First-line Non-small Cell Lung Cancer Research Articles

OA11.04 Volrustomig + platinum doublet chemotherapy (CTx) in first-line non-small cell lung cancer (NSCLC): Phase 1b trial update

OA11.04 Volrustomig + platinum doublet chemotherapy (CTx) in first-line non-small cell lung cancer (NSCLC): Phase 1b trial update

The Impact of Additive Population(s), Intervention, Comparator(s), and Outcomes in a European Joint Clinical Health Technology Assessment

ObjectivesTo assess the potential number of European Union (EU) population(s), intervention, comparator(s), and outcomes (PICOs) based on European Network for Health Technology Assessment 21 (EUnetHTA 21) guidance and to explore further evidence-based opportunities to produce more predictable and workable EU PICOs. MethodsThe consolidated EU PICOs of 2 future hypothetical medicines in first-line non-small cell lung cancer (1L NSCLC) and third line multiple myeloma (3L MM) were derived using published health technology assessment reports of 2 recent medicines in similar indications based on EUnetHTA 21 proposed guidance. Sensitivity analysis assessed the impact of additional PICO requests. The number of analyses requested was estimated. ResultsIn 1L NSCLC and 3L MM, 6 and 9 EU Member States (MS), respectively, had published health technology assessment reports. PICO consolidation resulted in 10 PICOs for 1L NSCLC and 16 PICOs for 3L MM, increasing to 14 and 18 PICOs, respectively, when England’s National Institute for Health and Care Excellence scope was included to proxy remaining MS. A minimum of 280 and 720 analyses would be requested, exponentially increasing as additional outcome measures and subgroups are requested. ConclusionsThe PICO approach outlined by EUnetHTA 21 results in a significant number of analysis requests and substantial resources. Use of complementary analyses alongside evidence-based methods to derive PICOs and engaging with the health technology developer throughout the process would create a workable EU PICO that is predictable and most impactful for the EU, resulting in a timely and high-quality assessment report that is more usable at a MS level.

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Results from the phase 2 PALOMA-2 study.

LBA8612 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, is approved as an intravenous (IV) formulation. IV ami + lazertinib (laz), a 3rd-generation EGFR TKI, demonstrated superior progression-free survival (PFS) in patients (pts) with treatment-naïve, advanced EGFR-mutated NSCLC vs osimertinib (Cho Ann Oncol 2023). Subcutaneous (SC) ami substantially reduced infusion-related reactions (16% vs 67%) and administration time (≤7 mins vs 2–4 hours) vs historical IV experience (Minchom JCO 2023). PALOMA-2 (NCT05498428) evaluated the efficacy, safety, and pharmacokinetics (PK) of first-line SC ami+laz. Methods: Cohorts 1 and 6 enrolled pts with treatment-naïve, EGFR Ex19del or L858R-mutated advanced NSCLC. Prophylactic anticoagulation for the first 4 months (mo) of treatment was recommended in cohort 1 and mandatory in cohort 6. SC ami was administered by manual injection in the abdomen at 1600 mg (≥80 kg: 2240 mg) weekly for the first 4 weeks and every 2 weeks thereafter. Laz was dosed orally at 240 mg daily. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1. Results: As of 6 Jan 2024, 68 and 58 pts were enrolled in cohorts 1 and 6, respectively. Overall, median age was 59 years, 60% were female, and 68% Asian. The median follow-up was 10 mo for cohort 1 and 6 mo for cohort 6. ORR (confirmed responses) in cohort 1 was 68% (95% CI, 55–79) by investigator and 72% (95% CI, 60–82) by independent central review. ORR in cohort 6 was 64% (95% CI, 49–78) and 73% (95% CI, 58–85), respectively. At data cutoff, 40/46 responders in cohort 1 and 29/29 responders in cohort 6 were receiving ongoing treatment. Best overall response rates (includes unconfirmed responses) were 81% (95% CI, 70–89) for cohort 1 and 76% (95% CI, 61–87) for cohort 6. Median time to response was 2 mo (range, 1.4–5.3). Median duration of response, PFS, and overall survival were not estimable. Administration-related reactions (ARRs) were reported in 13 (19%) pts in cohort 1 and 6 (11%) pts in cohort 6, all grade 1–2. EGFR- and MET-related AEs were primarily grade 1–2. Total of 71% of pts in cohort 1 and 100% in cohort 6 received prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 18% and 7% of pts in cohorts 1 and 6, respectively. There were no dose reductions or discontinuations due to VTE. Rate of bleeding was 2% among pts receiving anticoagulation. Mean ami concentrations on cycle 2 day 1 were 328 µg/mL (n=49) in cohort 1 and 371 µg/mL (n=41) in cohort 6, consistent with historic IV levels. Conclusions: SC ami+laz showed a response rate similar to historic IV ami+laz in first-line EGFR-mutated NSCLC, with an improved safety profile that included significantly lower ARR rates. Further, prophylactic anticoagulation can be safely implemented and reduced incidence of VTE. Clinical trial information: NCT05498428 .

