bluuebunny/crossref_metadata_2025 huggingface dataset:
METex14 ctDNA dynamics & resistance mechanisms detected in liquid biopsy (LBx) from patients (pts) with METex14 skipping NSCLC treated with tepotinib.
Authors: Paik Paul K. , Veillon Remi , Felip Enriqueta , Cortot Alexis , Sakai Hiroshi , Mazieres Julien , Thomas Michael , Reinmuth Niels , Raskin Jo , Conte Pier Franco , Garassino Marina Chiara , Iams Wade Thomas , Griesinger Frank , Kowalski Dariusz M. , Stroh Christopher , Juraeva Dilafruz , Scheuenpflug Juergen , Johne Andreas , Le Xiuning
Published: June 2021

9012

Background: In the VISION study, tepotinib in METex14 skipping NSCLC pts (Cohort A) had robust and durable clinical activity. Serial LBx samples were collected for biomarker analyses, presented herein. Methods: LBx samples taken at baseline (BL), Week 6, 12, & end of treatment (EOT) were analyzed using Guardant360® CDx (73 genes). Investigator (INV)-assessed clinical outcome was evaluated per BL biomarker profiles and by molecular response (MR; defined as > 75% depletion from BL in METex14 variant allele frequency [VAF] ctDNA confirmed in 2 consecutive samples) or molecular progression (MP; defined as VAF increase > 0 from BL). Acquired resistance was investigated in EOT samples, following progression per INV. Results: LBx pts (n = 99) had a median age of 72 yrs (range 49–88), 53% were male, 44% never smokers, 85% had adenocarcinoma. INV ORR was 53% (95% CI 42, 63); ORR in 1L (n = 44) was 59% (43, 74) & ≥2L (n = 55) was 47% (33, 61). 94 pts had BL biomarker profiles; these were similar in 1L and ≥2L pts, except EGFR amp: 1/43 1L [2%] vs 8/51 ≥2L [16%]. Outcomes were not impacted by location/type of METex14 alteration. 1 pt with concomitant MET M1250T mutation had a PFS of 17.3 months. A trend towards better efficacy was seen in pts with concomitant MET amp (6 responses in 8 pts). Response to tepotinib occurred both in pts with wt or mutant TP53; however, there was a trend for longer mDOR in pts with wt TP53 (18.3 [95% CI 9.7, ne] vs 7.1 [4.7, 10.9] months) and mPFS (9.5 [6.7, 19.7] vs 5.1 [2.8, 6.9] months). Concomitant oncogenic mutations were rare, with no responses in 3 pts with KRAS, NRAS alterations and 3 responses in 5 pts with PI3K/AKT alterations. 65 pts had 2 consecutive on-treatment samples: 46 (71%) had confirmed MR, 5 (8%) had confirmed MP, 14 (22%) had no change in VAF or lacked confirmation. MR was associated with clinical response and MP was associated with no response/short PFS (Table). 52 pts with progression had EOT LBx samples. Emerging MET resistance mutations (Y1230H/C & D1228H/N) occurred in 7 (13%) pts, all responders and 5/7 had PFS > 10 months. Analyses on non-MET-driven resistance mechanisms will be presented. Conclusions: LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in METex14 skipping NSCLC, showed that ctDNA depletion in METex14 VAF is associated with improved clinical response in pts treated with tepotinib. This suggests serial LBx could help us to monitor response/non-response, understand resistance, and guide trials that test escalation/de-escalation strategies to improve outcomes and maximize QOL. Clinical trial information: NCT02864992. [Table: see text]
Effect of antibiotic therapy on immunotherapy outcomes for non-small cell lung cancer: Analysis from the Veterans Health Administration Database.
Authors: Stokes William A. , Behera Madhusmita , Jiang Renjian , Gutman David , Giuste Felipe , Burns Abigail , Sebastian Nikhil , Ramalingam Selvi , Sukhatme Vidula , Lowe Michael C. , Ramalingam Suresh S. , Sukhatme Vikas , Moghanaki Drew
Published: June 2021

9017

Background: Dysregulation of the gut microbiota induced by antibiotic therapy (Abx) may alter the anticancer immune response. Multiple small studies have associated Abx use with inferior immune checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC). We aimed to study the impact of Abx in a larger population of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a nested cohort study of Veterans who were diagnosed with NSCLC between 2010 & 2018 and treated with ICI. Two exposures to Abx were specified and separately analyzed: prior Abx (pAbx) was defined as receipt of an Abx prescription within 30 days prior to initiation of ICI, and concurrent Abx (cAbx) was defined as receipt of an Abx prescription within 60 days following ICI initiation. A landmark analysis of 2 months from ICI start was applied to the cAbx analysis to exclude any Veterans with an OS event before that time point. OS was measured from start of ICI using Cox proportional hazard multivariate analyses (MVA). Results: 3,634 Veterans received ICI, mostly nivolumab (59.3%) or pembrolizumab (35.1%). Their median age was 69, and a plurality had male gender (97.0%), white race (73.0%), comorbidity count ≥1 (60.4%), adenocarcinoma (47.8%), and stage IV disease at diagnosis (40.9%). Of the 762 (21.0%) Veterans prescribed pAbx, beta-lactams, quinolones, and macrolides were the most common classes. These patients had shorter OS than those without pAbx (median 7 versus 10 months). Receipt of pAbx was also associated with lower OS on MVA (HR 1.31, p<0.01). In the propensity-matched cohort analysis, Veterans receiving pAbx had lower OS (HR 1.27, p<0.01) (Table top). For the cAbx analysis, 3,223 Veterans survived to the 2-month landmark, of whom 970 (30.1%) received cAbx. These Veterans had shorter OS than those without cAbx (median 7 versus 10 months). Lower OS with cAbx was also observed both on Cox MVA (HR 1.33, p<0.01) and in the matched cohort (HR 1.32, p<0.01) (Table bottom). Conclusions: In the largest analysis to date of Abx use in NSCLC patients receiving ICI, receipt of Abx within either 30 days before or 60 days after start of ICI was associated with lower OS. These findings suggest Abx therapy may have a detrimental effect on immunotherapy outcomes.[Table: see text]
Clinicogenomic real-world data analysis of patients (pts) with KRAS G12C-mutant advanced non-small cell lung cancer (aNSCLC) from the natural history cohort of the Blood First Assay Screening Trial (BFAST).
Authors: Dziadziuszko Rafal , Li Xiao , Anderson Eric C. , Zer Alona , Corrales-Rodriguez Luis , Cheema Parneet , Szczesna Aleksandra , Philco Manuel , Mathisen Michael , Paul Sarah M. , Bhagawati-Prasad Vijay , Pathria Gaurav , Shi Zhen , Hilton Magalie , zhang qing
Published: June 2021

