aNSCLC Patients Research Articles

Impact of KRAS G12C mutation in patients with advanced non-squamous non-small cell lung cancer treated with first-line pembrolizumab monotherapy

ObjectivesFew data are available on the impact of KRAS mutation in patients with advanced non-squamous non-small cell lung cancer (aNSCLC) treated with immunotherapy. This analysis assessed the impact of KRAS mutation on the efficiency of first-line pembrolizumab immunotherapy in aNSCLC patients with PD-L1 ≥ 50 %. MethodsThis was a secondary analysis of the ESCKEYP study, a retrospective, national, multicenter study which included consecutively all metastatic NSCLC patients who initiated first-line treatment with pembrolizumab monotherapy from May 2017 (date of pembrolizumab availability in this indication in France) to November 22, 2019 (pembrolizumab-chemotherapy combination approval). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of pembrolizumab treatment by the Kaplan-Meier method. Tumor response and PFS were assessed locally. ResultsAmong the 681 non-squamous aNSCLC PD-L1 ≥ 50 % patients treated with pembrolizumab in the first line, 227 (33.0 %) had a KRAS mutation (KRAS G12C, 12.5 %; KRAS non-G12C, 20.5 %). Except among non-smokers (KRAS G12C, 0 %; KRAS non-G12C, 2.9 %; no KRAS mutation, 9.2 %), patients presented no differences in terms of sex, age, number and sites of metastatic disease at diagnosis, use of corticosteroids, use of antibiotics, and for biological factors between wild-type KRAS, KRAS G12C and non-KRAS G12C groups. Median (95 % CI) PFS in months were 7.0 (3.7–14) for KRAS G12C, 4.8 (3.4–6.7) for KRAS non-G12C and 8.5 (7.3–10.6) for wild-type KRAS genotypes (p = 0.23). Median OS were 18.4 (12.6-NR), 20.6 (11.4-NR) and 27.1 (18.7–34.2) months, respectively (p = 0.57). ConclusionNo difference in efficacy was observed in non-squamous aNSCLC patients treated with first-line pembrolizumab immunotherapy whether they presented a KRAS G12C, non KRAS G12C or wild-type KRAS genotype.

Biological Rationale for Peripheral Blood Cell-Derived Inflammatory Indices and Related Prognostic Scores in Patients with Advanced Non-Small-Cell Lung Cancer.

To describe the biological rationale of peripheral blood cells (PBC)-derived inflammatory indexes and assess the related prognostic scores for patients with advanced non-small cell lung cancer (aNSCLC) treated with immune-checkpoint inhibitors (ICI). Inflammatory indexes based on PBC may indicate a pro-inflammatory condition affecting the immune response to cancer. The lung immune prognostic index (LIPI), consisting of derived neutrophils-to-lymphocyte ratio (NLR) and lactate dehydrogenase, is a validated prognostic tool, especially for pretreated aNSCLC patients, where the combination of NLR and PD-L1 tumour expression might also be predictive of immunotherapy benefit. In untreated high-PD-L1 aNSCLC patients, the Lung-Immune-Prognostic score (LIPS), including NLR, ECOG PS and concomitant steroids, is prognostic, and its modified version might indicate patients with favourable outcomes despite an ECOG PS of 2. NLR times platelets (i.e., SII), included in the NHS-Lung score, might improve the prognostication for combined chemoimmunotherapy. PBC-derived inflammatory indexes and related scores represent accurate, reproducible and non-expensive prognostic tools with clinical and research utility.

Systemic anti-cancer therapy patterns in advanced non-small cell lung cancer in Europe