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-smallcell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab+chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR=1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR=0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR=1.30; 95% CI: 1.08-1.54, borrowing weight=1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight=1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Non-tumor-related prognostic factors for immunotherapy–chemotherapy or immunotherapy alone as first-line in advanced non-small cell lung cancer (NSCLC)

Besides programmed death ligand 1 (PD-L1) expression, rapid, cost-effective and validated scores or models are critical for the prognosis and prediction of patients received immune checkpoint inhibitors (ICIs). In this retrospective study, 182 patients with NSCLC receiving ICIs from 2015 to 2022 were divided 1:1 into a training cohort and a validation cohort. We identified a score established by three factors and analyzed the prognostic implications by Kaplan–Meier approach (Log rank test) and time-dependent receiver operating characteristic (ROC) analyses. A non-tumor-related score (NTRS) was established that could be used as a prognostic factor (HR 2.260, 95% CI 1.559–3.276, P < 0.001 in training cohort; HR 2.114, 95% CI 1.493–2.994, P < 0.001 in validation cohort) and had a high time-dependent ROC for overall survival (OS) (AUC 0.670–0.782 in training cohort; AUC 0.682–0.841 in validation cohort). PD-L1 (1–49%) and NTRS (score = 0, 1, 2, 3) combination significantly improved the assessment of patients’ OS and progress-free survival (PFS), which was statistically different in training cohorts (P < 0.001 for OS, 0.012 for PFS) and validation cohorts (P = 0.01 for OS, < 0.001 for PFS). The NTRS provided a better assessment of durable clinical benefit (DCB) compared to PD-L1 expression (P = 0.009 vs. 0.232 in training cohort; P = 0.004 vs. 0.434 in validation cohort). NTRS may help improve prognosis stratification of patients receiving ICIs in first-line NSCLC and may be combined with tumor-related parameters.

Examining crossover and postprotocol therapies in first-line immunotherapy trials in non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

Treatment-related adverse events of combination chemoimmunotherapy versus chemotherapy alone in first-line treatment for non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials.

Numerous meta-analyses have examined immunotherapy-induced adverse events (AEs) in non-small cell lung cancer (NSCLC). However, there is limited research comparing AEs from combination chemoimmunotherapy versus chemotherapy alone in the first-line NSCLC treatment, particularly regarding specific toxic symptoms and hematological toxicities associated with the addition of immune checkpoint inhibitors (ICIs). We conducted a meta-analysis of randomized clinical trials (RCTs) comparing ICIs + non-ICIs versus non-ICIs alone as first-line therapy in NSCLC, sourced from PubMed and Scopus databases. Our objective was to assess treatment-related AEs in both regimens, focusing on identifying the more prevalent toxic symptoms and hematological toxicities with ICI treatment. We calculated the relative risks (RRs) and 95% confidence intervals (CIs), and estimated the pooled RRs and 95% CIs using common- or random-effects models. Our analysis included 10 trials with 6,008 patients. Combination chemoimmunotherapy significantly increased the risk of grade 3 or higher treatment-related AEs, treatment discontinuation, and deaths due to treatment-related AEs. Moreover, patients receiving combination chemoimmunotherapy had a significantly higher risk of certain toxic symptoms (all-grade: vomiting, diarrhea, and constipation; high-grade: fatigue and diarrhea) and pneumonitis (both all-grade and high-grade). These findings offer crucial insights into the toxicity profile of combination chemoimmunotherapy, serving as a valuable resource for clinicians managing lung cancer care.

