Regional variations in molecular testing and treatment of patients with metastatic NSCLC in the Netherlands.

In Italy, the management of metastatic non-small cell lung cancer and melanoma leads to significant healthcare challenges, necessitating cost-effective treatment strategies and offering valuable insights for healthcare policymakers and stakeholders. This study was designed to assess the costs, quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs) associated with the health and economic outcomes of (1) pembrolizumab-combined chemotherapy administered as a first-line treatment for metastatic non-squamous and squamous non-small cell lung cancer (NSCLC) where the tumour presents with a programmed death-ligand 1 expression level <50% and of (2) adjuvant pembrolizumab treatment for stage III melanoma. Three cost-effectiveness models developed by MSD were investigated for each treatment indication. A unique model was built to assess the overall effect of pembrolizumab versus chemotherapy or watchful waiting in patients with lung cancer or melanoma, respectively. Theoretical cohorts of patients with metastatic squamous and non-squamous NSCLC were followed over time using a partitioned survival model with weekly cycles. A weekly cycle Markov model was employed for melanoma. The analysis was conducted from the Italian National Health Service perspective, considering a time horizon of 40 years (lifetime). A single closed cohort of treatable patients was followed over time for each indication (4000, 7000 and 900 for NSCLC squamous, non-squamous and melanoma, respectively). The costs evaluated included those for adverse drug events, non-drug disease management, subsequent treatment and terminal care. Drug acquisition and administration costs were excluded. For each treatment indication assessed, pembrolizumab produced downstream direct cost offsets (- €122,498,568, -€133,369,076 and -€32,993,242 for NSCLC squamous, non-squamous and melanoma indications, respectively), increased quality of life (+2088, +5317 and +2307 QALYs for NSCLC squamous, non-squamous and melanoma indications, respectively) and reduced disability (-2658, -7202 and -3029 DALYs for NSCLC squamous, non-squamous and melanoma indications, respectively). Across indications, the total cost offsets of pembrolizumab were -€288,860,885, with 9712 QALYs gained and 12,889 DALYs avoided. The analysis demonstrated that, compared with chemotherapy, pembrolizumab is more cost effective in Italy as a first-line treatment in patients with metastatic squamous or non-squamous NSCLC and, if compared with watchful waiting, as adjuvant treatment in patients with stage III melanoma. The present analysis suggested that pembrolizumab use could lead to important health benefits for patients while offsetting a portion of cancer care costs.

: On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7-15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0-10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%-24%) in the nivolumab arm and 12% (95% CI: 9%-17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako's PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use.