9023

Background: BFAST (NCT03178552) is a global, multicohort trial of targeted therapies or cancer immunotherapy (CIT) in treatment (tx)-naive aNSCLC. Pts are screened for the study using comprehensive blood-based next-generation sequencing (NGS). In the BFAST natural history cohort, data were collected for pts who received tx or care outside the study’s interventional cohorts. Here, we analyzed the subset of pts whose tumors have KRAS G12C mutations (mut). Methods: Pts eligible for blood-based NGS screening had unresectable aNSCLC, ECOG PS 0-2 and no prior systemic tx for aNSCLC. Pts without tissue samples were eligible. Key genomic and molecular features, including bTMB, PD-L1 and ctDNA concentration; cancer tx; tx response and survival data were collected and analyzed in an exploratory analysis. Results: In the full BFAST screening population through December 2020 (N = 5917), 23% of pts had tumors with any KRAS mut; 9% were KRAS G12C. Pts were enrolled in the natural history cohort from October 2018 to October 2020 (n = 1017); 63 pts had tumors with KRAS G12C mut. Median age was 68 y, 59% were male, 86% had ECOG PS 0-1 and 84% had non-squamous histology. Co-mut in TP53 (60%) and STK11 and/or KEAP1 (25%) were detected; 8% of pts had bTMB ≥16. High PD-L1 expression per local testing was reported in 32% of pts; 38% were not tested. Among pts with 1L tx (n = 50), 50%, 28% and 20% received chemo, CIT or CIT + chemo, respectively, with real-world response rates (CR/PR per physician assessment) of 20%, 29% and 30%, respectively. Of the 13 pts (21%) without documented 1L tx, 7 died ≤3 mo from enrollment. Median OS was 14 mo overall, with differences found between key genomic subsets (Table). Conclusions: BFAST is the first study to identify KRAS G12C mut using blood-based NGS and describe the natural history, clinical characteristics and genomic landscape of this pt subset. Up to 21% of pts may not receive 1L tx. Pts with TP53 co-mut appear to have favorable outcomes, while those with STK11 and/or KEAP1 co-mut appear to have inferior outcomes vs pts without these mut. The lack of PD-L1 testing in many pts indicates a lack of tissue for comprehensive tissue testing, highlighting a potential benefit of blood-based detection of biomarkers, including KRAS G12C. Clinical trial information: NCT03178552. [Table: see text]
Clinical performance of artificial intelligence-powered annotation of tumor cell PD-L1 expression for treatment of immune-checkpoint inhibitor (ICI) in advanced non-small cell lung cancer (NSCLC).
Authors: Kim Hyojin , Choi Sangjoon , Kim Seokhwi , Aum Jaehong , Pereira Sergio , Park Seonwook , Ma Minuk , Shin Seunghwan , Paeng Kyunghyun , Yoo Donggeun , Jung Wonkyung , Ock Chan-Young , Lee Se-Hoon , Chung Jin-haeng , Choi Yoon-La , Mok Tony S. K.
Published: June 2021