BackgroundSystemic anti-cancer therapy (SACT) is the recommended treatment modality in patients with advanced non-small cell lung cancer (aNSCLC) in clinical guidelines. SACT options in aNSCLC have multiplied in recent years with the introduction of immunotherapy and targeted therapy. This article presents findings from the first comparative analysis of SACT patterns in Europe. MethodsSACT rates in aNSCLC were estimated as the ratio between the number of patients treated with SACT (chemotherapy, immunotherapy, targeted therapy) and the number of potentially eligible patients for SACT in 11 countries (Belgium, Bulgaria, Finland, Hungary, Ireland, Netherlands, Norway, Poland, Portugal, Romania, UK) between 2014 and 2020. Treated patients were estimated by combining national sales volume data of cancer drugs and average drug use per patient based on clinical trials. Potentially eligible patients were estimated from national epidemiological data. ResultsSACT rates in aNSCLC differed greatly, ranging from around 30 % in Hungary, Poland, and the UK to almost 60 % in Ireland, Norway, and Portugal in 2014. SACT rates seemed to increase over time in most countries, but differences were still large by 2020, ranging from around 40 % in the UK to 75 % or more in Belgium, Norway, and Portugal. Even in countries with the highest SACT rates, far from all patients seemed to receive guideline-recommended SACT options, as underuse of immunotherapy and targeted therapy was common. ConclusionUp to 35 % of eligible patients with aNSCLC receives no SACT in certain European countries, although improvements have been achieved over time. The use of immunotherapy and targeted therapy is suboptimal even in countries with high SACT rates, indicating room to improve the quality of care and patient outcomes. Policy summaryMeasuring if and what kind of therapy cancer patients have access to is vital to assess quality of care. The care of aNSCLC patients seems to be suboptimal in Europe, due to factors such as exclusion of patients with moderate performance status from SACT, limited resources for diagnostic testing, long reimbursement timelines and slow adoption of new medicines in clinical practice.

1091P Predictive and prognostic value of Patras Immunotherapy Score (PIOS) in patients with advanced NSCLC treated with immunotherapy/chemotherapy combination

Although immune checkpoint inhibitors (ICIs) have significantly changed the treatment algorithm of patients with advanced non-small cell lung cancer (aNSCLC), the discovery of clinically useful biomarkers remain a challenging issue. Recently, a new score, Patras Immunotherapy Score (PIOS), has been proposed by our group focusing on the results of aNSCLC patients treated with nivolumab or pembrolizumab. The aim of the current study was to investigate the prognostic and predictive value of PIOS in aNSCLC patients treated with combination of immunotherapy with chemotherapy.

1111P Real-world treatment duration in patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations receiving mobocertinib through the global Expanded Access Program (EAP)

Mobocertinib is a first-in-class, potent, oral, irreversible tyrosine kinase inhibitor that selectively targets in-frame EGFRex20ins mutations in NSCLC. It was recently approved in the US (Sep-2021) and the UK (Mar-2022) for patients with locally advanced or metastatic NSCLC (aNSCLC) with EGFRex20ins mutations whose disease has progressed on platinum-based chemotherapy. This report describes the real-world treatment duration of mobocertinib in post-platinum EGFRexon20ins aNSCLC patients enrolled in a global EAP that provides access to mobocertinib for patients with unmet medical need.

1115P Amivantamab vs real-world (RW) therapies for advanced non-small cell lung cancer (aNSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (E20i) in Japan

In the single-arm CHRYSALIS study, amivantamab, an EGFR-MET bispecific antibody, showed durable responses in EGFR E20i aNSCLC patients (pts). We conducted an indirect treatment comparison study to evaluate the efficacy of amivantamab compared to current systemic anti-cancer therapies. Here we also explore amivantamab versus docetaxel (DOC), EGFR tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO) in RW practice in Japan using a lung cancer genomic screening platform (LC-SCRUM-Asia) with more than 16,000 NSCLC pts from 2013.

EP08.01-072 Clinical Value of Patras Immunotherapy Score (PIOS) Formula in Patients With Advanced NSCLC Treated With Immunotherapy/Chemotherapy

Clinical course of patients with advanced non-small cell lung cancer (aNSCLC) has tremendously changed the last decade due to immune checkpoint inhibitors (ICIs). However, clinical useful biomarkers remain an unmet need. Recently, our group has proposed a new score, Patras Immunotherapy Score (PIOS), based on the results of aNSCLC patients treated with ICIs monotherapy. The objective of the current study was to assess the clinical significance of PIOS formula in aNSCLC patients treated with combination of immunotherapy with chemotherapy.

