bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes among patients with advanced non-small cell lung cancer who received targeted therapy in a real-world setting.
Authors: Yang Mo , MacEwan Joanna P. , Sriteja Boppudi Sai , McClain Monica , O'Hara Richard , Liu Frank , Paik Paul K.
Published: June 2023

9051

Background: In the past decade, therapies targeting EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET, HER2 and PD-L1 were approved and recommended by National Comprehensive Cancer Network (NCCN) for use in advanced non-small cell lung cancer (aNSCLC). This study compared real-world clinical outcomes in biomarker positive patients with aNSCLC who received treatments based on the NCCN NSCLC Guidelines (v5.2021) versus other therapies in the US. Methods: This is a retrospective cohort study of patients with aNSCLC using the TEMPUS oncology dataset. Patients were included if they were diagnosed with stage IIIB-IV NSCLC (index date) between 1/1/2012 and 12/31/2020, ≥18 years of age at index, were biomarker (i.e., EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET, or PD-L1) positive, and received at least one line of treatment. Patients were stratified by NCCN recommended treatment (v5.2021) receipt anytime following aNSCLC diagnosis. Median overall survival (mOS), progression free survival (mPFS), and time to next treatment (mTTNT) were evaluated by treatment group using Kaplan Meier analysis. Patient demographic and clinical characteristics were evaluated as potential predictors of receipt of NCCN recommended therapy. Results: Of the 2,158 biomarker positive patients who met study criteria, 55.7% (N=1,201) received NCCN recommended treatment. PDL1 (38.0%), EGFR (32.2%), and/or KRAS (30.3%) were the most common over-expressions/mutations. Biomarker positive patients with aNSCLC treated with NCCN recommended treatment (N=1,201) in any line had significantly longer mOS (24.7mo, 95% CI: 22.5–27.6) than those treated with non-recommended treatment (N=957, 19.8mo, 95% CI: 17.5–22.6) (p<0.001). Biomarker positive patients with aNSCLC treated with NCCN recommended treatment also had significantly longer mPFS (8.5mo, 95% CI: 7.9–9.0) and mTTNT (20.6mo, 95% CI:19.3–23.7) than those treated with non-recommended treatment (4.9mo, 95% CI: 4.5–5.4) and (11.0mo, 95% CI: 10.0–12.7), respectively (both p<0.001). Never smokers (vs current smokers), patients of unknown or other race (vs whites), and patients who received 2 or more lines of treatment (vs 1) were more likely to receive NCCN recommended treatment and those with squamous or other/unknown histology (vs non-squamous) or missing ECOG scores (vs ECOG 0) were less likely to receive NCCN recommended treatment. Conclusions: In this study, biomarker positive patients with aNSCLC who received NCCN recommended treatment had significantly longer mOS, mPFS, and mTTNT than those who were treated with non-recommended regimens. Following the recommendations of the NCCN NSCLC Panel improves real-world clinical outcomes among biomarker positive patients with aNSCLC. Meanwhile, some biomarker positive patients—including current smokers and those with squamous cell histology—were less likely to receive targeted treatments.
Long-term outcomes of tepotinib in patients with MET exon 14 skipping NSCLC from the VISION study.
Authors: Paik Paul K. , Garassino Marina Chiara , Le Xiuning , Thomas Michael , Sakai Hiroshi , Veillon Remi , Smit Egbert F. , Mazieres Julien , Cortot Alexis B , Raskin Jo , Viteri Santiago , Yang James Chih-Hsin , Ahn Myung-Ju , Wu Yi-Long , Zhao Jun , Adrian Svenja , Berghoff Karin , Bruns Rolf , Johne Andreas , Felip Enriqueta
Published: June 2023

9060

Background: Tepotinib is a highly selective MET inhibitor with clinical activity in patients (pts) with MET exon 14 ( METex14) skipping NSCLC. We previously reported robust and durable activity of tepotinib from the Phase II VISION study (NCT02864992; data cut: Feb 20, 2022; median follow-up: 26.1 months [mos]; Thomas, et al. WCLC 2022). Here, we report long-term outcomes from VISION, fulfilling an FDA post-market requirement (data cut: Nov 20, 2022; follow-up: Cohort A [primary cohort] ≥35 mos, Cohort C [confirmatory cohort] ≥18 mos). Methods: Pts with advanced METex14 skipping NSCLC detected by liquid and/or tissue (T+) biopsy received tepotinib 500 mg (450 mg active moiety) once daily. The primary endpoint was objective response by independent review using RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Of 313 pts enrolled, median age was 72 years (range 41–94) and pts received tepotinib for a mean (standard deviation [SD]) of 11.5 mos (11.6); median follow-up was 32.6 mos (range 0.3–71.9). First line (1L) pts (n=164; median age: 74 years [range 47–94]; male: 50.6%; ECOG PS 1: 72.0%; smoking history: 53.7%) received tepotinib for a mean (SD) of 12.4 mos (12.2), with 27 pts still receiving treatment. ORR was 57.3% (95% CI: 49.4, 65.0), mDOR was 46.4 mos (13.8, not estimable [ne]), mPFS was 12.6 mos (9.7, 17.7), and mOS was 21.3 mos (14.2, 25.9). Among 111 1L T+ pts, ORR was 58.6% (48.8, 67.8), mDOR was 46.4 mos (15.2, ne), mPFS was 15.9 mos (11.0, 49.7), and mOS was 29.7 mos (18.8, ne) (Table). Second-or-later line (2L+) pts (n=149; median age: 71 years [range 41–89]; male: 47.7%; ECOG PS 1: 75.8%; smoking history: 40.9%) received tepotinib for a mean (SD) of 10.5 mos (11.0), with 10 pts still receiving treatment. ORR was 45.0% (36.8, 53.3) and mDOR was 12.6 mos (9.5, 18.5). Across all 313 pts, ORR was 51.4% (45.8, 57.1), mDOR was 18.0 mos (12.4, 46.4), mPFS was 11.2 mos (9.5, 13.8), and mOS was 19.6 mos (16.2, 22.9). No new safety concerns were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 34.8% of pts; 14.7% of pts discontinued treatment due to TRAEs. Any grade related peripheral edema occurred in 67.1% of pts (Grade ≥3: 11.2%). Conclusions: The long-term outcomes of VISION demonstrate the robust and durable clinical activity of tepotinib, particularly in 1L T+ pts, and manageable safety profile, further defining its use in clinical practice. Clinical trial information: NCT02864992 . [Table: see text]
Management of patients with ALK-positive advanced non-small cell lung cancer who received brain radiotherapy on study in the phase 3 CROWN trial.
Authors: Bauer Todd Michael , Felip Enriqueta , Mok Tony S. K. , Wu Yi-Long , Liu Geoffrey , Goto Yasushi , Kim Dong-Wan , Paolini Jolanda , Polli Anna , Solomon Benjamin J.
Published: June 2023