9026

Background: Programmed death ligand 1 (PD-L1) expression is the standard biomarker for first line ICI in advanced NSCLC. However, manual evaluation of tumor proportion score (TPS) by pathologists has practical limitations including intra/inter-observer bias, variation in subjectivity on area of interest and intensive labor. We developed an artificial intelligence (AI)-powered TPS analyzer, namely Lunit SCOPE PD-L1, for objective annotation of tumor cell PD-L1 expression for prediction of ICI response in advanced NSCLC. Methods: Lunit SCOPE PD-L1 was developed by a total of 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSI) stained by 22C3 pharmDx immunohistochemistry. A After excluding the in-house control tissue regions, the WSI were divided into patches, from which a deep learning-based model detected the location and PD-L1 positivity of tumor cells. The patch-level cell predictions were aggregated for TPS estimation. Clinical performance of the model was validated in an external cohort of 430 NSCLC tumor slides from patients treated with ≥ ICI at Seoul National University Bundang Hospital and Samsung Medical Center. Independent control TPS annotation of this external validation cohort was performed by three pathologists, and their consensus TPS was calculated by mean value of such. Results: AI-model (Lunit SCOPE PD-L1) predicts PD-L1-positive tumor cell with the area under the curves of 0.889 and PD-L1-negative tumor cells with that of 0.809 at cell-level analysis. At WSI-level, significant positive correlation was observed between TPS by AI model and control TPS by pathologists (Spearman coefficient = 0.9247, P < 0.001). Concordance rate between AI-model and control TPS by pathologists according to expression level of PD-L1 ≥ 50%, 1-49%, and < 1% status was 85.7%, 89.3%, and 52.4%, respectively. Median progression-free survival (mPFS) according to TPS by AI model ≥ 1% vs. < 1% were 2.8 vs. 1.7 months (hazard ratio, HR, 0.52, 95% confidence interval, CI, 0.38-0.71, P < 0.001). In contrast, mPFS according to control TPS was 2.8 vs. 2.1 months (HR 0.70, 95% CI 0.55-0.91, P < 0.001). Forty out of 84 patients (47.6%) annotated as control TPS < 1% by pathologists were considered as TPS ≥ 1% by AI-model and mPFS of this subgroup was 2.7 months. Conclusions: PD-L1 expression by AI-model correlates with PD-L1 expression by pathologists. Clinical performance of AI-model in WSI-level is comparable with assessment by pathologists. The AI-model can accurately predict tumor response and progression-free survival of ICI in advanced NSCLC.
Determination of clinical benefit among patients with radiological stable disease to immune checkpoint inhibitors.
Authors: Luo Jia , Wu Song , Rizvi Hira , Zhang Qu , Egger Jacklynn V. , Osorio Juan C. , Schoenfeld Adam Jacob , Plodkowski Andrew J. , Ginsberg Michelle S. , Gupta Ashok Kumar , Raja Rajiv , Kris Mark G. , Hellmann Matthew D.
Published: June 2021

9041

Background: SD is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs) and likely represents a heterogenous mix of responders and non-responders. This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. The ability to distinguish whom among patients with SD is actually benefiting from treatment would facilitate drug development and improve precision in correlative research. Methods: A systematic review was performed to characterize SD in ICI trials. SD and objective response was compared to proliferation index using TCGA gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of NSCLC treated with ICIs and had RECIST assessment. In patients with best overall response (BOR) of SD, serial cutpoints of two variables, % BOR and PFS, were tested to define a subgroup with similar survival as PR-minor (patients with partial response [PR] and % shrinkage < median among responders). Results were then tested in two external validation cohorts (n = 326, n = 381). Results: Among trials of ICIs (59 studies, 14,280 patients), SD ranged from 16-42% in different tumor types and was associated with disease-specific proliferation index (Spearman rho = -0.75, p = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of 1220 patients with NSCLC who were treated with ICIs, 26% had SD, 19% had PR/CR, and 55% had PD. Outcomes among those with SD ranged widely (OS range 0.5-76 months, PFS range 0.2-49 months). The subset of SD with PFS > 6 months and no tumor growth mirrored PR-minor (OS HR 1.0) and was proposed as the definition of “SD-responder”. SD-responders (n = 87) represented 7% (95% CI 6-9%) of the overall population and 28% (95% CI 23-33%) of the SD population. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab. Conclusions: RECIST-defined SD to immunotherapy is common, heterogenous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS > 6 months and no tumor growth (̃1/3 of SD) may be considered “SD responders.” This definition may improve the efficiency of and insight derivable from clinical and translational research.
Subgroup-level network meta-analysis for efficacy of first-line immunotherapy-based treatments in advanced non-small cell lung cancer.
Authors: Wu Fang , Tian Wentao , Cao Chenghui , Ke Jiawen , Tan Nuopei , Cai Yuwen , Zeng Yue , Pan Yue , Liu Xiaohan , Zhao Lishu , Shu Long , Liu Junqi
Published: June 2021