CO90 Augmenting Synthetic Control Arms Using Bayesian Borrowing: A Case Study in First-Line Non-Small Cell Lung Cancer

CO90 Augmenting Synthetic Control Arms Using Bayesian Borrowing: A Case Study in First-Line Non-Small Cell Lung Cancer

Understanding the feasibility of chemotherapeutic and immunotherapeutic targets against non-small cell lung cancers: an update of resistant responses and recent combinatorial therapies

Despite consistent progress in prompt diagnosis and curative therapies in the last decade, lung cancer (LC) continues to threaten mankind, accounting for nearly twice the casualties compared to prostate, breast, and other cancers. Statistics associate ~25% of 2021 cancer-related deaths with LC, more than 80% of which are explicitly caused by tobacco smoking. Prevailing as small and non-small cell pathologies, with respective occurring frequency of nearly 15% and 80–85%, non-small cell LCs (NSCLCs) are prominently distinguished into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes. Since the first use of epidermal growth factor receptor (EGFR) inhibitor gefitinib for NSCLC treatment in 2002, immense progress has been made for targeted therapies with the next generation of drugs spanning across the chronological generations of small molecule inhibitors. The last two years have overseen the clinical approval of more than 10 therapeutic agents as first-line NSCLC medications. However, uncertain mutational aberrations as well as systemic resistant responses, and abysmal overall survival curtail the combating efficacies. Of late, immune checkpoint inhibitors (ICIs) against various molecules including programmed cell death-1 (PD-1) and its ligand (PD-L1) have been demonstrated as reliable LC treatment targets. Keeping these aspects in mind, this review article discusses the success of NSCLC chemo and immunotherapies with their characteristic effectiveness and future perspectives.

EE40 Identifying and Quantifying Elements of Value for Nivolumab and Ipilimumab in First-Line Non-Small Cell Lung Cancer

Cost-effectiveness analyses are often used by health technology appraisal agencies to inform reimbursement decisions for new therapies. These evaluations, however, are often performed adopting a payer’s perspective that does not include important elements of value that treatments may generate (e.g., increased productivity, reduced caregiving costs, patients’ hope, option value, or insurance value). There is currently limited evidence quantifying condition-specific novel value elements.

Abstract 4398: Validation of an updated algorithm to identify non-small cell lung cancer (NSCLC) patients in administrative claims databases

Abstract Purpose: Administrative claims data using the ICD-9-CM or ICD-10-CM coding systems are not detailed enough to distinguish between lung cancer subtypes, which presents challenges for real-world research. This study updated and validated a previous treatment-based algorithm that uses claims data to identify NSCLC vs small-cell lung cancer (SCLC) (Turner RM, et al. Front Pharmacol 2017;8:883). Methods: This study used Optum’s de-identified Market Clarity Data (2007-2021) which deterministically links medical and pharmacy claims with electronic health record (EHR) data from providers across the continuum of care. Included patients had lung cancer diagnosis and histology information available in the EHR, which is the gold standard for validation. Patients were required to have ≥3 months of continuous health plan enrollment before and after the diagnosis date. First, to replicate the Turner algorithm, patients were identified between Jun 2014 and Oct 2015 with any first-line NSCLC treatment and no SCLC treatment (Step 1). Next, the Turner algorithm was applied from Nov 2015 to Dec 2020 to evaluate if performance decreased given the approval of immunotherapies since 2015 (Step 2). Finally, the Turner algorithm was updated with NSCLC treatments approved since 2015 in concordance with the latest US treatment guidelines. Algorithm performance at each step was measured using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results: Sample sizes and performance statistics for each step are presented in the Table. From Step 1 to Step 2, specificity and PPV decreased while sensitivity and NPV increased. Algorithm performance improved slightly for all measures from Step 2 to Step 3. Conclusions: This updated treatment-based algorithm improves validity and accuracy in identifying NSCLC patients in claims databases and supports its use in real-world research using claims databases when histology data is unavailable. Step 1: Turner replication Step 2: Turner 2015-2020 Step 3: Updated Turner 2015-2020 Date range Jun 2014-Oct 2015 Nov 2015-Dec 2020 Nov 2015-Dec 2020 Sample size 406 2573 2744 Sensitivity 0.873 0.920 0.932 Specificity 0.933 0.865 0.923 PPV 0.987 0.976 0.988 NPV 0.560 0.640 0.673 Citation Format: Sandip Pravin Patel, Rongrong Wang, Summera Qiheng Zhou, Daniel Sheinson, Ann Johnson, Janet Lee. Validation of an updated algorithm to identify non-small cell lung cancer (NSCLC) patients in administrative claims databases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4398.