9063

Background: Approximately 30% of patients with ALK-positive non-small cell lung cancer (NSCLC) present with brain metastases at diagnosis. Lorlatinib is a potent brain-penetrant ALK tyrosine kinase inhibitor (TKI) that showed improved time to intracranial (IC) progression compared with crizotinib in patients with and without brain metastases at baseline. This post hoc analysis from the phase 3 CROWN study summarizes the management of patients who received brain radiotherapy (RT) during the study. Methods: In the CROWN study, 296 patients with previously untreated ALK-positive advanced NSCLC were randomized 1:1 to receive oral lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). Patients who received brain RT while on study treatment or after the initiation of subsequent systemic anticancer therapy were included in this post hoc analysis. Results: As of September 20, 2021, at approximately 3 years of follow-up, median time to IC progression was not reached (NR; 95% CI, NR-NR) in the lorlatinib arm and was 16.6 (95% CI, 11.1-NR) months in the crizotinib arm. At the time of this analysis, 4 of 149 patients (2.7%) in the lorlatinib arm and 20 of 147 patients (13.6%) in the crizotinib arm received brain RT; study treatment was ongoing in 2 of 4 patients (50.0%) in the lorlatinib arm and discontinued in all 20 patients in the crizotinib arm. Median time from randomization to first brain RT was 18.2 (range, 6.4-31.3) months in the lorlatinib arm and 11.1 (range, 2.5-37.5) months in the crizotinib arm. In patients who had brain RT, median duration of treatment was 20.0 (IQR, 6.3-37.1) months with lorlatinib and 7.8 (IQR, 4.0-11.1) months with crizotinib. In the lorlatinib arm, 2 of 4 patients (50.0%) received concomitant brain RT and continued lorlatinib beyond progression. In the crizotinib arm, patients received brain RT while on study treatment or on subsequent systemic anticancer therapies with ALK TKIs or chemotherapy. Follow-up analysis is ongoing. Conclusions: At approximately 3 years of follow-up in the CROWN study, fewer patients in the lorlatinib arm received brain RT than those in the crizotinib arm. At the time of this analysis, study treatment was ongoing in 2 of 4 patients (50.0%) in the lorlatinib arm but was discontinued in all patients in the crizotinib arm. Patients were mostly managed with other ALK TKIs and/or chemotherapy following brain RT in the crizotinib arm. ClinicalTrials.gov: NCT03052608. Clinical trial information: NCT03052608 .
Sex differences in prognostic utility of peripheral eosinophil count in first-line immune checkpoint therapy against metastatic NSCLC.
Authors: Kwon Hyunwoo , Li Mingjia , Chian Kenneth , Gauntner Timothy , Jones Nicholas , Khorasanchi Adam , Spakowicz Daniel , Lopez Gabrielle , Goodyear Evelyn , Secor Austin , He Kai , Alahmadi Asrar , Memmott Regan Michelle , Kaufman Jacob , Shields Peter G. , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Li Zihai , Owen Dwight Hall
Published: June 2023

9067

Background: To date, few studies have associated elevated Absolute Eosinophil Count (AEC) with improved outcome to a single agent immune checkpoint inhibitor (ICI) as first or subsequent line of therapy in patients with NSCLC. Here, we investigated prognostic utility of AEC and the sex difference in patients undergoing standard-of-care first-line ICI with or without chemotherapy for metastatic NSCLC. Methods: This was a retrospective cohort study of 310 patients with Stage IV NSCLC treated with first-line ICI-based therapies (alone or in combination with chemotherapy) under IRB approved protocol 2021C0069. Demographic data are summarized in the table. Peripheral AEC measured by cells/microL was collected within 1 week before the start of therapy. Eosinophil count was evaluated in males and females by both descriptive statistics and Chi-squared test as a continuous and categorical variable, respectively. High level of baseline AEC was defined as 75th percentile (270 cells/microL). Overall Survival (OS) was plotted using the Kaplan-Meier method and p-values from log-rank test were reported. PD‐L1 was assessed by tumor proportion score (TPS) and classified into < 1%, 1 to 49% and ≥ 50%. Results: 14% male vs 6% female patients were found to have peripheral eosinophilia (AEC ≥ 500) at the start of immunotherapy, p = 0.02. Patients with lower AEC had a median OS of 18.6 months vs 29.3 months in those with higher AEC ( p = 0.02, HR: 1.465, 95% Cl: 1.073-2.001). Patients with higher baseline AEC showed a sex difference, with median OS of 23.9 months in males vs NR median OS in females with over 60% survival at the time of last follow up ( p = 0.04, HR: 1.934, 95% Cl: 1.040-3.597). This difference was seen with ICI monotherapy ( p = 0.02, HR: 2.630, 95% Cl: 1.192-5.805), but not ICI with chemotherapy ( p = 0.83, HR: 1.116, 95% Cl: 0.4054-3.070). Higher AEC was associated with TPS ≥ 50% in both males and females ( p = 0.004 and 0.001, respectively), though no significant sex difference was observed. Conclusions: Our data highlight critical sex differences in interpretation of baseline AEC in patients on ICI therapy for metastatic NSCLC. While males have a higher frequency of peripheral eosinophilia, higher AEC correlates to improved OS predominantly in females. Further, this female-biased outcome is seen only with ICI monotherapy, even though higher AEC is associated with high PD-L1 expression in both sexes. Future studies are indicated to assess the longitudinal trend in eosinophil count as well as their active versus passive role in anti-tumor immunity and toxicity in the presence or absence of chemotherapy. [Table: see text]
A biomarker study of atezolizumab (atezo) + bevacizumab (bev) + carboplatin (carbo) + paclitaxel (pac) (ABCP) for patients with NSCLC harboring EGFR mutations (EGFRm) after failure of TKI therapy: NEJ043.
Authors: Watanabe Satoshi , Furuya Naoki , Nakamura Atsushi , Shiihara Jun , Nakachi Ichiro , Tanaka Hisashi , Nakao Mika , Minato Koichi , Seike Masahiro , Sasaki Shinichi , Kisohara Akira , Takeuchi Susumu , Honda Ryoichi , Takamura Kei , Ling Yiwei , Okuda Shujiro , Kagamu Hiroshi , Yoshimura Kenichi , Kikuchi Toshiaki , Kobayashi Kunihiko ,   North East Japan Study Group
Published: June 2023

