months in the United States vs. 4.1months in Canada. When measured from the start of 1LOT, patients had a median OS of 10.7months in the United States, 10.9months in Canada, and 10.9months in Germany. OS from the start of 1LOT improved in all three countries from 2011 to 2020 by approximately 3 to 4months. Observed continuous improvement in OS among patients receiving at least a 1LOT from 2011 to 2020 was likely driven by improved care and changes in the treatment landscape. The difference in the proportion of patients receiving a 1LOT in the observed countries requires further investigation.

Socioeconomic influence of insurance coverage and ethnicities on efficacy outcomes and side effects related to immune checkpoint inhibitors in non-small cell lung cancer.

168 Background: Immune checkpoint inhibitors (ICI) are approved for treatment of various malignancies. However, ethnic minorities and underprivileged patient populations are often not adequately represented in clinical studies. We hereby delineate updated data on efficacy outcomes and immune-related adverse effects (IRAEs) among patients with advanced non-small cell lung cancer (aNSCLC) belonging to diverse ethnicities, and government sponsored (Medicare/Medicaid-MM) vs commercial insurance (COI) vs uninsured (UNI). Methods: A retrospective study of adult patients who received ICI or ICI plus chemotherapy was conducted at an urban safety net hospital. The timeline was expanded from January 2015 to June 2022. Data was collected from the electronic medical record with IRB approval. All grade (CTCAE v5.0) IRAEs were identified. Progression at 1 year (1y-PFS) in addition to survival at 1-year (1y-OS) from ICI initiation was calculated for aNSCLC patients using RECIST 1.1. Chi-square analysis and ANOVA testing were utilized to determine statistical significance. Results: 291 patients were identified with ICI use. 104 patients had aNSCLC and had follow up for at least 1 year. This aNSCLC population had 42 African American (AA) and 62 Caucasian patients (CC). 79 patients had MM, 24 possessed COI and 7 were UNI. AA patients with aNSCLC had poorer 1y-OS at 44% (p=0.12) and 1y-PFS at 15% (p=0.0005) compared to CC patients which had 1y-OS of 61% and 1y-PFS of 51%. CC patients had more all grade IRAEs (42.4%) in comparison to AA patients (36.2%) (p=0.58). 1y-PFS and 1y-OS were 39% and 67% respectively in COI patients compared to MM patients who had 38% and 50% (p=0.51 and p=0.46 respectively). Self-pay had the worst 1y-PFS (19%) and 1-yr OS (36%). All grade IRAEs were 41% in MM patients, 40% in UNI and 35% in COI patients (p=0.68). Conclusions: This expanded study with updated data further upholds the influence of ethnicities and insurance coverage on the incidence of IRAEs and efficacy with ICI. There was a significant difference with worse outcome in AA population compared to CC with ICI use in aNSCLC. COI patients showed better outcome trend (non-significant) than patients with government sponsored insurance and uninsured patients had worst outcomes. This implies that impoverished patients and ethnic minorities may have inferior outcomes with ICI therapy. Larger population studies may provide further validation of these findings.[Table: see text]

EP11.03-38 Comparison of Real-World Outcomes in aNSCLC Patients Receiving 1L Immunotherapy Alone or in Combination with Chemotherapy

EP11.03-38 Comparison of Real-World Outcomes in aNSCLC Patients Receiving 1L Immunotherapy Alone or in Combination with Chemotherapy

EP11.03-35 Impact of KRAS Mutation Subtype and Comutations across PD-L1 Levels in aNSCLC Patients Treated with (Chemo)Immunotherapy

EP11.03-35 Impact of KRAS Mutation Subtype and Comutations across PD-L1 Levels in aNSCLC Patients Treated with (Chemo)Immunotherapy

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

BackgroundBone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. MethodsData from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike’s information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. ResultsOf 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9–12.8) versus (vs) 6.8 m (95% CI 4.0–9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4–14.2) vs 3.5 m (95% CI 2.9–4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6–4.4) vs 1.8 m (95% CI 1.6–2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1–30.7) vs 3.5 m (95% CI 2.9–4.1) p = 0.002]. ConclusionsIn the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Exploring the Role of Immunotherapy-Based Treatments for Advanced Non–Small-Cell Lung Cancer With Novel Driver Alterations

BackgroundImmunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non–small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported. Materials and MethodsData of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test. Resultsm-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort. ConclusionIO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required.

Quantitative multiplexed imaging technologies for single-cell analysis to assess predictive markers for immunotherapy in thoracic immuno-oncology: promises and challenges.