Association Between Survival and Very High Versus High PD-L1 Expression in Patients Receiving Pembrolizumab as First-line Treatment for Advanced Non-Small Cell Lung Cancer

BackgroundA prior study found that, among advanced non-small cell lung cancer (aNSCLC) patients with PD-L1 expression 50% to 100% receiving immunotherapy as monotherapy, PD-L1 expression ≥ 90% was associated with longer survival. We sought to replicate this finding using real-world data from community oncology practices across the US. MethodsRetrospective cohort study of aNSCLC patients who initiated pembrolizumab monotherapy for first line and had a PD-L1 expression ≥ 50% using a nationwide, deidentified longitudinal electronic health record–derived real-world database. The exposure of interest was very high PD-L1 expression, which was defined as ≥ 90%, compared to high PD-L1 expression, defined as 50% to 89%. The primary outcome was overall survival, measured from initiation of pembrolizumab to date of death, with censoring at last healthcare encounter. Multiple imputation was used to impute missing covariates. Propensity score-based inverse probability weighting (IPW) was used to address confounding in Kaplan-Meier curves and Cox proportional hazard regression models. ResultsThe cohort included 1952 aNSCLC patients receiving first-line pembrolizumab monotherapy. Half of cohort members were female, median age was 73 years (interquartile range, 65-80), 71% had non-squamous histology, 94% had a history of smoking, and 46% had very high PD-L1 expression. Median overall survival in the propensity score-weighted sample was 15.84 months for very high PD-L1 expression and 12.72 months for high PD-L1 expression. Having a very high PD-L1 expression was associated with lower hazard of mortality (IPW hazard ratio 0.79, 95% CI 0.69-0.91). ConclusionsIn this large national US cohort, patients with very high PD-L1 expression (≥ 90%) aNSCLC receiving first-line pembrolizumab experienced better median survival than those with high PD-L1 expression (50% to 89%).

Comprehensive characterization reveals sputum supernatant as a valuable alternative liquid biopsy for genome profiling in advanced non-small cell lung cancer

BackgroundSputum biopsies offer unique advantages such as non-invasiveness and convenient collection. The one investigation so far on sputum for genome profiling in advanced non-small cell lung cancer (aNSCLC) suggested promising performance. However, it remains undefined whether clinicohistologic characteristics were associated with performance and how this knowledge could help guide choice of liquid biopsy.MethodsTargeted sequencing with a 520-gene panel was performed on prospectively collected matched tumor tissue (TIS), plasma (PLA), and sputum supernatant (SPU) from 71 aNSCLC patients (NCT05034445). Genomic alteration detection was characterized in a series of aspects and interrogated for association with 14 clinicohistologic features. Nomograms were constructed with logistic regression for predicting the liquid biopsy type with greater sensitivity.ResultsCompared with PLA, SPU showed comparable quality control metrics, mutation detection rate (SPU: 67.6%, PLA: 70.4%), concordance with tumor tissue (67.6% vs. 73.2%), and correlation with tissue-based tumor mutation burden levels (r = 0.92 vs. 0.94). For driver alterations, detection was less sensitive with SPU (50.0%) than PLA (63.5%) in the entire cohort but similarly or more sensitive in patients with centrally located lung tumors or smoking history or for altered ALK or KRAS. Two nomograms were constructed and enabled predicting the probability of superior sensitivity with SPU with moderate to borderline high accuracy.ConclusionIn addition to demonstrating comparable performance in multiple aspects, this study is the first to propose nomograms for choosing liquid biopsy based on clinicohistologic characteristics. Future research is warranted to delineate the clinical utility of sputum for genome profiling.

Efficacy outcomes and prognostic factors from real-world patients with advanced non-small-cell lung cancer treated with first-line chemoimmunotherapy: The Spinnaker retrospective study

