bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC).
Authors: Camidge D. Ross , Bar Jair , Horinouchi Hidehito , Goldman Jonathan W. , Moiseenko Fedor Vladimirovich , Filippova Elena , Cicin Irfan , Bradbury Penelope Ann , Daaboul Nathalie , Tomasini Pascale , Ciuleanu Tudor-Eliade , Planchard David , Moskovitz Mor , Girard Nicolas , Jin Janet Yikai , Dunbar Martin , Bolotin Ellen , Looman Jim , Ratajczak Christine , Lu Shun 
Published: June 2022

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to <50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536. [Table: see text]
Phase 1/2a trial of nadunolimab, a first-in-class fully humanized monoclonal antibody against IL1RAP, in combination with cisplatin and gemcitabine (CG) in patients with non-small cell lung cancer (NSCLC).
Authors: Paulus Astrid , Cicenas Saulius , Zvirbule Zanete , Paz-Ares Luis G. , Awada Ahmad , Garcia-Ribas Ignacio , Losic Nedjad , Zemaitis Marius 
Published: June 2022

9020 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed by cancer and stromal cells of many solid tumors. The IL-1 pathway is active in tumors and upregulated in response to chemotherapy. IL1RAP interacts with IL-1R1 and modulates downstream factors (e.g. IL-6, IL-8) and CRP level. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α and IL-1β signaling. Here, results are reported from the phase 1/2a clinical trial CANFOUR evaluating nadunolimab combined with CG in NSCLC. Methods: Patients (pts) with unresectable, locally advanced or metastatic NSCLC, progressed on pembrolizumab or in first line for advanced disease, were eligible. Pts received 1 (n =17), 2.5 (n = 3) or 5 mg/kg (= 13) nadunolimab given Q1W in Cycle 1 and Q2W from Cycle 2, combined with standard CG. Due to risk of infusion-related reactions, a priming dose of 0.5 mg/kg nadunolimab was given one week before CG. Primary objective was safety; secondary objectives included ORR, PFS and OS, and exploratory objectives included effects on serum and tumor tissue biomarkers. Results: Thirty-three pts were enrolled: median age 64 years (39-77), 30% female, 42% ECOG 0, 55% non-squamous histology, 82% stage IV, 45% received previous pembrolizumab monotherapy. Treatment-related adverse events of grade≥3 were observed in 73% of pts, including neutropenia (58%), febrile neutropenia (9%), thrombocytopenia (30%) and anemia (18%). Neutropenia could be managed by G-CSF. Thirty pts received combination therapy and were included in the efficacy analysis. Three pts did not receive chemotherapy due to clinical deterioration (n = 2) or consent withdrawal (n = 1). ORR was 53% (95% CI 34-72%), disease control rate 80% (61-92%) and median duration of response 5.5 months (3.7-7.0) with 23% of pts still on treatment. The lower limit of the 95% CI for the observed ORR excludes the pre-specified 30%. ORR in pts with squamous histology was 46% and non-squamous 56%. Median PFS was 6.7 months (5.5-7.3) and median OS 13.7 months. The neutrophil-lymphocyte ratio was reduced throughout the trial and was driven by the reduction in circulating neutrophil numbers. IL1RAP expression on both cancer and stromal cells was confirmed in tumor biopsies. Conclusions: Nadunolimab combined with CG shows manageable safety and promising efficacy with a response rate of 53% in NSCLC pts. Nadunolimab is currently evaluated in several clinical trials investigating chemotherapy or IO combinations, including carboplatin and pemetrexed in non-squamous NSCLC. Clinical trial information: NCT03267316.
CtDNA shed as a tool to select immune checkpoint inhibitors (ICPI) with or without chemotherapy for patients (pts) with advanced non–small cell lung cancer (aNSCLC).
Authors: Besse Benjamin , Madison Russell , Cho-Phan Cheryl D. , Snider Jeremy , Snow Tamara , Dall'Olio Filippo Gustavo , Tolba Khaled A. , Schrock Alexa Betzig , Oxnard Geoffrey R. 
Published: June 2022