9079

Background: EGFRm NSCLC patients (pts) have limited treatment options after EGFR-TKI failure. We previously showed that the NEJ043 study investigating ABCP in EGFRm NSCLC pts after EGFR-TKI failure had a clinically meaningful efficacy (Furuya et al, ASCO 2022). Here we report the results of the biomarker study of NEJ043. Methods: NEJ043 study is a phase II study to evaluate the efficacy of ABCP in sensitizing EGFRm nonsquamous NSCLC pts after TKI failure. Pts received atezo (1200 mg), bev (15 mg/kg), carbo (AUC 6 mg/mL/min), and pac (175 mg/m2) every 3 weeks up to 4 cycles followed by atezo plus bev until loss of clinical benefit. Before treatment initiation and three cycles of ABCP, peripheral blood mononuclear cells (PBMCs) were collected, and immunophenotypic data at each time point was obtained by flow cytometry. Results: 60 pts were included in the NEJ043 study and PBMCs were obtained from 31 pts. Pts with a higher percentage of CD11b+DRlowCD3-CD14+ myeloid-derived suppressor cells (MDSCs) before ABCP had significantly longer PFS (median, 9.7 months (95% CI, 5.3-17.7) vs 5.6 months (95% CI, 3.9-8.1); HR 0.38; P = 0.0313). Further analysis of the immune cell phenotypes that changed between pre-treatment and the third course showed that pts with increased CD62LlowCD8+ cells (median, 12.8 months (95% CI, 5.6-20.3) vs 5.7 months (95% CI, 4.4-8.1); HR 0.25; P = 0.003) and PD-1+CCR7-CD45RA-CD8+ cells (median, 8.5 months (95% CI, 5.6-13.8) vs 5.7 months (95% CI, 2.6-8.1); HR 0.37; P = 0.0324) had significantly longer PFS. Conclusions: Inhibition of MDSCs by ABCP, especially bev, may be important for EGFRm pts whose antitumor immunity is suppressed by MDSCs before treatment. Better PFS may be expected in pts in whom ABCP therapy induced CD62LlowCD8+ effector T cells and PD-1+CCR7-CD45RA-CD8+ effector memory T cells. Clinical trial information: jRCTs031190066 .
Tislelizumab plus chemotherapy in patients with advanced brain metastases of non-squamous non-small cell lung cancer: A multicenter, prospective, open-label phase 2 study.
Authors: Huang Yan , Yu Qitao , Yang Nong , Liu Li , Yu Yan , Wang Qiming , Zhao Yuanyuan , Yang Yunpeng , Jiang Wei , Tan Liping , Zhou Chunhua , Zeng Fanxu , Zhang Kai , Qin You , Zhang Shuai , Ma Shuxiang , Zhang Li
Published: June 2023

9080

Background: Patients (pts) with brain metastases (BM) were usually unrepresented in clinical trials assessing the efficacy of PD-(L) 1 inhibitors. Here, we investigated the efficacy and safety of tislelizumab (TIS) plus chemotherapy in NSCLC pts with asymptomatic untreated BM or with stable BM after local radiotherapy. Methods: This multicenter, prospective, open-label phase 2 study enrolled systemic treatment-naïve pts with stage IV non-squamous (nsq) NSCLC without EGFR or ALK mutations who had BM. Pts received TIS combined with pemetrexed and carboplatin for 4 cycles, followed by maintenance TIS and pemetrexed. RECIST v1.1 and RANO-BM were applied for assessment for systematic and brain disease, respectively. The primary endpoint was the investigator-assessed 1-year PFS rate per RECIST v1.1. Results: 36 pts were enrolled with 77.8% having stage IVB disease, 25.0% liver metastases and 41.7% bone metastases. 29 (80.6%) pts were with untreated, asymptomatic brain metastases, and the other 7 (19.4%) received radiotherapy for BM previously. As of 30 Nov 2022, the median follow-up was 12.3 months. 1-year systematic PFS rate was 36.8% (95% CI, 18.0-55.7), with median PFS of 7.5 months (95% CI, 5.1-NE). Systematic ORR was 50.0% (95% CI, 31.9-68.1%). Median OS was not reached, with 1-year OS rate of 70.5% (95% CI, 51.7-83.1). For intracranial efficacy assessment per RANO-BM, 1-year intracranial PFS (iPFS) rate was 56.6 % (95% CI, 31.7-75.5), with 45.5% (95% CI, 19.4, 68.5) and 100% in pts with untreated and pretreated BM, respectively. Intracranial ORR was 56.7% (95% CI, 37.4-74.5%), with 53.8% (95% CI, 33.4-73.4%) in pts with untreated BM and 75% (95% CI, 19.4-99.4%) in pretreated BM. No grade 5 toxicities were observed. Grade 3-4 TRAEs occurred in 33.3% (12/36) of pts. 13.9% of pts experienced irAEs; grade 3-4 irAEs occurred in 2 (5.6%) pts. Conclusions: TIS plus chemotherapy yielded promising systematic and intracranial PFS, and was generally well tolerated in nsq-NSCLC pts with untreated or pretreated BM. Clinical trial information: NCT04507217 . [Table: see text]
Patient-reported outcomes of furmonertinib versus gefitinib in patients with locally advanced or metastatic, EGFR mutation-positive non-small cell lung cancer (FURLONG): A multicenter, double-blind, randomized phase 3 study.
Authors: Shi Yuankai , Chen Gongyan , Wang Xiang , Liu Yunpeng , Wu Lin , Hao Yanrong , Liu Chunling , Zhu Shuyang , Zhang Xiaodong , Li Yuping , Liu Jiwei , Cao Lejie , Cheng Ying , Zhao Hui , Zhang Shucai , Zang Ai-min , Cui Jiuwei , Feng Jian , Yang Nong , Hu Jie
Published: June 2023