BackgroundEfficacy outcomes and prognostic factors of real-world patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line chemoimmunotherapy are still limited. Patients and MethodsIn the retrospective Spinnaker study, data was collected from patients in six United Kingdom and one Swiss oncology centres with first-line pembrolizumab plus platinum-based chemotherapy. Efficacy outcomes and potential prognostic factors were estimated aiming at developing a prognostic model. ResultsThree-hundred-eight patients were included, 32% ≥ 70 years, with ≥ 3 metastatic sites in 33%, brain or liver metastases in 10% and 12%, respectively. With a median follow-up of 18.0 months (mo.) (range, 15.9–20.1), median overall survival (OS) and progression-free survival (PFS) were 12.7 mo. (range, 10.2–15.2), and 8.0 mo. (range, 7.1–8.8), respectively. The neutrophils-to-lymphocytes ratio (NLR) and systemic immune-inflammatory index (SII) (i.e., NLR × platelet count) were both significantly higher in ECOG PS 1 (p = 0.0147 and p = 0.0018, respectively), underweight or normal body mass index (p = 0.0456 and p = 0.0062, respectively), ≥3 metastatic sites (p = 0.0069 and p = 0.112), pretreatment steroids (p = 0.0019 and p = 0.0017). By MVA, the number of metastatic sites ≥ 3 (p < 0.001 and p = 0.002), squamous histology (p = 0.033 and p = 0.013) and SII ≥ 1444 (p = 0.031 and p = 0.009, respectively) were associated with both worse OS and PFS and led to a highly discriminating three-class risk prognostic model. ConclusionReal-world PFS with chemoimmunotherapy in aNSCLC patients is similar to that reported in clinical trials. A high number of metastatic sites, squamous histology and high SII are adverse prognostic factors that might contribute to a clinically useful prognostic model.

Very high PD-L1 expression as a prognostic indicator of overall survival among patients with advanced non-small cell lung cancer receiving anti-PD-(L)1 monotherapies in routine practice.

Programmed death or ligand-1 (PD-(L)1) pathway inhibitors confer improved survival as the first-line treatment for advanced non-small cell lung cancer (aNSCLC) in patients with PD-L1 expression (PD-L1 + e ≥ 50%) compared to platinum-doublet chemotherapy and have become a standard therapy. Some recent evidence suggests that among aNSCLC patients with PD-L1 + e of ≥50% receiving pembrolizumab monotherapy, very high levels of PD-L1 + e (≥90%) may be associated with better outcomes. We sought to assess whether very high PD-L1 + e (≥90%) compared to high PD-L1 + e (50%-89%) is associated with an overall survival benefit in aNSCLC patients receiving anti-PD-(L)1 monotherapies. We conducted a single-site retrospective cohort study of aNSCLC patients who initiated PD-(L)1 inhibitor monotherapy as the first-line treatment from October 24, 2016, to August 25, 2021, and had a PD-L1 + e ≥ 50%. The primary outcome was overall survival, measured from the start of the first-line PD-(L)1 inhibitor monotherapy (index date) to date of death or last confirmed activity prior to the cohort exit date. Propensity score-based inverse probability weighting (IPW) was used to control for confounding in Kaplan-Meier curves and Cox proportional hazard regression analysis. One hundred sixty-six patients with aNSCLC receiving PD-(L)1 inhibitor monotherapy met inclusion criteria. 54% were female, 90% received pembrolizumab, median age was 68 years, 70% had non-squamous cell carcinoma, 94% had a history of smoking, 29% had a KRAS mutation, and 37% had very high PD-L1 + e. Unweighted covariates at cohort entry were similar between groups (absolute standardized mean differences [SMDs] <0.1) except for race (SMD=0.2); age at therapy initiation (SMD=0.13); smoking status (SMD=0.13), and BRAF mutation status (SMD=0.11). After weighting, baseline covariates were well balanced (all absolute SMDs <0.1). In the weighted analysis, having a very high PD-L1 + e was associated with lower mortality (weighted hazard ratio 0.57, 95% CI 0.36-0.90) and longer median survival: 3.85 versus 1.49 years. Very high PD-L1 + e (≥90%) was associated with an overall survival benefit over high PD-L1 + e (50%-89%) in patients receiving the first-line PD-(L)1 inhibitor monotherapy in a model controlling for potential confounders. These findings should be confirmed in a larger real-world data set.

Prognostic role of neutrophil-to-lymphocyte ratio and EPSILoN score in advanced non-small-cell lung cancer patients treated with first-line chemo-immunotherapy.

Background: Clinical and laboratory biomarkers in patients withadvanced non-small-cell lung cancer (aNSCLC) receiving chemo-immunotherapy (CIT) are still poorly explored. Materials & methods: All consecutive aNSCLC patients who received at least one cycle of first-line CIT were enrolled. The impact of several clinical and laboratory biomarkers on outcomes was evaluated through Cox proportional hazard models. Results: Higher neutrophil-to-lymphocyte ratio was shown to be an independent prognostic biomarker of both worse progression-free survival and worse overall survival. The EPSILoN score was able to divide patients into three different prognostic groups, with a median overallsurvival of 73.2, 45.6 and 8.6months for the favorable, intermediate and poor groups, respectively. Conclusion: The neutrophil-to-lymphocyte ratio and EPSILoN score were shown to have a prognostic value in aNSCLC patients treated with CIT.

