First-line Non-small Cell Lung Cancer Research Articles

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 (NSCLC).

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 survival 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. .

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

Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant KRAS Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function.

Our findings depict how CERK inhibition may serve as a new key point in combination therapeutic strategy for NSCLC, specifically precision therapeutics targeting NSCLC possessing a KRAS mutation.

Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data.

The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Network meta-analysis of immune-oncology monotherapy as first-line treatment for advanced non-small-cell lung cancer in patients with PD-L1 expression ⩾50%

Background:For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published in November 2010–2020.Methods:Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses.Results:The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50–0.86), 1–12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04–2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54–1.10), 1–12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3–5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83–2.60)], immune-mediated AEs [1.75 (0.33–7.49)], and all-cause discontinuation due to AEs [1.21 (0.58–2.61)].Conclusions:Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Treatment patterns for advanced non-small cell lung cancer in the US: A systematic review of observational studies

BackgroundThe advent of immunotherapies (I-O) and targeted therapies has transformed the treatment landscape in advanced non-small cell lung cancer (NSCLC). However, adoption of new treatment guidelines and evolving treatment patterns in clinical practice are largely unknown. The aim of this systematic literature review (SLR) was to capture real-world first-line treatment patterns in advanced (staged IIIB–IV) or recurrent NSCLC patients in the US. MethodsElectronic databases were systematically searched for observational studies published 2012–2020 that reported on adult patients receiving first-line therapy for advanced NSCLC. Included studies were reviewed and treatment patterns were summarized descriptively. ResultsEighteen studies were included. Platinum-doublet (PD) chemotherapy and unspecified chemotherapy regimens were the most commonly used first-line treatments (up to 71% and 96%, respectively). Chemotherapy as monotherapy was mainly utilized in patients ≥65 years. While chemotherapy use was continuously high, I-O became the preferred front-line treatment in 2018 (32.9%). I-O monotherapy was more prevalent among patients with PD-L1 ≥50%, compared to patients with lower levels. First-line use of tyrosine kinase inhibitors and bevacizumab-based therapies was common in 2010 (33.4% and 21.7%, respectively), but gradually declined to <1% in 2018. ConclusionConsistent with the evolving first-line NSCLC treatment landscape in the US, this SLR captures the increasing use of I-O in recent years. While the brief lag in I-O use from the time of authorization may be attributable to an initial resistance to treatment adoption or publication delays, continued use of chemotherapy regimens may reflect an unmet treatment need, which warrants further research.

First-Line Pembrolizumab Mono- or Combination Therapy of Non-Small Cell Lung Cancer: Baseline Metabolic Biomarkers Predict Outcomes.

Simple SummaryPositron-emission tomography/computed tomography (PET/CT) is used for staging of non-small cell lung cancer (NSCLC) and can help to estimate prognosis in patients treated with immune checkpoint inhibitor (ICI) therapy. Most available data in that field were derived from cohorts treated in higher therapy lines using ICI monotherapy with different drugs. Currently, however, most advanced NSCLC patients receive first-line ICI treatment, often in combination with cytotoxic chemotherapy. We evaluated prognostic PET/CT biomarkers in 85 patients receiving first-line ICI, 70 (82%) of them as a chemotherapy–ICI combination. We found that patients with a higher metabolically active tumor volume (MTV) had a significantly poorer survival and lower radiological response rate. In patients with high MTV, a concomitantly low bone marrow to liver ratio indicated a better prognosis. Our results demonstrate that PET/CT-derived biomarkers can aid therapeutic decision-making in ICI-treated NSCLC.Quantitative biomarkers derived from positron-emission tomography/computed tomography (PET/CT) have been suggested as prognostic variables in immune-checkpoint inhibitor (ICI) treated non-small cell lung cancer (NSCLC). As such, data for first-line ICI therapy and especially for chemotherapy–ICI combinations are still scarce, we retrospectively evaluated baseline 18F-FDG-PET/CT of 85 consecutive patients receiving first-line pembrolizumab with chemotherapy (n = 70) or as monotherapy (n = 15). Maximum and mean standardized uptake value, total metabolic tumor volume (MTV), total lesion glycolysis, bone marrow-/and spleen to liver ratio (BLR/SLR) were calculated. Kaplan–Meier analyses and Cox regression models were used to assess progression-free/overall survival (PFS/OS) and their determinant variables. Median follow-up was 12 months (M; 95% confidence interval 10–14). Multivariate selection for PFS/OS revealed MTV as most relevant PET/CT biomarker (p < 0.001). Median PFS/OS were significantly longer in patients with MTV ≤ 70 mL vs. >70 mL (PFS: 10 M (4–16) vs. 4 M (3–5), p = 0.001; OS: not reached vs. 10 M (5–15), p = 0.004). Disease control rate was 81% vs. 53% for MTV ≤/> 70 mL (p = 0.007). BLR ≤ 1.06 vs. >1.06 was associated with better outcomes (PFS: 8 M (4–13) vs. 4 M (3–6), p = 0.034; OS: 19 M (12-/) vs. 6 M (4–12), p = 0.005). In patients with MTV > 70 mL, concomitant BLR ≤ 1.06 indicated a better prognosis. Higher MTV is associated with inferior PFS/OS in first-line ICI-treated NSCLC, with BLR allowing additional risk stratification.