9064

Background: Immunotherapy has unequal efficacies in populations with different clinical or histological features. This study aims to explore inter-subgroup differences in responses to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and find the optimal treatments for each subgroup. Methods: We performed (network) meta-analyses of phase III random controlled trials, in which efficacies of 10 immunotherapy-based treatments were compared, including anti-programmed death receptor-1 (PD-1) (+chemotherapy), anti-programmed death ligand-1 (PD-L1) (+chemotherapy), anti-PD-L1+anti-cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-PD-1+anti-CTLA-4 (+chemotherapy), anti-CTLA-4+chemotherapy, anti-PD-1+anti-angiogenic therapy (AT)+chemotherapy, and anti-PD-L1+AT+chemotherapy, for 19 subgroups by sex, age, smoking status, metastatic site (liver/brain/bone), histological type (squamous/non-squamous cancer), and PD-L1 expression, using hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and their 95% confidence intervals (CIs). Results: 22 studies comprised of 12678 patients with advanced NSCLC were included in our study. The results showed OS and PFS advantages of immunotherapy-based treatments in 16 out of 19 subgroups comparing with chemotherapy. Never-smokers (OS-HR 0.81, 95% CI 0.55-1.18; PFS-HR 0.73, 95% CI 0.51-1.07), ¡Ý75-year-old patients (OS-HR 0.9, 95% CI 0.71-1.13), and patients with liver metastases (OS-HR 0.88, 95% CI 0.77-1) showed indisposed responses to immunotherapy. In patients with PD-L1 tumor proportion score (TPS)<1%, anti-CTLA-4+anti-PD-1 and anti-PD-1+anti-CTLA-4+chemotherapy had significant OS benefit comparing with anti-PD-L1 monotherapy (HR 0.6, 95% CI 0.44-0.81; HR 0.6, 95% CI 0.41-0.87; respectively) and anti-PD-L1+AT+chemotherapy (HR 0.66, 95% CI 0.48-0.92; HR 0.66, 95% CI 0.45-0.98; respectively). In patients with liver metastases, anti-PD-L1+AT+chemotherapy showed significant PFS advantage comparing with anti-PD-L1+chemotherapy (HR 0.51, 95% CI 0.33-0.77). As for other populations, anti-PD-1+chemotherapy showed wide-ranging promising efficacies in multiple subgroups. Conclusions: Patients with advanced NSCLC generally benefit from immunotherapy. Specific immunotherapy treatments should be applied according to different clinical or histological features. Meanwhile, we expect more preclinical and clinical studies to focus on therapeutic strategies for populations with impaired responses towards immunotherapy. Funding: CSCO-BMS Oncologic Research Foundation (Grant No. Y-BMS2019-100); Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120) and Guangdong Association of Clinical Trials (GACT); Changsha Science and Technology Bureau (Grant No. kq1907077).
Neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC) and central nervous system (CNS) involvement: Findings from the SUMMIT basket trial.
Authors: Goldman Jonathan Wade , Viteri Ramirez Santiago , Mahipal Amit , Suga Jennifer Marie Marie , Eli Lisa DeFazio , Lalani Alshad S. , Bryce Richard , Xu Feng , Shah Naisargee , Kabbinavar Fairooz , Boni Valentina , Haley Barbara B.
Published: June 2021

9068

Background: The phase 2 SUMMIT basket trial (NCT01953926) demonstrated efficacy of neratinib in patients with EGFR exon 18-mutant NSCLC [Boni et al. WCLC 2020]. Neratinib also has documented activity in HER2+ metastatic breast cancer with CNS metastases [Saura et al. SABCS 2020 & J Clin Oncol 2020]. Here we report neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant NSCLC and CNS involvement from SUMMIT. Methods: Patients with EGFR exon 18-mutant NSCLC were treated with single-agent neratinib (240 mg po daily). Prior EGFR tyrosine kinase inhibitors (TKIs), chemotherapy, and checkpoint inhibitors (IO) were allowed. Patients with stable, asymptomatic CNS metastasis were enrolled. Study endpoints: objective response rate (ORR) at week 8 (±1 week); ORR (RECIST 1.1 confirmed); duration of response (DOR); clinical benefit rate (CBR); progression-free survival (PFS); safety; biomarkers. Results: Baseline characteristics of 11 patients with EGFR exon 18-mutant NSCLC: median age 67 (range 56–83) years; ECOG PS 0/1 (45%/55%). Prior lines of therapies: 2 (range 1–3): EGFR TKIs (91%); chemotherapy (55%); IO (27%). 3/11 patients had baseline CNS metastasis and received radiation 8–22 months prior to study enrollment. Best CNS response in these 3 patients was stable disease with overall individual PFS of 1.9 (censored), 6.9 and 9.1 months and OS of 2.6 (censored), 17.7 (censored), and 17.9 months. Efficacy is summarized in Table. Efficacy summary: TKI-pretreated EGFR exon 18-mutant NSCLC cohort receiving neratinib monotherapy. Conclusions: Activity of single-agent neratinib was observed in prior TKI-exposed patients with EGFR exon 18-mutant NSCLC. Despite the small sample size of only 3 patients with baseline CNS metastases, findings suggest a potential role for neratinib as a systemic treatment option for patients with NSCLC and difficult-to-treat uncommon mutations with CNS involvement. The SUMMIT trial continues to enroll patients with EGFR exon 18-mutant NSCLC. Clinical trial information: NCT01953926. [Table: see text]
The effects of tislelizumab treatment on the health-related quality of life of non-small cell lung cancer patients who progressed on a prior platinum-containing regimen.
Authors: Zhou Cai , Huang Dingzhi , Ma Yiyuan , Pan Zhenyu , Barnes Gisoo , Tang Boxiong
Published: June 2021