9081

Background: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in Chinese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), along with an acceptable safety profile without new signals in the FURLONG study. Here we present patient-reported outcomes (PROs). Methods: FURLONG is a multicenter, double-blind, double dummy, randomized phase 3 study done in 55 hospitals across mainland China. Eligible patients were randomly assigned (1:1) to receive either furmonertinib or gefitinib. The primary endpoint of IRC-assessed progression-free survival has been reported previously. PROs as prespecified secondary outcomes by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and Quality-of-Life Questionnaire Lung Cancer 13 (QLQ-LC13), were analyzed in randomly assigned patients who had received at least one dose of study drug and completed at least one PRO assessment. Changes from baseline to randomized treatment discontinuation were analyzed with mixed model for repeated measures and time-to-event analyses. This study is ongoing for survival follow-up. Results: 357 patients received at least one dose of study drug, all of them completed at least one PRO assessment. Questionnaire completion rates were ≥95% at most time points. Baseline mean scores were similar in the furmonertinib and gefitinib groups. From baseline to randomized treatment discontinuation, statistically significant differences favoring furmonertinib for physical function, nausea/vomiting, appetite loss, diarrhea, alopecia, and other pain (any pain other than chest, arm, or shoulder pain) were observed. Time to deterioration in physical function, cognitive function, nausea/vomiting, appetite loss, diarrhea, cough, dyspnea, dysphagia, and alopecia were significantly longer with furmonertinib versus gefitinib (Table). Conclusions: Furmonertinib demonstrated favorable PROs as measured by the EORTC QLQ-C30 and QLQ-L13 versus gefitinib. These data presented the positive benefit risk profile of first-line furmonertinib and further support this novel third generation EGFR-TKI as a new standard of first line treatment in EGFR mutation-positive NSCLC. Clinical trial information: NCT03787992 . [Table: see text]
Mobocertinib efficacy in patients with NSCLC and EGFR exon 20 insertion mutations (ex20ins) identified by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Neal Joel W. , Li Ying , Yu Ziji , Fram Robert J. , Danes Christopher , Vincent Sylvie , Piotrowska Zofia
Published: June 2023

9082

Background: EGFR ex20ins are distinct targetable driver mutations present in ~2% of all NSCLC. While most EGFR TKIs have limited effectiveness, mobocertinib is the first oral therapy approved for this unmet need. EGFR ex20ins are heterogeneous ( > 60 variants), and PCR testing detects a limited number of variants, leading to undetected disease in ~50% of cases, whereas NGS can identify all such mutations. Testing plasma ctDNA is a noninvasive approach for detection of genomic variants, such as EGFR ex20ins. Methods: In the mobocertinib phase 1/2 study (NCT02716116), patients were enrolled based on EGFR ex20ins detected by various local tissue or liquid clinical trial assays (CTAs). Baseline plasma samples were collected and processed to extract cell-free DNA and were evaluated for EGFR ex20ins status using FoundationOne Liquid CDX (F1LCDX), an NGS-based plasma ctDNA test. Concordance between F1LCDX and the CTAs was demonstrated by testing patient samples from the phase 1/2 trial and paired tissue and plasma samples from commercially acquired and stage-matched patients with NSCLC (N = 305). Efficacy analyses by assay method were performed in EGFR ex20ins–positive platinum-pretreated patients (PPP; n = 114 [FDA approved population]; data cutoff: 1 Nov 2021) in the phase 1/2 trial. Results: Concordance between F1LCDX and CTAs was demonstrated with samples from the CTA-positive (n = 159) and CTA-negative populations (n = 87) tested by F1LCDX where tissue and plasma were assessable; the point estimate of positive percentage agreement (95% CI) was 68.6% (61.0–75.3), and the point estimate of negative percentage agreement was 100% (95.8–100). F1LCDX detected 34 individual EGFR ex20ins variant types. In the response evaluable population, patients who tested EGFR ex20ins positive by F1LCDX (n = 55) demonstrated confirmed ORR (34.5%) and disease control rate (74.5%), which was comparable to those observed among all PPP in the phase 1/2 trial (confirmed ORR: 28%; confirmed disease control rate: 78%). Conclusions: Mobocertinib has shown efficacy in PPP with EGFR ex20ins NSCLC. F1LCDX effectively identified patients with EGFR ex20ins who may benefit from mobocertinib, providing an additional noninvasive diagnostic option to guide treatment. Clinical trial information: NCT02716116 .
Impact on turnaround times (TAT) among non-squamous non-small cell lung cancer (NSCLC) patients across three time periods with varying biomarker testing techniques.
Authors: Fan Zhen (Jason) , Tudor Roxana , Le Lisa W , Law Jennifer H. , Fung Andrea S. , Kuang Shelley , Meti Nicholas , Perdrizet Kirstin , Ranich Laura , Wei Cuihong , Sabatini Peter , Pal Prodipto , Tsao Ming Sound , Liu Geoffrey , Shepherd Frances A. , Bradbury Penelope Ann , Sacher Adrian G. , Eng Lawson , Cabanero Michael , Leighl Natasha B.
Published: June 2023