Time to treatment discontinuation in first-line non-small cell lung carcinoma: an overview

Objective Time To Discontinuation (TTD) is defined as the time from the start of treatment to the end of treatment, usually occurring due to loss of efficacy or occurrence of adverse events. It has become an important surrogate efficacy endpoint especially in real-world studies due to its correlation with endpoints such as Progression Free Survival (PFS). The aim of the study is to conduct a literature review of all studies reporting TTD in first-line therapy of Non-Small Cell Lung Cancer (NSCLC). Methods All articles that reported TTD for any first-line treatment of NSCLC as of 30 June 2022 were extracted from the PubMed search engine. From these articles, the drugs, study type, and TTD values were extracted. A descriptive analysis of the studies was made, dividing the TTD by subgroup according to the type of treatment (traditional chemotherapy, target therapy, immunotherapy) and study design (clinical trials, real world studies). Results Fifty-five studies were considered for the analysis, of which 12 were published in 2021; 28 were clinical trials and 27 were real-world studies. Thirty of the studies considered involved conventional chemotherapy and expressed TTD values from 1.4 to 4.5 months, 5 of the studies considered involved immunotherapy with TTD values from 2.1 to 7.4 months and 18 of the studies considered target therapy, with TTD values from 4 to 31 months. The clinical trials reported TTD values from 1.4 to 16 months and the real-world studies from 2 to 31 months. Conclusion Studies reporting TTD are increasing, most notably real-world studies. Given the increasing importance of TTD as an efficacy endpoint, it becomes critical to measure and monitor it in various therapeutic settings such as NSCLC. This is the first study to review all TTD values of drugs used in first-line NSCLC.

Descriptive Analysis of First-Line Non-Small Cell Lung Cancer Treatment with Pembrolizumab in Tumors Expressing PD-L1 ≥ 50% in Patients Treated in Quebec's University Teaching Hospitals (DALP-First Study).

Since July 2017, pembrolizumab has been approved as a first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with a PD-L1 score ≥ 50% in Quebec. Study objectives were to describe and assess the real-world use of pembrolizumab; report progression-free survival (PFS), overall survival (OS), and immune-related adverse events (IRAEs); and compare outcomes between a fixed dose (FD) and a weight-based capped dose (WCD). Medical records of patients treated in one of Quebec's four adult university teaching hospitals who received pembrolizumab between 1 November 2017 and 31 October 2019 were reviewed and followed until 29 February 2020. Two hundred and seventy-nine patients were included. The median real-world PFS and OS were 9.4 (95% CI, 6.6 to 11.2) and 17.3 months (95% CI, 12.9 to not reached), respectively. IRAEs causing delays or treatment interruptions were seen in 34.4% of patients. Initiating treatment with a FD (49 patients) or using a WCD (230 patients) does not appear to affect PFS, OS, or the occurrence of IRAEs. The use of a WCD strategy allowed approximately CAD 5.8 million in savings during the course of our study. These findings support the effectiveness and safety of pembrolizumab in a real-world setting. The use of a WCD does not appear to have a negative impact on patient outcomes.

Initial Treatment of Aumolertinib in Combination with Bevacizumab for Advanced NSCLC with Primary EGFR T790M Mutation: A Report of Three Cases and Literature Review

With the development of sequencing technology, the detection rate of non-small cell lung cancer (NSCLC) with primary epidermal growth factor receptor (EGFR) T790M mutation is increasing. However, the first-line treatment for primary EGFR T790M-mutated NSCLC still lacks standard recommendations. Here, we reported three advanced NSCLC cases with EGFR-activating mutation and primary T790M mutation. The patients were initially treated with Aumolertinib combination with Bevacizumab; among which, one case was discontinued Bevacizumab due to bleeding risk after treatment for three months. Treatment was switched to Osimertinib after ten months of treatment. Another case switched to Osimertinib and discontinued Bevacizumab after thirteen months of treatment. The best effect response in all three cases was partial response (PR) after initial treatment. Two cases progressed after first-line treatment and progression-free survival (PFS) was eleven months and seven months respectively. The other one patient had persistent response after treatment, and the treatment duration has reached nineteen months. Two cases had multiple brain metastases before administration and the best response to intracranial lesions was PR. The intracranial PFS was fourteen months and not reached (16+ months), respectively. There were no new adverse events (AEs), and no AEs of grade three or above were reported. In addition, we summarized the research progress of Osimertinib in the treatment of NSCLC with primary EGFR T790M mutation. In conclusion, Aumolertinib combined with Bevacizumab in the treatment of advanced NSCLC with primary EGFR T790M mutation has a high objective response rate (ORR) and control ability of intracranial lesions, which can be used as one of the initial options for first-line advanced NSCLC with primary EGFR T790M mutation. .