9069

Background: Anti-PD-1/L1 therapies have improved overall survival (OS) by 2-4 months vs docetaxel in patients with advanced non−small cell lung cancer (NSCLC) who progressed after receiving a platinum regimen. Tislelizumab, an anti-PD-1 antibody, has been tested as monotherapy in the RATONALE (NCT 03358875) trial, which found that tislelizumab prolonged OS (median OS difference 5.3 months in ITT population) as compared to docetaxel, improved progression-free survival (median 4.1 vs 2.6 months), as well as overall response rate (ORR difference = 14.9%).Here we report health-related quality of life (HRQoL) of patients receiving tislelizumab vs docetaxel in this clinical trial. Methods: NSCLC patients in this open-label, multicenter Phase 3 study were randomized to either the tislelizumab or docetaxel. HRQoL was measured using the QLQ-C30 global health status/quality of life score (GHS/QoL) from EORTC QLQ-C30 as well as the lung cancer specific subscales of the EORTC QLQ-LC13. Descriptive analysis for the GHS/QoL score was performed for baseline through cycle 10; changes from baseline to cycle 12 were examined for the symptom subscales. Results: 805 patients were randomized to tislelizumab (n = 535) or docetaxel (n = 270). Patients were 77% male with an average age of 60 years (range 28-88 years). The compliance rates were mostly > 98% and were similar across arms. The GHS/QoL score in the tislelizumab arm improved relative to baseline from cycles 5 through 10 while declining in cycles 6 through 10 in the docetaxel arm. The tislelizumab arm showed a reduction from baseline at cycle 12 in the symptom scores of coughing, chest pain, and dyspnea while patients in the docetaxel arm experienced an increase in symptoms. Conclusions: The study results show that tislelizumab monotherapy improved HRQoL in patients who previously failed treatment with a platinum containing chemotherapy; this is especially important as the NSCLC patients treated with tislelizumab not only experienced improvements in OS, but also reductions in their symptomology. Clinical trial information: NCT 03358875.
Brigatinib (BRG) in ALK+ crizotinib (CRZ)-refractory non-small cell lung cancer (NSCLC): Final results of the phase 1/2 and phase 2 (ALTA) trials.
Authors: Gettinger Scott N. , Huber Rudolf M. , Kim Dong-Wan , Bazhenova Lyudmila , Holmskov Hansen Karin , Tiseo Marcello , Langer Corey J. , Paz-Ares Luis G. , West Howard , Reckamp Karen L. , Weiss Glen J. , Smit Egbert F. , Hochmair Maximilian , Kim Sang-We , Ahn Myung-Ju , Kim Edward S. , Groen Harry J.M. , Pye Joanna , Vranceanu Florin , Camidge D. Ross
Published: June 2021

9071

Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]
Activity of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients (pts) with NSCLC with uncommon EGFR mutations: A real-world cohort study (UpSwinG).
Authors: Miura Satoru , Hsia Te-Chun , Hung Jen-Yu , Jung Hyun Ae , Shih Jin-Yuan , Park Cheol-Kyu , Lee Seung Hyeun , Okamoto Tatsuro , Ahn Hee Kyung , Lee Yong Chul , Sato Yuki , Lee Sung Sook , Mascaux Celine , Daoud Hasan , Maerten Angela , Popat Sanjay
Published: June 2021

9072

Background: EGFR TKIs are an established treatment (tx) option for pts with EGFR mutation-positive NSCLC with common mutations (Del19 or L858R); however, 7–23% of NSCLC tumors harbor uncommon EGFR mutations, where EGFR TKI efficacy is less established. These mutations are highly heterogeneous, and developments in detection by NGS are helping to identify mutations with little or no clinical data. Methods: In this non-interventional, global, multi-center study (NCT04179890), existing medical or electronic health records were identified for consecutive EGFR TKI-naïve pts with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q or S768I], ‘other’ or compound mutations) treated with erlotinib, gefitinib, afatinib, osimertinib or other systemic therapy. Endpoints were time to tx failure (TTF), ORR, OS and duration of response (DoR). Results: Overall, 246 pts (median age: 69.5 yrs; Asian: 84%; brain metastases: 8%; ECOG PS ≥2: 16%) were recruited from 9 countries. Most pts (n=226; 92%) received an EGFR TKI as 1st-line therapy; 132 (54%), 105 (43%) and 7 (3%) received afatinib, 1st-gen TKIs and osimertinib, respectively. 57% of pts received >1 line of therapy. Most pts (73%) had a major uncommon mutation, 9% had other mutations and 33% had a compound mutation; these were detected using PCR (75%) or sequencing (25%), mainly based on tissue biopsy (86%). Pathology reports varied in quality, often lacking detail on specific mutations e.g. 21% of ex18 and 72% of ex20ins were undefined. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 mos; ORR was 42%. In pts treated with 1st-line chemotherapy (n=20), median TTF and ORR were 6.6 mos and 41%. Outcomes were most favorable in major uncommon and compound mutations (Table). TTF appeared to be higher with afatinib vs 1st-gen EGFR TKIs. In most mutation categories, median OS was >2 yrs, possibly reflecting high subsequent therapy uptake. Conclusions: In a real-world setting, EGFR TKIs were the preferred tx option in pts with uncommon EGFR mutations; strongest outcomes were seen in major uncommon and compound mutations, and in pts treated with afatinib. Data were in line with recent analyses of afatinib in uncommon mutations. Tx with an EGFR TKI should be considered as standard for most pts with uncommon mutations. Optimal tx for pts with uncommon mutations requires improvements in pathology reports, with more emphasis on NGS methodology and precise definition of mutations. Clinical trial information: NCT04179890. [Table: see text]
Patient-reported symptoms, functioning, and quality of life (QoL) in patients treated with cemiplimab monotherapy for first-line treatment of advanced NSCLC with PD-L1 ≥ 50%: Results from EMPOWER-Lung 1 study.
Authors: Gumus Mahmut , Chen Chieh-I , Ivanescu Cristina , Kilickap Saadettin , Bondarenko Igor , Ozguroglu Mustafa , Gogishvili Miranda , Turk Haci M. , Cicin Irfan , Harnett James , Mastey Vera , Naumann Ulrike , Reaney Matthew , Konidaris Gerasimos , Sasane Medha , Brady Keri , Li Siyu , Gullo Giuseppe , Rietschel Petra , Sezer Ahmet
Published: June 2021