9085

Background: Biomarker testing and identification of actionable genomic alterations (AGAs) in NSCLC patients have led to targeted therapy use and improved outcomes, particularly in advanced stages. We sought to evaluate the impact of different testing paradigms on TAT, particularly with respect to treatment decision and time to initiation of treatment, across three time periods. Methods: A retrospective review of stage III or IV non-squamous NSCLC patients at the Princess Margaret Cancer Centre (Toronto, Canada) was conducted. Both de novo advanced and patients with metastatic progressions are included. Cohort 1 (C1; 01/2015 – 01/2017) underwent reflex EGFR (EntroGen) and ALK (5A4 immunohistochemistry, IHC) single gene testing. Cohort 2 (C2; 02/2017 – 09/2020) underwent reflex next generation sequencing (NGS; Trusight Tumor 15), ALK and ROS1 testing. Cohort 3 (C3; 10/2020 – 01/2022) underwent reflex comprehensive NGS (161 genes, Oncomine OCA v3). Descriptive statistics are presented, including AGAs found and TAT from biopsy to result sign-out, and treatment related TAT. Results: Three cohorts of stage III and IV patients were identified, with C1 having proportionally more females (60%), never smokers (42%) with adenocarcinomas (98%). More patients with AGA were identified using NGS with larger panels (42%, 41%, 57%, respectively across C1 – C3). However, there is a longer median time from first oncology visit to treatment (14, 22, 27 days, respectively across C1-C3), and longer biopsy to treatment TAT trended towards more comprehensive testing (34, 38, 40 days, respectively across C1 - C3) in stage IV patients. Conclusions: As more comprehensive biomarker testing became available, more AGAs are identified with an increase in TAT from biopsy to sign-out and treatment start. Despite our institutional policy of reflex testing, future endeavours will be focus on ways to reduce TAT. [Table: see text]
Immune checkpoint inhibitors use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.
Authors: Hong Joohyun , Lee Jiyun , Park Sehhoon , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Sinn Dong Hyun , Ahn Myung-Ju
Published: June 2023

9086

Background: The safety and efficacy of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). We analyzed incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients treated with ICIs according to HBV DNA and hepatitis B serologic markers in real-world setting. Methods: A total of 1,277, consecutive NSCLC patients treated with ICIs from January 2015 to December 2020 at the Samsung Medical Center, Seoul, Korea were analyzed. Among them, 52 patients were hepatitis B surface antigen (+) (Group A, CHB), 759 patients were HBsAg (-)/anti-HBc IgG (+) (Group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (Group C). Among 52 patients with CHB, 38 patients (73.1%) were receiving antiviral therapy. Primary endpoint was HBV reactivation, immune-related hepatitis and jaundice. Secondary endpoints include other immune-related adverse events, objective response rate, progression free survival (PFS) and overall survival (OS). Results: HBV reactivation was observed in two patients (0.2%) which was exclusively observed in Group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed for 14.3% (2/14 patients). Incidence of immune-related hepatitis were 21.2%, 30.3% and 30.5% for Group A, Group B and Group C (p > 0.05), respectively, and incidence of immune-related of jaundice was 3.8%, 4.0% and 2.8% for Group A, Group B and Group C (p > 0.05), respectively. Incidence of ≥ grade 3 other immune-related adverse events, objective response rate, PFS, and OS were comparable among three group (p > 0.05 for all comparison). Conclusions: In this large, real-world cohort study, safety and efficacy of ICIs were comparable in patients with CHB or OBI, suggesting similar outcomes can be expected with ICIs in patients with CHB or OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis might be required for them. For patients with OBI, risk of HBV reactivation was null.
First line (1L) durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2): Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17.
Authors: Mark Michael Thomas , Froesch Patrizia , Gysel Katrin , Rothschild Sacha , Addeo Alfredo , Ackermann Christoph J. , Chiquet Sabrina , Schneider Martina , Ribi Karin , Fischer Maranta Angela , Bastian Sara , Von Moos Roger Anton Fredy , Joerger Markus , Früh Martin
Published: June 2023