The past decade has witnessed a revolution in cancer treatment by the shift from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular the immune-checkpoint inhibitors (ICIs). These immunotherapies selectively release the host immune system against the tumour and have shown unprecedented durable remission for patients with cancers that were thought incurable such as advanced non-small cell lung cancer (aNSCLC). The prediction of therapy response is based since the first anti-PD-1/PD-L1 molecules FDA and EMA approvals on the level of PD-L1 tumour cells expression evaluated by immunohistochemistry, and recently more or less on tumour mutation burden in the USA. However, not all aNSCLC patients benefit from immunotherapy equally, since only around 30% of them received ICIs and among them 30% have an initial response to these treatments. Conversely, a few aNSCLC patients could have an efficacy ICIs response despite low PD-L1 tumour cells expression. In this context, there is an urgent need to look for additional robust predictive markers for ICIs efficacy in thoracic oncology. Understanding of the mechanisms that enable cancer cells to adapt to and eventually overcome therapy and identifying such mechanisms can help circumvent resistance and improve treatment. However, more than a unique universal marker, the evaluation of several molecules in the tumour at the same time, particularly by using multiplex immunostaining is a promising open room to optimise the selection of patients who benefit from ICIs. Therefore, urgent further efforts are needed to optimise to individualise immunotherapy based on both patient-specific and tumour-specific characteristics. This review aims to rethink the role of multiplex immunostaining in immuno-thoracic oncology, with the current advantages and limitations in the near-daily practice use.

Real-World Treatment Outcomes of MET Exon14 Skipping in Non-small Cell Lung Cancer: GFPC 03-18 Study.

MET-targeted tyrosine kinase inhibitors (TKIs) demonstrated efficacy in advanced non-small cell lung cancer (aNSCLC) with MET exon14 skipping mutations (METexon14); yet, data on the management of these patients in clinical practice is sparse. The aim of this study was to describe the management of METexon14 aNSCLC patients. This real-life, retrospective study analyzed the management of METexon14 aNSCLC. The primary endpoint was the median overall survival (mOS). Secondary endpoints were to assess investigator-progression-free survival (PFS) and mOS in different subgroups: patients treated with (a) crizotinib, regardless of treatment line; (b) anti-MET TKIs (crizotinib, tepotinib, capmatinib); and (c) immunotherapy. A total of 118 patients were included between December 2015 and January 1, 2020 in 13 centers. Median age was 73 years, 62.7% were female, 83.9% had adenocarcinoma, 92.4% at stage IV, and 27% had more than three metastatic sites. The majority of the patients (106, 89.8%) received at least one systemic treatment; 73% received at least one anti-MET TKI: crizotinib (68.6%), tepotinib (16%), capmatinib (10%). Only 10% received two anti-MET TKIs in their treatment sequences. With a median follow-up of 16 months (95% CI 13.6-29.7), mOS was 27.1 months (95% CI 18-31.4). There was no significant difference between mOS of patients treated and never treated with crizotinib, 19.7 (95% CI 13.6-29.7) and 28 (95% CI 16.4-NR) months, respectively (p=0.16); mOS of the TKI cohort and of the TKI-naïve patient cohort were 27.1 (95% CI 18-29.7) and 35.6 (95% CI 8.6-NR) months respectively, with no significant difference (p=0.7). In this real-life study, there was no evidence of benefit in mOS with anti-MET TKIs.

RET testing and treatment patterns among patients with aNSCLC in US clinical practice.

9091 Background: Biomarker testing, including for rearrangement during transfection (RET), is recommended and important in selecting efficacious targeted therapy for patients with advanced non-small cell lung cancer (aNSCLC). This retrospective cohort study characterized RET testing and treatment patterns among aNSCLC patients in clinical practice. Methods: We used the nationwide Flatiron Health electronic health record-derived de-identified database to select patients diagnosed with aNSCLC (stage ≥IIIB) from 2017-2022. We measured rates of RET testing (test result ≤90 days after advanced diagnosis). We used logistic regression to identify baseline characteristics predictive of timely testing. Finally, we described treatment patterns for patients with RET+ aNSCLC before and after the US approval of RET inhibitors. Results: Among 26,329 aNSCLC patients, rates of RET testing ≤90 days after advanced diagnosis increased from 25% (2017 Q1) to 73% (2022 Q1). Patients were less likely to receive RET testing within 90 days if they were Black (multivariate odds ratio [OR] 0.8) or Hispanic (OR 0.8) compared to White, or had Medicare (OR 0.9; all p&lt;0.001) compared to commercial insurance. Patients were more likely to receive RET testing within 90 days if they were in the highest socioeconomic quintile (OR 1.4), had de novo disease (OR 2.1), or no history of smoking (OR 1.3; all p&lt;0.001). Between 2017 and 2022, there were increases in the use of next-generation sequencing (66% to 89%) and blood samples for biomarker testing (25% to 49%) and a decrease in mean days from diagnosis to test result (33 to 28) for the first RET test among those who had testing within 90 days. Among all patients with aNSCLC tested within 90 days (n=12,275), 73 were RET+ and received 1L treatment ≤90 days after advanced diagnosis. The most common 1L treatments before (n=35) and after (n=38) RET inhibitor approval were chemotherapy (40%) and RET inhibitor (42%), respectively (Table). Conclusions: RET testing has increased over time, but certain patient subgroups are less likely to receive timely RET testing and therefore may not be optimally treated. Among patients with RET+ aNSCLC identified after RET inhibitor approval, only 42% were treated with a RET inhibitor in the 1L setting. These results suggest both disparities in access to RET testing and unmet medical need among patients with RET+ aNSCLC. [Table: see text]