Abstract 6350: Very high PD-L1 expression as a prognostic indicator of overall survival amongst advanced non-small cell lung cancer patients receiving anti PD-(L)1 monotherapies in the first line setting: An IPW weighted health system analysis

Abstract Background Programmed death or ligand-1 (PD-(L)1) pathway inhibitors, a type of immunotherapy (IO), have become a standard anti-tumor strategy for advanced non-small cell lung cancer (aNSCLC) resulting in improved survival compared to platinum-doublet chemotherapy in PD-L1 expression (PD-L1+e ≥50%) in the 1L treatment setting. Limited evidence to suggest that amongst aNSCLC patients with PD-L1+e of 50%-100%, very high levels of PD-L1e (≥90%) would have any additional prognostic value leading to improved outcomes. Identifying additional PDL1+e cutoffs in aNSCLC with PDL1+e of 50%-100% would help treatment selection in routine practice as well as future IO clinical trials design ensuring trial groups are evenly balanced based on PD-L1+e levels. Objective To assess very high PD-L1+e (≥90%) as a prognostic indicator of overall survival in aNSCLC patients with PDL1+e ≥50% receiving anti PD-(L)1 monotherapies, using a single university EMR based health database. Methods Cohort study of aNSCLC patients, who initiated IO monotherapy in the 1L treatment setting from October 2016, to August 2021, and had a PDL1+e ≥ 50%. This study was conducted in the University of Pennsylvania Health System. Patients with incomplete treatment data or those harboring sensitizing alterations in EGFR, ALK, or ROS1 genes were excluded. The primary outcome was overall survival, measured from the start of 1L IO monotherapy (index date) to date of death or last confirmed activity. Propensity score-based inverse probability weighting (IPW) was used to address confounding in KM curves and Cox hazard regression. Baseline characteristics included age at therapy initiation, race, gender, smoking status, tumor histology, presence of KRAS or BRAF mutation, and ECOG PS. Results 196 aNSCLC receiving IO monotherapy met the inclusion criteria; n=30 had missing ECOG PS. 53% of the cohort were female, the median age at therapy initiation was 68 years, 72% had non-squamous cell carcinoma with 92% having a history of smoking, 28% had a KRAS mutation, and 37% had very high PDL1+e. Covariates were well balanced between groups after IPW weighting (all │standardized differences│&amp;lt;0.1). 92% received Pembrolizumab IO monotherapy. Median overall survival was 3.85 years (v high -PDL1+e) vs 1.52 years (high -PDL1+e), respectively. In the complete case analysis (n=166), having a very high PDL1+e (HR 0.57, 95% CI 0.36-0.90) was associated with lower mortality. Study limitations include the potential for unmeasured confounding and potentially limited generalizability. Conclusion Patients with aNSCLC having very high PDL1+e (≥90%) receiving IO monotherapy appear to have improved survival in the 1L setting. These findings should be confirmed in a larger real-world data set. Citation Format: Mohsin Shah, Rebecca A. Hubbard, Ronac Mamtani, Sean Hennessy. Very high PD-L1 expression as a prognostic indicator of overall survival amongst advanced non-small cell lung cancer patients receiving anti PD-(L)1 monotherapies in the first line setting: An IPW weighted health system analysis [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 6350.