The non-small cell lung cancer (NSCLC) accounts approximately 85% of lung cancers and includes predominantly adenocarcinomas, which is the most common type and squamous cell carcinomas. The treatment options include surgery, radiation therapy, and chemotherapy and the decision depends on the patient’s medical status and stage of disease. From 1970 the standard first line treatment for most patients with unresectable NSCLC and good performance status was the use of a combination of chemotherapy regimens and usually cisplatin-based. The most common combination regimens in use at present are platinum based regimens with gemcitabine, with paclitaxel or docetaxel and with vinorelbine combinations. The addition of the recombinant humanized monoclonal antibody bevacizumab that binds to vascular endothelial growth factor (VEGF) to carboplatin and paclitaxel for the treatment of non-squamous advanced NSCLC has demonstrated to increase response rate (RR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy alone. Despite recent advances with approval of more active chemotherapeutic and anti-angiogenesis agents for stage IV NSCLC, standard therapy can provide only modest clinical benefits with significant toxicities when used in unselected patients. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first glimpse of a possible target for a treatment which could maximize clinical outcome in those patients who could benefit from a personalized therapy. Identifying mutations in oncogenes associated with non-squamous NSCLC can help determine which patients are more likely to benefit from a targeted therapy. Such oncogenes include EGFR, KRAS, and ALK. The presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of EGFR TKIs is based upon the detection of these mutations. The incidence of EGFR mutations in tumors with non-small-cell histology ranges from ~15% in Caucasians to ~50% in East Asians; 95% of such mutations have been found in adenocarcinomas. Patients bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy suggesting that EGFR may be a predictive and a prognostic factor. Activation of the EGFR protein stimulates protein tyrosine kinase, which leads to activation of signaling pathways associated with cell growth and survival. Both EGFR overexpression and activating mutations in the tyrosine kinase domain of the EGFR gene lead to tumor growth and progression. Erlotinib, gefitinib and afatinib are examples of EGFR TKIs that can prevent activation of the signaling pathways and improve RRs in selected NSCLC patients. These mutations which are associated with increased sensitivity to EGFR TKIs, predominate in never-smokers, females, and tumors with adenocarcinoma histology. The most common mutations associated with sensitivity to EGFR TKIs include exon 19 deletions and the L858R point mutation and they are associated with RRs of >70%. Other EGFR mutations like T790M and exon 20 insertion, have been associated with much lower response or acquired resistance to TKI’s. The predictive value of EGFR mutations for use of gefitinib has been strengthened by the results of three randomized phase III trials that specifically compared TKIs used as first-line therapy with traditional platinum-based chemotherapy in patients with advanced NSCLC. In 2009 the results of IRESSA Pan-Asia Study were presented. This trial included a big number of Asian ethnicity patients (1,217) who were never smokers or former light smokers with histologic diagnosis of adenocarcinoma. The trial demonstrated an improvement in PFS and RR, with no statistical difference in OS, with the use of gefitinib in EGFR-mutated tumors and better RR and PFS with standard chemotherapy in patients without mutations. The first phase III trial of gefitinib versus chemotherapy as initial treatment of recurrent or advanced NSCLC, based on selection of patients with known activating EGFR mutations was the WJTOG3405 trial, reported in 2010. This trial documented important achievements in RR and PFS with the use of TKIs. Almost the same results were confirmed by another similar Japanese phase III trial, NEJ002, with RR and PFS definitely favoring the use of gefitinib in the first-line setting of metastatic EGFR-mutated NSCLC. Based on the results of the IPASS study, gefitinib was approved for use in Europe for the initial treatment of patients with NSCLC exhibiting EGFR mutations. The positive results of the EURTAC trial, NCT00446225, which was a randomized phase III trial of erlotinib versus standard chemotherapy, suggested that responsiveness in mutation-positive patients was not a function of ethnicity. Afatinib is approved as monotherapy for the treatment of EGFR TKI—naïve adults with locally advanced or metastatic NSCLC with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. EGFR-TKIs as a class are generally well tolerated. The two most common toxicities include dermatologic and GI effects, which are mild to moderate, easily managed and reversible. In order to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy, the latest guidelines recommend mutation testing for all patients with advanced NSCLC tumor. The aim of this prospective study is to compare the efficacy of gefitinib, erlotinib and afatinib in patients with advanced NSCLC harboring activating EGFR mutations in first line of treatment. These agents are recommended as first line treatments for NSCLCs with such mutations. The primary endpoint will be the PFS and the secondaries will be the OS and the record of the toxicities. In each of the 3 arms will be participate 20 patients with EGFR mutated tumors. The technique for screening NSCLC patients for driver mutations that it will be used is next-generation sequencing, which overcomes many of the shortcomings of direct sequencing. This massively parallel approach, relying heavily on automation, data storage, and computational processing, allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes, but is not yet used routinely in clinical practice. In addition, KRAS mutation analysis will be performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking.