9088

Background: The safety and efficacy of 1L durvalumab in PS2 patients (pts) with advanced NSCLC is unknown. Important safety data leading to exclusion of pts with relevant respiratory symptoms have been published as an interim report. Here we present the primary analysis of 1L durvalumab in PS2 pts, unsuitable for combination chemotherapy and PD-L1 expression in ≥25% of tumor cells. Methods: In this single-arm, multicenter, phase II trial pts with PD-L1 positive (tumor proportional score, TPS ≥25%), advanced NSCLC with PS2, unsuitable for combination chemotherapy determined by the investigators, in the absence of known contraindications for immunotherapy and sufficient organ function, received a fixed dose of 1500 mg durvalumab every four weeks. The primary endpoint was overall survival (OS) at 6 months. The statistical hypothesis was to improve OS at 6 months from ≤35% to ≥53%. Adverse events (AEs) were assessed according to National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) version 5.0. Results: Forty-eight pts were included (29 males, 19 females). Median age was 76 years (range, 37-87). OS at 6 months was 60% (95% CI: 45-74%). OS at 6 months after the exclusion of pts with initially relevant respiratory symptoms was 67% (95% CI: 46-84%, n = 27) compared to the subgroup of pts without this exclusion criteria who were recruited before the amendment (52%, 95% CI: 30-74%, n = 21). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median PFS were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1). Thirty-three deaths (69%) were observed to date. Ten early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failures in pts with advanced symptomatic primary lung tumors. Only 3 more early fatal events occurred after the protocol amendment excluding pts with severe respiratory symptoms. Thirty-nine patients (81%) had an AE grade ≥3 (G3). The most frequent AEs ≥G3 were lung infection (19%), dyspnea (15%) and hypertension (10%), respectively. Treatment-related AEs ≥G3 were reported in 9 pts (19%) and included colonic perforation in one patient (grade 5), colitis in 5 pts (10%), hepatitis and increased lipase in 3 pts each (6%). Conclusions: 1L durvalumab in PS2 pts with advanced PD-L1 positive (TPS ≥25%) NSCLC is effective and led to a promising 6-month OS of 60%. Four-weekly durvalumab can be safely offered to pts presenting without severe pulmonary symptoms who are not candidates for chemotherapy. Clinical trial information: NCT03620669 .
A phase I trial of sequential dosing of sonidegib and pembrolizumab in advanced solid tumors (aST) and non–small-cell lung cancer (NSCLC).
Authors: Shanshal Mohamed , Foster Nathan R. , Lou Yanyan , Zhao Yujie , Seetharam Mahesh , Mansfield Aaron Scott , Leventakos Konstantinos , Zhu Mojun , Steinert Kimberly O. , Mikula Elizabeth , Shi Qian , Kizilbash Sani Haider , Dong Haidong , Adjei Alex A. , Ma Wen Wee
Published: June 2023

9093

Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance invariably emerges in the majority of patients. Potential mechanisms include activation of compensatory pathways. The inhibition of sonic hedgehog signaling (sHH) was previously shown to induce intra-tumoral (IT) infiltration by CD4+, CD8+ and HLA-DR class II cells. Our preclinical data showed sHH inhibitor enhanced IT penetration by monoclonal antibodies and induced PD-L1 expression. We conducted a phase I study using a novel sequential pulse dosing of sonedegib followed by pembrolizumab in aST with an expansion cohort to determine the maximum tolerated dose (MTD), tolerability and preliminary efficacy. Methods: The dose escalation utilized a 3+3 design to determine the MTD and proceeded to expansion cohort upon determination of the MTD. Patients enrolled to each dose level were observed for dose limiting toxicities (DLTs) during the 1st cycle. The expansion cohort consisted of NSCLC and head/neck squamous cell carcinoma (HNSCC) previously treated by anti-PD1/-L1. The recommended phase 2 dose (RP2D) was determined following the review of the toxicity profile of the combination from all cycles. The study treatment consisted of sonidegib oral daily from day 1 to 8 and pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle. The sonidegib dose levels explored were 400, 600 and 800 mg. Archival tumor and blood specimens were collected for correlative studies. Adverse events (AEs) were categorized and graded per CTCAE v5.0, and tumor response by RECIST v1.1. Results: The study enrolled a total of 33 patients and 29 received treatment (13 in escalation and 16 in expansion), including patients with NSCLC, HNSCC, skin cancer, gastric cancer and melanoma. The enrollment to the NSCLC cohort is complete and HNSCC continues. No DLT was encountered during dose escalation and the MTD was not reached. The highest planned dose level was selected to proceed to expansion (sonidegib 800mg days 1-8 in combination with pembrolizumab I.V. 200 mg on day 8 on an every 3-week cycle). The expansion cohort proceeded to enroll 15 patients evaluable for AEs (10 NSCLC and 5 HSNCC). Grade 3 and above treatment-related AEs across all patients were hyperglycemia, fatigue, dyspepsia, abdominal pain. The mature efficacy data will be reported at the meeting. Conclusions: The study successfully determined the RP2D of sonidegib when dosed sequentially with pembrolizumab in advanced solid tumors. The AE profile of the combination is similar to that for respective agents given individually. The efficacy data among anti-PD1/-PDL1-treated NSCLC will be reported at the meeting. Clinical trial information: NCT04007744 .
Retrospective clinical analysis of circulating tumor DNA (ctDNA)–based molecular response (MR) and baseline blood-based tumor mutational burden (bTMB) for monitoring response in phase 3 trial of bintrafusp alfa vs. pembrolizumab treatment of non-small cell lung cancer (NSCLC).
Authors: Feng Zheng , Machl Andreas , Wang Danyi , Overstreet Brooke , Yablonovitch Arielle , Scheuenpflug Juergen
Published: June 2023

9098

Background: The clinical utility of ctDNA-based approaches, such as bTMB and MR, to monitor and predict response during chemo-immunotherapy was evaluated using longitudinal cohort samples from a Phase 3 study of bintrafusp alfa versus pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC. Methods: ctDNA was collected at baseline and day 42 after treatment with bintrafusp alfa (Q2W, 1200mg) or pembrolizumab (Q3W, 200mg). The GuardantOMNI liquid biopsy (LBx) assay was used to detect somatic alterations in 497 genes and generate bTMB from baseline, and MR scores from baseline and day 42 (n = 424 samples). bTMB and somatic alterations influencing response were explored. MR scores were calculated using the validated Guardant Response algorithm. Associations between ctDNA metrics and PFS were assessed. Results: 418/424 samples passed sequencing QC; of these, somatic mutations were detected in 236/237 baseline samples and 177/181 day 42 samples. Of 212 NSCLC patients with eligible bTMB results at baseline, 104 (49.1%) patients received bintrafusp alpha and 108 (50.9%) received pembrolizumab. bTMB high (bTMB-H) is defined as >20mut/MB. In the bintrafusp alpha arm, PFS was significantly longer in patients with bTMB-H (median 8.3 months vs 2.7 months, p = 0.00086). In the pembrolizumab arm, PFS was also longer in patients with bTMB-H (median 5.65 months vs 5.5 months, p = 0.0898). Of 132 NSCLC patients with eligible MR results, 67 (50.8%) patients received bintrafusp alpha and 65 (49.2%) patients received pembrolizumab. In the bintrafusp alpha arm, molecular responders had significantly longer PFS (median 7.9 months vs 4.2 months, p = 0.00042). In the pembrolizumab arm, molecular responders also had significantly longer PFS (median 8.95 months vs 4.1 months, p = 0.00054). Conclusions: ctDNA analysis from plasma samples supported MR assessment in patients treated with ICI, indicating its utility as an adjunct to RECIST in monitoring of tumor response. Blood-based TMB-high was associated with immunotherapy treatment benefit. Analysis of b-TMB and MR allowed identification of patients with improved PFS in both treatment arms. Investigation of treatment specific TMB cut off selection and potential clinical utility of defined somatic mutations is ongoing. Clinical trial information: NCT03631706 .
Association between duration of immunotherapy and overall survival in advanced non–small-cell lung cancer.
Authors: Sun Lova , Bleiberg Benjamin Aaron , Hwang Wei-Ting , Marmarelis Melina Elpi , Langer Corey J. , Singh Aditi Puri , Cohen Roger B. , Mamtani Ronac , Aggarwal Charu
Published: June 2023