Abstract 3668: Socioeconomic disparities in healthcare utilization and overall survival among patients with cancer: Application of area-level socioeconomic status in a nationwide electronic health record-derived database

Abstract Introduction: While lower socioeconomic status (SES) is associated with worse cancer outcomes, most electronic health records (EHRs) lack documentation of SES. Here we apply an area-level SES measure to an EHR-derived database to evaluate representativeness according to SES. We then examine socioeconomic disparities in the timeliness of healthcare utilization (biomarker testing and systemic treatment) and overall survival (OS) in 3 common cancers. Methods: This retrospective study uses the nationwide Flatiron Health EHR-derived de-identified database of cancer patients who have clinical activity between January 2011-August 2021. Census block group data from the American Community Survey (2015-2019) was used to measure SES per the Yost Index (incorporating income, home values, rental costs, poverty, blue-collar employment, unemployment, and education information). SES quintiles were determined from the US population and then applied to patients based on their residential addresses. Our database included 2,067,644 cancer patients from community practices. Patients with advanced non-small-cell lung cancer (aNSCLC, n=51,596), metastatic breast cancer (mBC, n=18,268), and multiple myeloma (MM, n=8,246) were sampled and followed from advanced, metastatic, or initial diagnosis date, respectively. Differences were evaluated using Χ2 tests for categorical variables and log-rank tests for Kaplan-Meier survivor functions. Results: Compared to the US population, our database of cancer patients has a similar SES distribution (differences &amp;lt;3%), capturing cancer patients living in the most (Q1) and least affluent areas (Q5) of the country. Yet, among the 1.5% of cancer patients who participated in clinical trials, only 15.2% lived in the least affluent areas. aNSCLC and mBC patients living in the least affluent areas were less likely to receive biomarker testing within 30 days of index diagnosis than those in the most affluent areas (59.4% vs. 68.7%; 74.9% vs. 81.0%, both p&amp;lt;.01). Similar patterns were observed in receipt of systemic treatment within 60 days of index diagnosis (aNSCLC: 58.9% vs. 64.9%; mBC: 76.0% vs. 80.1%, both p&amp;lt;.01). No differences in healthcare utilization were observed among MM patients. Patients in the least affluent areas had lower median OS (months) than those in the most affluent areas (aNSCLC: 10.8 [95% CI: 10.4-11.3] vs. 12.2 [95% CI: 11.8-12.7]; mBC: 28.0 [95% CI: 26.6-29.5] vs. 34.5 [95% CI: 33.1-36.9], MM: 57.4 [95% CI: 53.5-61.5] vs. 67.5 [95% CI: 62.5-76.4]; all p&amp;lt;.01). Conclusion: Lower SES was associated with reduced clinical trial participation, less timely healthcare utilization, and worse OS. Making SES available in real-world data can support the development of inclusive clinical trials and inform interventions to reduce cancer care disparities. Citation Format: Jenny S. Guadamuz, Xiaoliang Wang, Jeremy Snider, James Walters, Rebecca A. Miksad, Gregory S. Calip. Socioeconomic disparities in healthcare utilization and overall survival among patients with cancer: Application of area-level socioeconomic status in a nationwide electronic health record-derived database [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 3668.

Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small cell lung cancer (NSCLC) patients

BackgroundGenomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC. MethodscfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019–October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results. ResultsOf 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001).A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001). ConclusionscfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. ‘Plasma-first’ upfront cfDNA-NGS use should be considered routinely for aNSCLC.

Prognostic value of PIOS (Patras Immunotherapy Score) model in patients with advanced NSCLC treated with combination of immunotherapy with chemotherapy: Preliminary results from a European retrospective study.

e21096 Background: Ιmmune checkpoint inhibitors (ICIs) have tremendously changed the daily clinical practice on the treatment of advanced non-small cell lung cancer (aNSCLC). However, clinical useful biomarkers remain an unmet need. Recently, a new score, Patras Immunotherapy Score (PIOS), has been proposed by our group proving its prognostic value in aNSCLC patients treated with ICIs monotherapy. The objective of the current study was to assess the clinical significance of PIOS formula in aNSCLC patients treated with combination of immunotherapy with chemotherapy. Methods: PIOS is a baseline formula derived by combining the following non-interventional clinical parameters, Performance Status (PS), Body Mass Index (BMI), age and Line Of Treatment (LOT) and it is calculated as PIOS = (PS×BMI)/(LOT×AGE). In the current study, 159 aNSCLC patients, treated with combination of immunotherapy with chemotherapy, were retrospectively selected, blindly to the clinical outcome, and enrolled. In addition, a second subcohort with 444 aNSCLC patients, who had been treated with chemotherapy alone, were also retrospectively included. The primary endpoint of this study was to investigate the prognostic value of PIOS in terms of progression free survival (PFS) and overall survival (OS). Results: Patients with higher PIOS score had longer PFS compared to patients with lower PIOS score (ΗR 0.575, 95% CI 0.364-0.908, p= 0.016), while multivariate analysis for PFS, adjusted for PD-L1, confirmed the clinical value of PIOS score (HR 0.561, 95% CI 0.352-0.893, p= 0.015). Moreover, PIOS score was also associated with prognosis ( p= 0.003). The median OS for the favorable group was 1067 days compared to 528 days for the unfavorable group with low PIOS score (HR 0.487, 95% CI 0.302-0.787, p&lt; 0.001) at univariate analysis. This association remained statistically significant (HR 0.468, 95% CI 0.286-0.764, p= 0.002) after adjusting for PD-L1 expression. Specificity of PIOS formula was also confirmed in the second cohort (n = 444) of patients with metastatic disease who had been treated with chemotherapy alone, in which no prognostic significance for PIOS was observed. Conclusions: This study for the first time documents the prognostic significance of PIOS model in aNSCLC patients treated with immunotherapy/chemotherapy combination and provides adequate evidence regarding the specificity of this association, since no similar finding was observed in the patients treated with chemotherapy alone.