BackgroundPredictive biomarker testing has a key role in the treatment decision-making for patients with non-small cell lung cancer (NSCLC) and is mandated by (inter)national guidelines. The aim of this study was to establish guideline-adherent biomarker testing rates in the Netherlands in 2019 and to examine associations of demographical, clinical, and environmental factors with guideline-adherent testing. MethodsThis study involved the integration of clinical data of the Netherlands Cancer Registry with pathology reports of the Dutch Nationwide Pathology Databank. Data extracted from these reports included sample type, diagnosis, and molecular testing status of predictive biomarkers. The study population comprised all patients diagnosed with metastatic non-squamous NSCLC in the Netherlands in 2019. ResultsIn the cohort of 3877 patients with metastatic non-squamous NSCLC under investigation, overall molecular testing rates for non-fusion predictive biomarkers (EGFR, KRAS, BRAF, ERBB2, MET) ranged from 73.9 to 89.0 %, while molecular testing for fusion-drivers (ALK, ROS1, RET, NTRK) ranged from 12.6 % to 63.9 %. Guideline-adherent testing of EGFR, KRAS, and ALK was performed in 85.2 % of patients, with regional rates spanning from 76.0 % to 90.8 %. Demographical and clinical factors associated with guideline-adherent biomarker testing included lower age (OR = 1.05 per one year decrease; p < 0.001), female sex (OR = 1.36; p = 0.002), diagnosis of adenocarcinoma (OR = 2.48; p < 0.001), availability of histological tumor material (OR = 2.46; p < 0.001), and clinical stage of metastatic disease (p = 0.002). Other factors associated with guideline-adherent biomarker testing included diagnosis at academic center (OR = 1.87; p = 0.002) and patient’s region of residence (p < 0∙001). ConclusionOptimization of the chain-of-care of predictive biomarker testing in patients with NSCLC in the Netherlands is needed to provide adequate care for these patients.

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Lung cancer is one of the most common malignant cancers in most countries, and non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Checkpoint inhibitor immunotherapy is the preferred therapy for metastatic NSCLC patients who do not exhibit EGFR exon 19 deletion or L858R or ALK, RET, or ROS1 rearrangements. A recent clinical study (PERLA, NCT04581824) reports that dostarlimab has comparable effectiveness to pembrolizumab and presents clinical reliability as a first-line treatment for patients with metastatic non-squamous NSCLC. Our study employed a partitioned survival model (PSM) to evaluate the cost-effectiveness of dostarlimab plus chemotherapy compared to pembrolizumab plus chemotherapy as a first-line treatment of metastatic NSCLC from the perspective of healthcare payers in China. We found that when the time horizon was 10 years, dostarlimab plus chemotherapy was not cost-effective at the willingness to pay (WTP) threshold of 287,247 Chinese yuan (CNY)/QALY (35,057 EUR/QALY at an exchange rate of 1 CNY = 0.122 EUR).

Targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the management of metastatic non-small cell lung cancer (NSCLC) over the past decade. This single-center observational study was conducted to describe programmed death-ligand 1 (PD-L1) testing, choice of therapy, and outcomes for adult patients with stage IV NSCLC initiating first-line therapy from 2017 through 2020, with follow-up through June 2021. Patient characteristics and study assessments were described according to four histomolecular subtypes, defined by histologic characteristics and availability of standard-of-care therapies for molecular subgroups at the time of study conduct. Of 507 eligible patients with metastatic NSCLC, 85 (17%) had squamous NSCLC; 288 (57%) had nonsquamous NSCLC with no actionable genomic alteration; 44 (9%) had nonsquamous NSCLC with KRAS G12C mutation; and 90 (18%) had nonsquamous NSCLC with ROS1, BRAF V600E, EGFR exon 20 insertion, or RET or NTRK genomic alteration. Most tumors were PD-L1 tested. After excluding 40 patients whose PD-L1 testing status was unknown, all but 55 tumors (12%) were tested for PD-L1 expression, and the percentages tested rose from 86% in 2017 to 100% in 2020. From 27% of nonsquamous NSCLC with no actionable genomic alteration to 46% of KRAS G12C-mutated NSCLC had PD-L1 expression ≥ 50%. Use of chemotherapy decreased and use of ICI-chemotherapy combinations increased from 2017 to 2020. In the squamous NSCLC group, single or combination chemotherapy was administered most commonly (42%), whereas ICI-chemotherapy combinations were the most common first-line regimens in the three nonsquamous NSCLC histomolecular groups. For patients with NSCLC and no actionable genomic alterations, ICI-chemotherapy combinations were the most common regimens in 2018-2020 in all but the PD-L1 ≥ 50% category, for whom ICI monotherapy was most common every year except 2020. Median overall survival was 25.0 months (95% CI, 19.1-28.3) for all patients, and, by histomolecular cohort, 14.3 months for squamous NSCLC, 25.3 months for nonsquamous NSCLC with no actionable genomic alteration, not reached for KRAS G12C-mutated NSCLC, and 27.7 months for nonsquamous NSCLC with other genomic alterations. Study findings highlight the increased use of PD-L1 testing over the years from 2017 to 2020 and recent changes in therapy, with decreased use of chemotherapy and increased use of ICI-chemotherapy combinations during the study in each histomolecular group. Moreover, we observed improvements in survival for patients with metastatic NSCLC relative to historical real-world data.