9078

Background: Cemiplimab, a PD-1 inhibitor, improved survival and progression-free survival vs platinum doublet chemotherapy (chemo) in patients (pts) with advanced NSCLC and PD-ligand(L)1 expression ≥50% in the EMPOWER-Lung 1 Phase 3 study (NCT03088540). Since pts with advanced NSCLC have a high symptom burden that adversely impacts QoL and functioning, these outcomes were evaluated as secondary endpoints in the clinical trial. Methods: Pts with advanced NSCLC with PD-L1 expression ≥50% and ECOG performance status ≤1 were randomized to IV cemiplimab 350 mg Q3W (n=356) or platinum doublet chemo (n=354). At baseline (BL) and day 1 of each treatment cycle (C) to C15, pts were administered the EORTC core questionnaire (QLQ-C30) and its lung cancer specific module (QLQ-LC13) to assess symptoms, functioning, and Global Health Status (GHS)/QoL. In the intent-to-treat population, mixed-effects repeated measures models were used to estimate least squares (LS) mean change from BL on all scales. Kaplan–Meier analysis estimated time to definitive deterioration, defined as worsening ≥10 points from BL observed at all subsequent time points or patient withdrawal after worsening; hazard ratios (HR) with 95% CIs estimated the likelihood of definitive deterioration. Results: BL scores showed moderate to high levels of functioning and low symptom burden. Cemiplimab-treated pts had lower likelihood of definitive deterioration vs chemo on key symptoms of dyspnea, cough, pain in chest, pain in other body parts, fatigue, nausea/vomiting, appetite loss, constipation, and diarrhea vs chemo (all P<.05). Treatment-related symptoms of peripheral neuropathy and alopecia had a lower likelihood of definitive deterioration with cemiplimab vs chemo (both P<.05). Cemiplimab resulted in significantly greater improvements vs chemo on all functioning scales and reduced the likelihood of definitive deterioration as indicated by HR <1 (Table). GHS/QoL improvements with cemiplimab at C2 were maintained to C15; LS mean change (SE) from BL across all timepoints was 7.1 (1.0) for cemiplimab vs 1.7 (1.2) for chemo ( P<.0001). Conclusions: In pts with advanced NSCLC and PD-L1 expression ≥50%, cemiplimab significantly improved GHS/QoL, functioning, and most symptoms vs chemo. Over 1 year of treatment, cemiplimab delayed worsening of key lung cancer symptoms and functioning. Clinical trial information: NCT03088540. [Table: see text]
Real-world patterns of biomarker testing and targeted therapy in metastatic non-small cell lung cancer (mNSCLC) in the community oncology setting.
Authors: Nadler Eric S. , Vasudevan Anupama , Davies Kalatu , Wang Yunfei , Gupta Ravindra , Ogale Sarika
Published: June 2021

9079

Background: National guidelines recommend biomarker testing in mNSCLC, and targeted therapy is associated with improved outcomes. The aim of this study was to understand the real-world biomarker testing and treatment patterns in the community setting. Methods: This was a retrospective study of adult patients diagnosed with de novo mNSCLC between 01-Jan-2016 and 30-Sep-2019, with follow-up through 31-Dec-2019 using The US Oncology Network structured electronic health records data. Patients who received systemic treatment for mNSCLC were included. Results: A total of 3213 patients were identified with median age 68 years (24, 90+); 52.7% were male and 10% were current smokers. ECOG score was 0-1 in 55.2%; 60% had adenocarcinoma, 16% had squamous cell carcinoma, and the rest had other/unknown histology. Since most of the biomarker-guided therapies were approved after 2016, testing patterns are described for 2017-2019 (n=2257). Overall, 23.6% were not tested for any biomarker (PD-L1 or driver mutation [DM]) at any time during the study period, and only 49% had a biomarker test result prior to 1L treatment. We observed similar patterns when assessing DM specifically; 35.8% were never tested for DM, and only 39.3% had a DM test result prior to 1L treatment. As an example, out of 42 ALK+ patients in this study population, only 5 had test results prior to 1L treatment and only 3 received an ALK inhibitor as their 1L treatment (Table). Similar patterns were observed for the other biomarkers. Conclusions: Despite availability of promising biomarker-based therapies, the lack of adequate testing in the community oncology setting means that not all eligible patients are receiving the most effective therapies upfront. Nearly 61% of patients had no DM test reported before 1L treatment in this mNSCLC cohort (all histologies), and some were determined to be DM positive at a later time, highlighting a missed opportunity to employ the most effective biomarker-directed front-line treatment. Next steps in this study will include assessing patterns by histology. Structured data, which are recorded for clinical management, might have gaps; future research with chart reviews could provide a more comprehensive assessment.[Table: see text]
Beyond steroids: Immunosuppressants in steroid-refractory/resistant immune related adverse events.
Authors: Luo Jia , Beattie Jason , Fuentes Paige , Rizvi Hira , Egger Jacklynn V. , Kern Jeffrey , Leung Donald Y. M. , Lacouture Mario E. , Kris Mark G. , Gambarin Maya , Santomasso Bianca , Faleck David M. , Hellmann Matthew D.
Published: June 2021