Disparities in timely treatment among lung cancer patients.

e18515 Background: NSCLC is the leading cause of cancer-related deaths in the US. There are no federal standardized guidelines regarding timely treatment (TT) of NSCLC care and little is known regarding the sociodemographic differences in TT of anticancer therapies among NSCLC patients. This is particularly notable among Black Americans, who are less likely to receive lung cancer screening, more likely to be diagnosed with advanced or metastatic NSCLCL, and less likely to receive NCCN-concordant targeted therapy relative to their white counterparts. The objective of this retrospective study is to assess racial differences in TT and related outcomes among patients with advanced or metastatic NSCLC (aNSCLC). Methods: We identified 3,603 patients from ConcertAI’s Real-world data (RWD) sources, including CancerLinQ Electronic Medical Records. Patient demographics included: a) aged 18 to 64 years; b) confirmed diagnosis of aNSCLC between January 1, 2010, and December 31, 2019; and c) self-identify as White or African American. For this study the primary endpoint was receipt of TT, defined as start of systemic therapy within 30 days after diagnosis of aNSCLC. Logistic regression was leveraged to obtain adjusted odds ratios of comparisons between White and Black American populations on receipt of TT, controlling for demographic and baseline characteristics such as type of setting, ECOG score and smoking status. Results: Descriptive analyses revealed 79.1% of Black aNSCLC patients did not receive TT, as compared to 71.4% of White aNSCLC patients. When controlling for associated confounding factors, Black aNSCLC patients had a 21.4% less chance of receiving TT as compared to White patients, and the same was evident from the predicted probabilities of TT for Black vs. White aNSCLC patients. When evaluating institutional setting type, 76.1% of community hospitals provided TT vs. 61.3% of academic centers. Conclusions: This real-world study shows Black aNSCLC patients were associated with treatment delay. While present findings suggest improving access to effective screening and timely access to NCCN-concordant targeted therapies may be used as a means through which to lessen NSCLC disparities, further investigation is required to assess how it may improve overall outcomes for minorities. [Table: see text]

Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study.

e21114 Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. &gt; 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p &lt; 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p &lt; 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p &lt; 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.

PEOPLE (NTC03447678), a phase II trial of first-line, single-agent pembrolizumab in advanced NSCLC with low PD-L1: Clinical outcomes and association with circulating immune biomarkers.