9101

Background: For patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with front line immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. We aimed to assess practice patterns surrounding ICI treatment discontinuation at two years, and to evaluate association of duration of therapy with overall survival by comparing pts who received fixed duration ICI therapy for 2 years vs those who continued therapy beyond two years. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, and included adult pts diagnosed with advanced NSCLC from 2016-2020, who received frontline immunotherapy-based treatment. Pts who were still on treatment without progression at 2 years were classified as “fixed duration” (treatment discontinuation at 2 years, between 700-760 days) vs “indefinite duration” (continued treatment beyond two years, > 760 days). Overall survival from 760 days was analyzed using Kaplan-Meier methodology. Multivariable Cox regression adjusted for patient and cancer-specific factors was used to compare survival between fixed and indefinite-duration groups. Results: Our analytic cohort consisted of 113 pts in the fixed duration group and 593 in the indefinite duration group; median age was 69, 49% were female, and 71% were White. Pts in the fixed duration group were more likely to have a history of smoking and be treated at an academic center. There was no significant difference in overall survival between pts in the fixed duration and indefinite duration groups, either on univariable (HR 1.26, 95% CI 0.77-2.08) or multivariable Cox regression (HR 1.33, 95% CI 0.78-2.25). Conclusions: In a real world cohort of advanced NSCLC pts treated with front line ICI, only about 1 in 5 stopped treatment at two years rather than continuing treatment beyond two years. The lack of significant overall survival advantage for the indefinite duration cohort on adjusted analysis provides reassurance to pts and providers who wish to stop therapy at 2 years.
The final analysis of a phase I/II study of nivolumab, ipilimumab combined with nintedanib in advanced non-small cell lung cancer.
Authors: Puri Sonam , Tanvetyanon Tawee , Creelan Ben C. , Shafique Michael Rahman , Saltos Andreas Nicholas , Chiappori Alberto , Haura Eric B. , Thapa Ram , Chen Dung-Tsa , Boyle Theresa A. , Antonia Scott Joseph , Gray Jhanelle Elaine
Published: June 2023

9102

Background: Nintedanib (NT) is an oral triple kinase inhibitor that is active against NSCLC and inhibits the activity of the immunosuppressive cancer associated fibroblasts in the tumor microenvironment (TME). Targeting the TME with NT may represent an important synergistic approach in improving immunotherapy (IO) outcomes for NSCLC. We initiated a phase Ib/II trial to evaluate the combination of NT, nivolumab (N) and ipilimumab (I) in advanced (a)NSCLC. Based on the phase IB (dose escalation) results, the combination of N (3mg/kg/2w), I (1mg/kg/6w) and NT (150mg once daily) was declared as the recommended phase 2 dose (RP2D). Here we present the final analysis of the regimen in treatment naïve (TN), and IO pretreated (IP) aNSCLC. Methods: This is a single institution, non- randomized, parallel assignment phase I/II clinical trial of aNSCLC pts. Eligible pts were TN (Arm A) or with disease progression following IO (Arm B) with planned sample size of 40/arm. Enrollment into phase II was by the Bayesian two-stage design method with the primary objective of determining the overall response rate (ORR) in the intent to treat population. Key secondary objectives were overall survival (OS) and progression-free survival (PFS). Descriptive statistics were used to summarize demographic and safety data. The Kaplan- Meier method with log-rank test (5% level of significance, 95% CI and 2-sided test) was used for survival analysis. Results: 22 and 29 pts received the N+I+NT at the RP2D in Arm A and B, respectively. The median age was 67 [42;92] with 53% (27/51) females, 84% (42/51) Caucasian, ECOG 1 in 88% (45/51), and a current/prior history of tobacco use in 88% (45/51) pts. Adenocarcinoma histology was common (64%, 33/51) with PD-L1 ≥1% in 52% (22/42) pts. As of Oct 24, 2022, 18 and 26 pts were evaluable for response in Arm A and B, respectively. Clinical efficacy was observed in the TN and IP cohorts (Table). The most common treatment-related adverse events (TRAEs) were similar in both cohorts. TRAE of any grade in Arm A were nausea (8, 36%), diarrhea (8, 36%), fatigue (7, 32%), and in Arm B were nausea (10, 34%), fatigue (9, 31%), anorexia (8,27%). Conclusions: The combination of nivolumab, ipilimumab and nintedanib had a manageable toxicity profile and demonstrated promising antitumor activity in both TN and IP aNSCLC patients. Clinical trial information: NCT03377023 . [Table: see text]
Association of alterations in multiple tumor suppressor genes with poor outcomes in patients with EGFR-mutant lung cancer.
Authors: Stockhammer Paul , Grant Michael J , Wurtz Anna , Foggetti Giorgia , Expósito Francisco , Gu Jianlei , Chung Sangyun , Li Fangyong , Walther Zenta , Gettinger Scott N. , Politi Katerina A. , Goldberg Sarah B.
Published: June 2023