TPS8648 Background: Approximately 2-4% of non-small cell lung cancer (NSCLC) harbor activating human epidermal growth factor receptor 2 ( HER2 ) mutations. This represents a major area of unmet medical need as no first-line HER2-targeted therapies are currently approved for patients with locally advanced or metastatic NSCLC with HER2 -activating mutations. BAY 2927088 is an oral, reversible tyrosine kinase inhibitor that potently targets HER2 and mutant epidermal growth factor receptor. Preliminary evidence from the Phase I/II SOHO-01 trial has demonstrated anti-tumor activity and a manageable safety profile in previously treated patients with NSCLC with HER2 -activating mutations (PL04.03 presented at IASLC 2024 World Conference on Lung Cancer). Here we introduce the SOHO-02 trial evaluating the efficacy and safety of BAY 2927088 as first-line therapy in patients with locally advanced or metastatic NSCLC with HER2 -activating mutations. Methods: SOHO-02 is an ongoing Phase III, open-label, randomized, multicenter trial of BAY 2927088 in patients with locally advanced or metastatic NSCLC with HER2 -activating mutations (NCT06452277). Eligibility criteria include patients aged ≥18 years with: documented histologically or cytologically confirmed, locally advanced or metastatic non-squamous NSCLC; documented activating mutation in the tyrosine kinase domain of HER2; measurable disease per RECIST v1.1; no previous systemic therapy for locally advanced or metastatic disease; and eligibility to receive treatment with the selected platinum-based doublet-chemotherapy and pembrolizumab. Overall, 278 eligible patients will be randomized to BAY 2927088 p.o. 20 mg twice daily or standard of care (SoC; pembrolizumab in combination with cisplatin/pemetrexed or carboplatin/pemetrexed) in 21-day cycles. The primary endpoint is BAY 2927088 efficacy vs. SoC on progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR). Key secondary endpoints include BAY 2927088 efficacy vs. SoC on overall survival, overall response rate, disease control rate, and duration of response per RECIST v1.1 by BICR, and BAY 2927088 safety and tolerability vs. SoC. Impact of BAY 2927088 on patient health-related quality of life and symptom severity will be evaluated using EORTC QLQ-C30 and NSCLC-SAQ. Enrollment is ongoing. Clinical trial information: NCT06452277 .

PC02.04 IO Should Be Given with Chemo

Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT280.