9092

Background: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion. Methods: We examined patients with advanced lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes. Results: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). All patients with hepatitis received mycophenolate mofetil 500-1000mg BID for a median of 3 months, range 2-5 months. Of the 18 patients with colitis who improved with a TNFα inhibitor, 10 needed just one dose. Of 13 patients who died, 4 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure). Those who died from immunosuppressive therapy received higher amounts of systemic steroids than those who did not (max median 525 vs 132 mg prednisone equivalent, Mann Whitney U p = 0.004, total median 5.9k vs 2.3k mg prednisone equivalent, p = 0.004). Of 31 patients who received at least 3 weeks of prednisone ≥ 20mg, most (90%, 28/31) had at least one side effect that was brought to clinical attention (most commonly altered mood/ sleep, 52%, increase in BMI > 1kg/m2, 45%, and infection, 32%). Conclusions: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, most patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. Systemic steroid use likely contributed to side effects and mortality. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically informed treatment regimens for severe irAEs to realize the true benefit of ICB therapy.
Impact of immune checkpoint inhibitor (CPI) and EGFR tyrosine kinase inhibitor (TKI) sequence on time to treatment failure (TTF) among EGFR plus NSCLC treated in a community-based cancer research network.
Authors: Jones Carissa , Lachs Rebecca , Sturgill Emma , Misch Amanda , Lietman Caressa , Jones Suzanne Fields , Johnson Melissa Lynne , Spigel David R. , McKenzie Andrew Jacob
Published: June 2021

9099

Background: The development of CPIs and driver-targeted TKIs has transformed the treatment of NSCLC and increased survival rates. However, the role of CPIs in patients with oncogenic-driven NSCLC remains an area of investigation. We sought to examine the impact of CPI sequence on treatment response among patients with oncogenic-driver mutation-positive NSCLC. Methods: Patients with NSCLC being treated within the Sarah Cannon Research Institute network were identified through Genospace, Sarah Cannon’s clinico-genomic analytics platform. Advanced stage oncogenic-driven tumors (driver+) were defined as those with a record of receiving an FDA-approved TKI targeting EGFR, ALK, RET, ROS1, NTRK, MET, or BRAF. Kaplan-Meier estimates were used to examine TTF (defined as time from therapy start to start of next therapy, death, or loss to follow-up) and overall survival (OS). Results: We identified 12,352 patients with lung cancer and available therapy data (2005-2020), including 2,270 (18%) driver+ patients. Eleven percent (N=245) of driver+ patients received a CPI, including 120 (49%) with CPI prior to TKI, 122 (50%) with CPI post TKI, and 3 (1%) who received CPI both pre and post TKI. The CPI TTF was significantly longer for those who received CPI post TKI compared to those who received it prior (Table). EGFR+ tumors accounted for 82% (N=1,867) of driver+ patients, 10% of whom (N=188) received a CPI. Of the EGFR+/CPI+ patients, 78 patients (41%) received CPI prior to TKI, 107 (57%) received CPI post TKI, and 3 (2%) received CPI both pre and post TKI. EGFR+ tumors exposed to a CPI post TKI had a longer CPI TTF compared to patients who received it prior (Table). In contrast, there was no difference in length of benefit from TKI if it was received pre vs. post CPI (Table). There was also no difference in OS based on sequence of TKI and CPI (p=0.88). Larger sample sizes are needed for analysis of additional driver-stratified cohorts. Conclusions: Patients with oncogenic-driven NSCLC benefited from CPI longer when it was administered after TKI compared to before. Importantly, therapy sequence only affected length of benefit from CPIs and did not affect length of benefit from TKIs. This effect was present in EGFR+ NSCLC, but sample sizes were too small to determine if the same is true for other oncogenic-drivers. Therapy sequence had no impact on OS, indicating the presence of additional clinical, therapeutic, and/or genomic factors contributing to disease progression. Continued research is needed to better understand markers of CPI response in driver+ NSCLC.[Table: see text]
Incidence and heterogeneity of C797S and other EGFR resistance mutations on routine comprehensive genomic profiling (CGP).
Authors: Janne Pasi A. , Lee Jessica Kim , Madison Russell , Venstrom Jeffrey Michael , Schrock Alexa Betzig , Oxnard Geoffrey R.
Published: June 2021

9101

Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance. There are now a number of therapeutic approaches aimed at overcoming EGFR resistance mutations (muts). We sought to understand the biology of EGFR C797S and other EGFR resistance muts through querying our clinico-genomic database (CGDB). Methods: CGP results from tissue (n = 60,889) or circulating tumor DNA (ctDNA; [n = 9,922]) samples from 70,811 NSCLC patients (pts) were queried for known osi resistance muts in EGFR (C797, L792, G796, L718, G724). Clinical outcomes were evaluated for a cohort of NSCLC pts with osi resistance from the Flatiron Health-Foundation Medicine CGDB, a nationwide de-identified EHR-derived database linked to CGP data. Results: Between 12/2014 and 11/2020, 261 osi resistance mutations in EGFR were detected in 228 samples. The most common were C797S (66%), L718X (14%), G724S (11%), and others (9%). 173 C797S muts were detected in 155 samples (123 ex19del, 30 L858R, 2 other EGFR muts); 100 tissue, 55 ctDNA (median VAF = 7.6%). EGFR T790M co-occurred with C797S muts (96% cis, 3.7% trans) in 118 (76%) samples and decreased over time, occurring in 92% (24/26) of C797S samples tested in 2017 vs 56% (20/36) of samples tested in 2020 (p = 0.002). In 19/155 (12%) samples with C797S (14 ctDNA), multiple changes resulting in EGFR resistance muts were present: 16 samples had > 1 nucleotide changes resulting in C797S (100% trans), 3 samples had other resistance muts (L718Q/V, L792H, L792F) and 3 samples had multiple C797S changes with other resistance muts (C797G, L792H/F + G796S, L718Q + G796S+C797G). 29 pts (14 ctDNA) had C797S with potential off-target resistance (17 PIK3CA muts, 4 BRAF muts, 3 CCDC6- RET fusions, 3 KRAS muts, 2 ERBB2 amplifications (amps), 1 ERBB2 ex16 del, 1 STRN- ALK fusion, 1 FGFR3- TACC3 fusion). In the CGDB, 527 EGFR-mut NSCLC pts had documented receipt of osi. Pre and post osi-treated specimens were available for 19 of these pts (12 ex19del, 6 L858R, 1 G719A/S768I). Heterogeneous acquired resistance mechanisms were observed in the post-osi specimen, including 2 CCDC6- RET fusions, 2 MET amps, 2 BRAF fusions, BRAF V600E, and secondary EGFR muts (C797S, L704F, L718V). 161/527 pts had a documented line of therapy after osi discontinuation and most frequently received platinum doublet + immunotherapy (27%) or platinum doublet alone (23%); 17 (11%) pts received another EGFR tyrosine kinase inhibitor. 214/527 had documented osi progression and median post-progression survival was 11.8 months. Conclusions: Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition. EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.
Genomic markers associated with hyperprogression in patients with lung cancer treated with immune checkpoint inhibitors.
Authors: Tadesse Eyob ale , Heslin Kayla , Hendawi Mohamed , Peterson Luke , Wolf Frank M. , Brown Thomas D. , Thompson Michael A.
Published: June 2021