Trends in the prescription of immune checkpoint inhibitors for non-small cell lung cancer in the Netherlands from 2016 to 2020, a national cancer registry analysis.

Lung cancer is the leading cause of cancer mortality globally, with a 5-year survival rate of 10-20%. In recent years, immune checkpoint inhibitors (ICIs) have significantly improved overall survival (OS) in patients with lung cancer. The approval of nivolumab in 2015 marked a milestone in non-small cell lung cancer (NSCLC) treatment, leading to ongoing trials and approvals of new ICI drugs that have reshaped treatment strategies and clinical outcomes for patients with lung cancer. This study aims to describe ICIs prescription trends for NSCLC in the Netherlands and their association with survival. We compared our results with data from randomized controlled trials (RCTs). We analyzed ICIs prescription trends and their relationship with survival using national-level data from the Netherlands Cancer Registry (NCR) for first-line treatments from 2016-2020. Additionally, we performed a secondary analysis using data from the Oncological Life Study (OncoLifeS) for any-line treatments. Descriptive statistics and annual percentage change (APC) assessed trends in patient and treatment characteristics. OS analyses were performed. In the Netherlands (2016-2020), the proportion of first-line ICI-treated NSCLC patients significantly increased from 1.1% to 54.9% (APC =14.5%, P=0.002), replacing chemotherapy monotherapy. Stage III ICI-treated patients' proportion increased (APC =3.5%, P=0.034), while the proportion of ICI-treated patients with ≥50% programmed death-ligand 1 (PD-L1) expression decreased (APC =-13.82%, P=0.04). Two-year OS was 25.9%. Median OS remained stable, increasing from 2016 to 2018 (16.6 to 19.4 months) and declining slightly in 2019 and 2020 (17.3 and 16.6 months, respectively). In the secondary analysis, median OS varied by treatment line, being 18.8, 9.4 and 7.5 months for first-, second- and third-line treated patients respectively. Using real-world data, we determined that ICI-based therapies replaced chemotherapy-only schemes as first-line treatment for NSCLC. Our survival data are comparable with data from RCTs on first-line ICI-treated NSCLC. Median OS of ICI treated patients has remained stable, with small decreases in recent years possibly attributed to the proportional decrease of individuals with high PD-L1 expressions in treatment regimens. Further-line treatments are associated with lower survival.

1094P The clinical potential of circulating-free DNA (cfDNA) for real-time longitudinally monitoring clinical outcomes in a real-world first-line non-small cell lung cancer (NSCLC) prospective study

In this real-word study, we prospectively evaluated longitudinal plasma samples to investigate the potential of cfDNA kinetics as early marker of therapeutic efficacy and predictor of prolonged survival in advanced NSCLC patients undergoing standard first-line treatments.

EP08.02-082 Treatment Patterns and Outcomes of First-line Osimertinib-treated Advanced EGFR Mutated NSCLC Patients: A Real-world Study

Based on the survival benefit seen in the FLAURA trial, first-line osimertinib has become the standard-of-care for patients with EGFR mutation in advanced non-small cell lung cancer (NSCLC). However, treatment options are limited after progression on osimertinib. We explored survival outcomes, subsequent treatment lines, and metastatic sites post-osimertinib in patients with EGFR-mutated NSCLC treated with first-line osimertinib in a real-world setting.

Association of progression-free survival and overall response rate with overall survival in first-line randomized trials of immune checkpoint inhibitor–based regimens for metastatic non–small cell lung cancer (NSCLC): An FDA pooled analysis.