9033 Background: In advanced NSCLC (aNSCLC) with PD-L1 &lt; 50% chemo-immunotherapy is the standard of care. Although the activity of single agent pembrolizumab was reported, no biomarkers have been identified able to select patients who mostly benefit. The trial aimed to identify immune biomarkers associated with PFS in aNSCLC patients with PD-L1 levels &lt; 50% treated with first-line pembrolizumab. Here we reported for the first time the clinical outcomes of the trial and circulating immune profiling (CIP) biomarkers correlated to PFS. Methods: This phase II trial was conducted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Eligible patients were previously untreated stage IIIB-IV NSCLC, EGFR and ALK wild type with PD-L1 &lt; 50%, PS 0-2. PD-L1 was assessed with 22-C3 antibody (Dako). Patients received pembrolizumab 200 mg every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. The primary endpoint was the association of immune biomarkers with PFS. OS, ORR, DCR, DoR and safety were secondary endpoints. CIP was performed by determination of absolute cell counts for 36 innate and adaptive immunity subsets through multiparametric flow cytometry on freshly isolated whole blood samples at baseline. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyse CIP variables and their correlation with clinical endpoints. Results: From May 2018 to October 2020, of 87 screened, 65 patients were enrolled. The median age was 70.9 years, most patients were male (67.7%), smoker (87.7%), non-squamous (83.1%), PDL1 + (70.8%). 12 patients (18.5%) had PS 2. During a median follow-up of 26.4 months (mo), 51 radiological progressions, 46 deaths and 60 PFS events were observed. The median PFS was 2.9 mo (95%CI 1.8 - 5.6) and the median OS was 12.1 mo (95%CI 8.7 - 17.1). The ORR was 24.1% (2 complete and 12 partial responses), DCR was 53.4% and median DoR was 14.5 mo (95%CI 6.4 - 24.9). Drug related G3-G4 adverse events were: 2 hyponatremia, 2 lipase increased, 1 pneumonitis. Out of 7 CIP clusters identified, 2 were statistically significant at multivariable analysis on 57 patients. Higher baseline counts of 8 subsets within these two clusters were associated with better PFS (HR values range: 0.88-0.98; p values range: 0.001- 0.016). The significant subsets included lymphocytes (cells expressing CD3, or CD19 or CD56, but lacking granulocyte and monocyte markers) and main NK subsets (including CD56dim CD16+, CD56dim CD16- and HLA-DR+ NK cells). Conclusions: This trial confirmed that pembrolizumab as first-line single agent is safe and active also in a subgroup of aNSCLC patients with PD-L1 &lt; 50%. CIP biomarkers can be useful to identify patients with a favourable outcome, thus avoiding the adding toxicity of chemotherapy. Clinical trial information: NTC03447678.

Machine learning modeling of real-world primary resistance and hyperprogression in immune checkpoint inhibitor (ICI) treated advanced non-small cell lung cancer (aNSCLC) patients.

e21127 Background: Many ICI-eligible patients display primary resistance (10-res), with some experiencing hyperprogressive disease (HPD). Machine learning (ML) on real-world data (RWD) can improve our clinical and mechanistic understanding related to ICI response. Methods: XGBoost models were built on ConcertAI’s oncology clinicogenomic database, comprising structured EMR, curated records from unstructured documents, and NGS reports, to predict 10-res and HPD in aNSCLC patients treated with ICI or chemotherapy (CT) within their 1st three lines between January 2015 and June 2021. HPD was defined as either tumor progression, treatment (Tx) discontinuation, or death within 49 days from Tx start (index date). 10-res was defined as any of these events after 49 days but within 180 days from Tx start. Models were trained on a clinical (N = 7647, ICI = 3265, 10-res = 3909, HPD = 2076), and a clinicogenomic (CG) (2304, 1271, 1084, 596) cohort. A 60:20:20 split was used for training, validation, and testing. Baseline period was defined as 180 days prior to the index date. Prognostic and predictive factors were identified from Shapley Additive Explanation (SHAP) values. Results: The clinical model was superior at predicting HPD; the CG model was better at predicting 10-res (AUROC = 0.67 for both). Total metastases (≥ 2) and lower levels of hemoglobin (HGB), and lymphocytes, higher ALP were risk factors for both HPD and 10-res. Elevated WBC and bilirubin, higher heart rate, lower body temperature, and history of anti-inflammatory medications were risk factors for HPD. Non-ICI-based regimens, low TMB, lower PD-L1 expression, and mutations in EGFR or KEAP1 were risk factors for 10-res. Mutation in KRAS was protective of 10-res. In addition to PD-L1 and TMB, the models identified prior lung radiation, smokers, higher baseline comorbidities, and positive MMR status as predictive of lower risk of 10-res from ICI but not in CT. STK11 mutation was predictive of higher risk of 10-res from ICI vs. CT. Non-adenocarcinoma histology was predictive of higher risk of HPD from ICI vs. CT. Conclusions: ML on RWD generated evidence to support both established and emerging prognostic and predictive markers for ICI response.[Table: see text]