Despite improvements in overall survival (OS) and clinical responses of unprecedented duration with the use of therapeutic monoclonal antibodies that target PD-1 or PD-L1, the majority of patients with non-small cell lung cancer (NSCLC) fail to respond to PD-1/PD-L1 axis inhibitors. The genomic determinants of PD-1/PD-L1 inhibitor efficacy in NSCLC are incompletely understood and likely key to the development of novel personalized immunotherapy approaches. Through integrative analysis of multiple independent datasets of patients with KRAS-mutant lung adenocarcinoma (LUAC) - the most prevalent oncogenic driver event in LUAC- we identified three major disease subsets defined on the basis of co-occurring genomic events in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B, the latter coupled with low expression of the TTF1 transcription factor (KC) (Skoulidis F et al., Cancer Discovery, 2015). STK11/LKB1 is somatically mutated in ~17% of LUAC and encodes a serine/threonine kinase with an established role in the regulation of cellular metabolism, growth and polarity. Gene set enrichment analysis of RNASeq data from the TCGA LUAC cohort indicated striking de-enrichment of multiple gene expression signatures pertaining to anti-tumor immunity in the KL subgroup, raising the possibility that inactivation of STK11/LKB1 may promote establishment of a non-T-cell inflamed immune microenvironment in lung adenocarcinoma. Indeed, STK11/LKB1-mutant LUAC exhibited significantly lower density of infiltrating CD3+ (P=0.0019) and CD8+ (P=0.0072) T-lymphocytes by automated quantitative immunohistochemistry (IHC) in a tumor microarray encompassing early stage, surgically resected, chemotherapy-naïve tumors with available whole exome sequencing (PROSPECT cohort). In an independent, unbiased analysis of a large dataset of 924 LUAC with comprehensive NGS-based genomic profiling and available tumor cell PD-L1 expression (Foundation Medicine dataset) seeking to identify candidate genomic drivers of immune evasion and immunotherapy resistance, STK11/LKB1 genomic alterations emerged as the only significantly enriched gene in PD-L1Negative;TMBIntermediate/High compared to PD-L1High Positive;TMBIntermediate/High tumors (adjusted P&amp;lt;0.001). Thus, establishment of a “cold” tumor immune microenvironment in STK11/LKB1-mutant NSCLC occurs despite the presence of an intermediate/high TMB. Based on these findings we further hypothesized that STK11/LKB1 genomic alterations may impact clinical responses to PD-1 blockade in lung adenocarcinoma. In order to address this critical question, we assembled five independent cohorts of non-squamous NSCLC patients treated with PD-1 axis inhibitors. Three independent retrospective cohorts were studied from members of the Stand Up to Cancer/American Cancer Society Lung Cancer Translational Dream Team (MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute/Massachusetts General Hospital), collectively forming the SU2C cohort (N=174). A fourth cohort of 66 patients with PD-L1 positive (≥1%) non-squamous NSCLC (regardless of KRAS status) from MD Anderson Cancer Center (MDACC) was assessed to determine the impact of STK11/LKB1 genomic alterations on clinical outcomes with anti-PD-1/PD-L1 therapy in PD-L1-positive tumors. A fifth independent cohort of 44 patients with KRAS-mutant NSCLC (24 treated with nivolumab and 20 treated with docetaxel) from the CheckMate-057 (CM-057) international phase III randomized controlled trial was also analyzed. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%) and K-only (28.6%) subgroups (P&amp;lt;0.001) in the SU2C cohort and in patients treated with nivolumab in the CheckMate-057 phase III randomized controlled trial (0% vs 57.1% vs. 18.2%; P=0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P&amp;lt;0.001) and overall (P=0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Because non-mutational mechanisms can also account for STK11/LKB1 inactivation in LUAC, we further assessed expression of STK11/LKB1 by IHC in a subset of tumors for which archival tissue was available. KRASMUT;STK11/LKB1MUT (KL) tumors expressed low to undetectable levels of STK11/LKB1 protein, whereas KRASMUT;STK11/LKB1WT tumors displayed variable levels of STK11/LKB1 expression, with 17.6% having a STK11/LKB1 H-score of zero. Patients bearing STK11/LKB1-deficient tumors (STK11/LKB1MUTor STK11/LKB1WT and STK11/LKB1 H-score zero) exhibited significantly shorter PFS (HR 1.80; 95% CI, 1.15-2.82; P = 0.0094) and OS (HR 2.03; 95% CI, 1.13-3.65; P = 0.016) compared with those harboring STK11/LKB1-proficient