9105

Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of non-small cell lung cancer (NSCLC) treatment. However, not all patients (pts) benefit with a subset paradoxically experiencing accelerated tumor growth while on ICI. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various gene alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR alterations, and STK11/LKB1 mutations. Kato et al. (doi: 10.1158/1078-0432.CCR-16-3133 ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. This report describes HP in pts with NSCLC treated with ICIs in a large health system. Methods: Pts with NSCLC treated with ICIs from Jan 2012 to Jan 2021 at Advocate Aurora Health were reviewed after IRB approval. Pts with NSCLC histology (ICD diagnosis codes and/or manual chart review), ICI treatment, and molecular testing were identified via the real world data integrated within the Syapse Learning Health Network platform. Additional chart review to ascertain HP was performed, and molecular results were analyzed. HP criteria include: 1) time-to-treatment failure < 2 months (from start to discontinuation of ICI for any reason), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥ 2 during the first 2 months of treatment. Based on the number of criteria fulfilled, HP = > 3, Progression = 1-2, and non-progressor = 0. Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 7,078 NSCLC pts, 1,389 (20%) were treated with ICI including atezolizumab (40 pts, 3%), durvalumab (17 pts, 1%), nivolumab (167 pts, 12%), pembrolizumab (190 pts, 14%), and multiple ICIs (12 pts, 1%). Of those pts treated with ICIs, molecular testing was performed in 427 (31%). 98 of 427 pts (23%)had HP and an additional 86 pts (20%) had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. By tumor gene alterations, HP was seen in pts with: EGFR (20/60), STK11/LKB1 (16/25); and MDM2/4 (4/7). Conclusions: EGFR, STK11/LKB1, and MDM2/4 gene alterations were all statistically significantly associated with HP. Clinical and molecular predictors of HP need to be explored in order to optimize selection of pts for ICI therapy.[Table: see text]
Population-based impacts of new therapies on outcomes for stage IV non-small cell lung cancer.
Authors: Rittberg Rebekah , Bucher Oliver , Xue Lin , Aurangzeb Zeb , Banerji Shantanu Otto , Dawe David
Published: June 2021

9120

Background: Over 15 years, diagnostic and therapeutic algorithms for Stage IV non-small cell lung cancer (NSCLC) have dramatically progressed. While clinical trials demonstrate overall survival (OS) advantages, population level impact remains uncertain. Here we evaluate real world, population-based outcomes for Stage IV NSCLC to assess impact of changing therapies on referral, treatment patterns and OS, which may help explain ongoing stigma/nihilism. Methods: A retrospective cohort analysis was completed to evaluate de novo Stage IV NSCLC diagnosed in Manitoba from 2006 to 2015. We evaluated treatment received (not seen by specialist, saw a specialist but did not receive therapy, radiation therapy (RT) only, and systemic therapy (mutation unknown and known)) and treatment era of diagnosis (2006-2009, 2010-2013 and 2014-2015). Multivariable logistic regression assessed systemic therapy predictors. Kaplan-Meier curve and Cox proportional hazard models evaluated OS. Results: 3,601 patients were diagnosed with Stage IV NSCLC, 53% male. Only 21% received systemic therapy, mean age of 62. Within the cohort, 973 (27%) patients did not see a specialist, 610 (17%) saw a specialist but did not receive therapy, 1248 (35%) only received RT, and 771 (21%) received systemic therapy (17% mutation status unknown and 4% known). Younger patients and those with confirmed histology were more likely to see a specialist and receive treatment, each (p < 0.001). Patients who received systemic therapy had lower comorbidity and higher income quintile, each (p < 0.001). Median OS did not differ between treatment era with median OS of 3.0, 2.9 and 2.8 months for 2006-2009, 2010-2013 and 2014-2015 respectively, p = 0.082. When survival analysis was restricted to patients who received systemic therapy, median OS improved by era to 10.9, 11.2 and 15.6 months respectively, p = 0.001. Variables found to be independently associated with survival included treatment type, age, sex and comorbidity. Conclusions: Improved systemic therapy and molecular testing has improved OS for patients who receive systemic therapy. However, due to the large proportion of Stage IV NSCLC patients who never receive systemic therapy we do not see improved survival at a population level between treatment eras.