9029 Background: Overall Survival (OS) has represented the endpoint of choice to support approvals of Immune Checkpoint Inhibitors (ICIs) in first-line metastatic NSCLC. Despite continued interest in the use of earlier clinical endpoints as true surrogates for OS in this setting, the correlation of Progression-Free Survival (PFS) and Overall Response Rate (ORR) with OS remain an area of active investigation. We conducted a patient-level and trial-level pooled analysis of first-line randomized trials of ICI-based regimens to assess correlations of early clinical endpoints of PFS and ORR with OS in first-line metastatic NSCLC. Methods: The analysis included randomized trials comparing ICI-based regimens (anti-PD-(L)1 with or without anti-CTLA4 antibodies, with or without platinum-based chemotherapy) to platinum-based chemotherapy alone for the first-line treatment of patients with metastatic NSCLC that were submitted to the U.S. Food and Drug Administration between July 2016 to March 2021 to support a marketing application. Patient-level associations were estimated using Spearman (rs) correlation coefficients for PFS and OS, and Cox Proportional Hazards models in RECIST response-based subgroups for ORR and OS. At the trial level, associations were estimated using R2 coefficients from weighted linear regression models, using the log of hazard-ratio (HRs) for PFS and OS and log-odds ratio for ORR. Results: The pooled analysis included 13 trials enrolling 9,285 patients total. Seven trials compared ICIs combined with chemotherapy vs chemotherapy; 6 trials compared ICIs alone vs chemotherapy. Among all patients, the distribution of PD-L1 expression was 31%, 66%, and 32% for PD-L1 &lt;1%, ≥1%, and ≥50%, respectively. The table shows the correlation coefficients for PFS and OS, and ORR and OS at the patient and trial levels. At the patient level, the OS HR comparing ICI-based regimens to chemotherapy was 0.54 (95% CI: 0.48, 0.61) for RECIST responders and 0.96 (95% CI: 0.90, 1.02) for non-responders. Conclusions: This pooled analysis did not indicate a strong correlation between endpoints of PFS and ORR with OS at the patient and trial levels in first-line randomized trials of ICI-based regimens for metastatic NSCLC, potentially because of use of subsequent therapies, cross-over to ICIs, and continuation of ICIs beyond progression. Future research will explore the correlation of alternative endpoints with OS, such as time to treatment discontinuation. Our analysis supports the continued importance of OS as an endpoint for first-line NSCLC trials of ICI-based regimens.[Table: see text]

Tiragolumab and atezolizumab in patients with PD-L1 positive non-small-cell lung cancer

Anti-PD-1 and anti-PD-L1 antibodies, alone or in combination with chemotherapy or anti-CTLA-4 antibodies, are standard therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC). In patients with NSCLC with high PD-L1 expression (ie, with more than 50% of cancer cells staining positive for PD-L1 on immunohistochemistry), pembrolizumab or atezolizumab monotherapy can substantially improve objective response rates, progression-free survival, and overall survival compared with chemotherapy, sparing selected patients from chemotherapy. 1 Jassem J de Marinis F Giaccone G et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. J Thorac Oncol. 2021; 16: 1872-1882 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar , 2 Reck M Rodríguez-Abreu D Robinson AG et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol. 2021; 39: 2339-2349 Crossref PubMed Scopus (114) Google Scholar Combining anti-PD-1 and anti-PD-L1 antibodies with chemotherapy for patients with non-squamous NSCLC with a high PD-L1 expression can push the median overall survival to 27·7–30·0 months (up from 20·2–26·3 months with pembrolizumab or atezolizumab monotherapy), although the combination can have higher adverse events. 3 Gray J Rodríguez-Abreu D Powell SF et al. FP13.02 Pembrolizumab + pemetrexed-platinum vs pemetrexed-platinum for metastatic NSCLC: 4-year follow-up from KEYNOTE-189. J Thorac Oncol. 2021; 16: S224 Summary Full Text Full Text PDF Google Scholar , 4 Socinski MA Nishio M Jotte RM et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021; 16: 1909-1924 Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Immunotherapy combinations such as nivolumab plus ipilimumab (with or without chemotherapy) are also standard regimens, but do not appear to add benefit versus single agents, as shown by a median overall survival of 21·2 months reported in a high-PD-L1 population. 5 Paz-Ares LG Ramalingam SS Ciuleanu T-E et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. 2022; 17: 289-308 Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar Therefore, there is an unmet need to improve outcomes for patients with NSCLC with a high expression of PD-L1, by use of immunotherapy combinations that dispense with the need for upfront chemotherapy. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 studyTiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC. Full-Text PDF