tumors (STK11/LKB1WT and STK11/LKB1 H-score &amp;gt; 0). Therefore, quantitative IHC for STK11/LKB1 can capture STK11/LKB1-deficient tumors with intact STK11/LKB1 genomic locus and may enhance the predictive utility of STK11/LKB1 genomic alterations. Importantly, the impact of STK11/LKB1 mutations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1 positive tumors. Among 66 PD-L1-positive (≥1%) non-squamous NSCLC treated with PD-1/PD-L1 inhibitors, STK11/LKB1-mutated tumors exhibited significantly lower objective response rates to PD-1/PD-L1 blockade compared with NSCLC with intact STK11/LKB1 (ORR 0% vs. 34.5%, P = 0.026) and dramatically shorter PFS (HR 4.76; 95% CI, 2.0-11.1, P = 0.00012, log-rank test) and OS (HR 14.3; 95% CI, 3.4-50.0, P &amp;lt; 0.0001, log-rank test). More recently, we also interrogated the impact of STK11/LKB1 genomic alterations on clinical outcomes with chemo-immunotherapy, the new standard of care for the first line treatment of patients with metastatic non-squamous NSCLC. Among 43 patients with metastatic non-squamous NSCLC (wild-type for EGFR and ALK) that received pemetrexed/carboplatin/pembrolizumab at MDACC. STK11/LKB1 alterations were associated with significantly lower objective response rate (31.3% vs. 65.6%, P=0.035) and shorter progression free survival (HR 2.73; 95% CI 1.15-6.48; P=0.018) compared to STK11/LKB1 wild-type tumors. Finally, in order to establish whether primary resistance to immunotherapy is causally linked with STK11/LKB1 inactivation, we generated Stk11/Lkb1-proficient/deficient isogenic derivatives of the LKR10 and LKR13 Kras-mutant murine LUAC cell lines using CRISPR/Cas9-mediated bi-allelic disruption of the Stk11/Lkb1locus, implanted them into the flanks of syngeneic recipient mice and randomized cohorts of tumor bearing mice to treatment with anti-PD-1 mAb (LKR10), anti-PD-L1 mAb (LKR13) or IgG control. Treatment with PD-1/PD-L1 axis inhibitors potently suppressed Stk11/Lkb1-proficient tumors in both the LKR13 and LKR10 models, whereas Stk11/Lkb1 deficient isogenic tumors were recalcitrant to PD-1 axis blockade. Therefore, in these immune-competent models of KRAS-mutant LUAC, loss of STK11/LKB1 directly promotes PD-1/PD-L1 inhibitor resistance, suggesting a causal role. In agreement with data from human tumors, significantly lower numbers of CD3+CD8+ and CD3+CD8+PD1+ T lymphocytes were present in Stk11/Lkb1-deficient murine tumors compared to their Stk11/Lkb1-proficient counterparts. Taken together, our results identify inactivating mutations in STK11/LKB1 as a highly prevalent genomic determinant of a “cold” tumor immune microenvironment and major driver of de novo resistance to PD-1/PD-L1 inhibitors in non-squamous NSCLC independently of TMB and tumor cell PD-L1 expression. Furthermore, attribution of a large fraction of primary resistance to PD-1 axis blockade in non-squamous NSCLC to inactivating mutations in a single tumor suppressor gene - and therefore potentially to a single molecular mechanism - paves the way for the development of rational, science-driven combination therapeutic strategies in order to restore effective anti-tumor immunity in STK11/LKB1-deficient tumors. Citation Format: Ferdinandos Skoulidis. Inactivating STK11/LKB1 genomic alterations are a major driver of primary resistance to PD-1 axis blockade in non-squamous non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-02.

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p &lt; 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p &lt; 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p &lt; 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

TPS8668 Background: EGFR exon 20 insertion mutations (ex20ins) occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (1). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. In FAVOUR, treatment naïve patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations showed preliminary clinical activity with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months when treated with 240 mg daily [QD] of furmonertinib (2). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively and included patients harboring near and far loop mutations. Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients have treatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR ex20ins mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastatic setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression can crossover to furmonertinib cohort. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Han et al., WCLC 2023. Clinical trial information: NCT05607550 .