9104

Background: Co-occurring alterations in tumor suppressor genes (TSG) have been described as determinants of disease heterogeneity in EGFR-mutant non-small cell lung cancer (NSCLC), however, detailed analyses of their impact on patient outcomes are limited. Methods: Patients with EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) at the Yale Cancer Center who had tumor genomic profiling either before EGFR-TKI therapy (pre-TKI) or at disease progression (post-TKI) were included. Whole exome sequencing (WES) of paired pre- and post-TKI tumor specimens were performed for a subset of patients. The cohort was divided into three subgroups based on alterations in TP53 and five additional TSGs ( RB1, NF1, ARID1A, BRCA1 and PTEN): patients with tumors harboring a TP53 mutation plus a mutation in at least 1 additional TSG ( TP53mut/TSGmut), patients with tumors harboring a TP53 mutation without an additional TSG mutation ( TP53mut/TSGwt), and patients with TP53wt tumors. Clinical characteristics including progression-free (PFS) and overall survival (OS) were assessed. Results: One-hundred-one patients were included in this retrospective study. TP53 mutations were identified in 65 (64%) tumors, of which 23 (35%) and 42 (65%) were classified as TP53mut/TSGmut and TP53mut/TSGwt, respectively. Among those cases with paired WES available (n = 34), frequencies of alterations in the six included TSGs did not significantly differ between pre- and post-TKI tumor specimens. In the full study cohort, the presence of a TP53 mutation was associated with numerically worse PFS (HR 1.46, CI 0.97 – 2.21, p = 0.09) and OS (HR 1.68, CI 1.05 – 2.70, p = 0.04) on first-line EGFR-TKI. Strikingly, after dividing the TP53mut cohort into TP53mut /TSGmut and TP53mut /TSGwt cases, alterations in additional TSG were found to drive the poor outcomes: TP53mut /TSGmut cases had significantly worse PFS and OS on first-line EGFR TKI than TP53mut /TSGwt(mPFS 8.0 vs 10.6 months, p = 0.006; mOS 30.0 vs 33.3 months, p = 0.12) or TP53wt cases (mPFS 8.0 vs 12.6 months, p < 0.0001; mOS 30.0 vs 48.8 months, p = 0.001). There was no significant difference in PFS or OS between patients with TP53mut /TSGwt and TP53wt tumors. Similar outcome differences between the three groups were found in patients who received osimertinib in the second-line setting. Conclusions: The inferior outcomes associated with EGFR/TP53-mutant NSCLC tumors may be due to additional TSG alterations rather than TP53 mutational status alone. Alterations in the investigated TSGs did not appear to emerge under EGFR-TKI therapy, which suggests that they are truncal. Our findings may have implications for understanding the biologic underpinnings of differential outcomes to EGFR TKIs.
Tissue and plasma-based mechanisms of resistance to first-line osimertinib in EGFR-mutant NSCLC: A multi-institutional cohort.
Authors: Piotrowska Zofia , Chen Lanyi Nora , Shum Elaine , Park Cathleen , Guo Matthew , Liu Ying , Tran Misha , Marks Jennifer Aline , Banwait Mandeep , Liu Stephen V. , Scott Susan Combs , Bestvina Christine M. , Riess Jonathan W. , Marrone Kristen A. , Hall Richard Delmar , Gentzler Ryan D. , Shu Catherine A.
Published: June 2023

9108

Background: Osimertinib (osi) is the preferred 1st line (1L) therapy for patients (pts) with EGFR+ NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent therapies. We report a retrospective, multi-institutional cohort of pts with tissue biopsy (TBx) and/or liquid biopsy (LBx) upon 1L osi progression (PD). Methods: Pts with advanced EGFR+ NSCLC who had TBx and/or LBx (for ctDNA analysis) obtained at PD on 1L osi at 8 participating institutions were included. Molecular testing was performed using next-generation sequencing (NGS) and, in a subset, FISH per local standards. We retrospectively collected clinical characteristics, tissue histology, NGS/FISH results and subsequent therapies. Results: 193 pts (128 female; median age 64 yrs) had TBx (n = 129) and/or LBx (n = 122) upon PD on 1L osi, 58/193 had both tissue and ctDNA. Primary EGFR mutations included del19 (102), L858R (76), and other (15). Median time from osi start to first bx was 14 mos (range, 1-55). MoRs are summarized in the table. In all, 86/193 (45%) pts had a known MoR identified on TBx and/or LBx. Among 129 pts with TBx, histologic transformation (trans) and MET amplification (amp) were the most common MoR, each seen in 16% pts. Among 122 pts with LBx, secondary EGFR mutations were the most common MoR, seen in 15%. Among the 58 pts with both TBx + LBx, discordance between major MoRs was seen in 21/58 pts (36%), most commonly due to histologic trans detected on TBx only (n = 7) and discordant MET amp status (n = 8; 6 TBx+/LBx-, 2 TBx-/LBx+). No MoR was identified in 53% TBx and 75% LBx (including 14% Lbx where the original EGFR mutation was not detected in ctDNA). Results of TBx led to MoR-directed 2L therapy in 41/129 (32%) pts, while LBx results led to MoR-directed 2L therapy in 16/122 (13%). Conclusions: In this large, multi-institutional cohort, histologic trans (16%) and MET amp (16%) were the most common MoR to 1L osimertinib on tissue bx. In ctDNA, secondary EGFR mutations (15%) were the most frequent MoR. The results of TBx were more likely to impact second-line therapy than LBx. Our results underscore the importance of tissue biopsy (and limitations of liquid biopsy) after osimertinib PD, where tissue testing remains the gold standard. In addition, with more than half of patients having no identifiable MoR despite comprehensive testing, our results highlight the need for MoR-agnostic treatment strategies. [Table: see text]