9045 Background: ICPI are compelling therapies for pts with aNSCLC given the potential for durable benefit and limited toxicity. Even in tumors with biomarkers associated with ICPI response, early progression (eP) can be seen, leading to chemotherapy combination approaches. We hypothesize that ctDNA tumor fraction (TF) may identify pts at risk of eP on ICPI, helping to select the optimal first-line regimen. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database (FH-FMI CGDB). The de-identified data originated from ~280 US cancer clinics (~800 sites of care). Real-world overall survival (rwOS) accounting for delayed entry and real-world progression free survival (rwPFS) were estimated with Kaplan-Meier analysis. Hazard ratios (HR) were calculated using multivariate Cox proportional hazard models adjusting for relevant covariates. TF was calculated using an aneuploidy-based measure plus variant-based estimate and was categorized as follows: ≥10%: elevated, 1-10%: intermediate, < 1%: low. eP was defined as rw progression within 8 weeks of starting therapy. Results: 426 pts with documented aNSCLC initiated 1st or 2nd line ICPI (128 ICPI, 298 ICPI+chemo) within 60 days of liquid biopsy. 88 (21%) pts had elevated TF, 193 (45%) had intermediate, and 145 (34%) had low. Pts with elevated TF had higher frequency of liver involvement (elevated: 27%; intermediate: 12%; low: 8%) and had worse performance status (ECOG 2+) near the start of therapy (elevated: 33%; intermediate 22%; low: 17%). PD-L1 was unknown for most pts (elevated: 44%; intermediate: 53%; low: 57%); elevated TF was associated with high PD-L1 positivity (elevated: 22%; intermediate: 17%; low: 12%). In pts with elevated TF, eP was more frequent (elevated: 26%, intermediate: 22%, low: 15%). Amongst all patients treated with either ICPI ± chemo, low TF was associated with better median rwPFS (low 6.7m [ref]; intermediate 5.1m, HR: 1.39 [1.11-1.74]; elevated 3.4m, HR: 1.74 [1.31-2.31]) and median rwOS: (low 14.2m [ref]; intermediate 8.4m, HR: 1.52 [1.10-2.09]; elevated 4.6m, HR: 2.17 [1.47-3.21]). In pts with elevated TF, the addition of chemo to ICPI was associated with favorable rwPFS and rwOS compared to pts who received ICPI alone (Table). Conclusions: ctDNA TF identifies pts with aNSCLC with an increased risk of eP on ICPI who may benefit from ICPI+chemo. In pts with low TF, outcomes on ICPI alone are favorable and similar to those receiving ICPI+chemo, suggesting low TF may be a non-invasive tool for identifying pts for single-agent ICPI. [Table: see text]
Multimodal integration of radiology, pathology, and genomics for prediction of response to PD-1 blockade in patients with non–small cell lung cancer.
Authors: Luo Jia , Vanguri Rami S , Aukerman Andrew T , Egger Jacklynn V. , Fong Christopher J , Horvat Natally , Pagano Andrew , Araujo-Filho Jose , Geneslaw Luke , Rizvi Hira , Sosa Ramon , Boehm Kevin , Yang Soo-Ryum , Ventura Katia , Hollman Travis , Ginsberg Michelle S. , Gao JianJiong , Hellmann Matthew David , Sauter Jennifer L. , Shah Sohrab P ,   MSK MIND Consortium
Published: June 2022

9064 Background: Immunotherapy is now given to almost all patients with advanced non-small cell lung cancer (NSCLC). However, developing robust biomarkers to predict benefit remains challenging. We set out to evaluate the predictive capacity of integrating medical imaging, histopathologic, and genomic features to develop a multimodal biomarker for immunotherapy response. Methods: We used baseline data that is routinely obtained during diagnostic clinical workup at a single center in patients with NSCLC and known outcomes following immunotherapy. The multimodal dataset included DNA alterations from NGS, CT scan images, and digitized PD-L1 immunohistochemistry (IHC) slides. Guided by experts in each field, we developed a workflow to extract data for each patient and used an attention-gated machine learning approach to integrate the features into a risk prediction model. Results: Our cohort included 247 patients with advanced NSCLC who received immunotherapy and had complete radiology, pathology, genomic, and clinical data. The patient cohort was 54% female, had a median age of 68 years (range 38-93), and 88% patients had a smoking history. Responders (CR/PR) vs non-responders (SD/PD) showed a median PFS and OS of 2.7 months (95% CI 2.5-3.0) and 11.4 months (95% CI 10.3-12.8), respectively. Of all patients, 187 (76%) had segmentable disease on chest CT scans. We used a radiomics approach and aggregated the average individual lesion predictions to construct patient-level response predictions which resulted in an overall AUC = 0.65, 95% CI 0.57-0.73. We next studied digitized FFPE slides of pre-treatment PD-L1 IHC staining of tumor specimens. Overall, 52% of slides showed PD-L1 tumor proportion score (TPS) ≥ 1% and were used to extract IHC-texture, a novel spatial characterization of PD-L1 staining. Logistic regression modeling on IHC-texture resulted in prediction accuracy of AUC = 0.62 (95% CI 0.51-0.73) which was inferior to the pathologist-assessed PD-L1 TPS (AUC = 0.73, 95% CI 0.65-0.81). We next implemented a dynamic deep attention-based multiple instance learning model with masking to evaluate the impact of combining features from all modalities. Our multimodal model (AUC = 0.80, 95% CI 0.74-0.86) outperformed unimodal measures, including tumor mutational burden (AUC = 0.61, 95% CI 0.52-0.70) and PD-L1 TPS (AUC = 0.73, 95% CI 0.65-0.81). Conclusions: Our study is a proof of concept for using multimodal features to improve prediction of immunotherapy response over standard-of-care approaches in patients with NSCLC using expert-guided machine learning.
Progression-free survival with subsequent anticancer therapies from a phase 3 trial of lorlatinib in treatment-naive patients (pts) with ALK+ advanced non–small cell lung cancer (NSCLC).
Authors: Solomon Benjamin J. , Bauer Todd Michael , Felip Enriqueta , Liu Geoffrey , Mazieres Julien , de Marinis Filippo , Goto Yasushi , Kim Dong-Wan , Laktionov Konstantin K. , Blackhall Fiona Helen , Dall’O Elisa , Polli Anna , Toffalorio Francesca , Mok Tony S. K. 
Published: June 2022

9069 Background: Lorlatinib, a brain-penetrant, third generation ALK tyrosine kinase inhibitor (TKI), demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs crizotinib in a phase 3 study in pts with previously untreated ALK+ advanced NSCLC (CROWN; NCT03052608). This study investigated the efficacy of treatments following progression on lorlatinib or crizotinib from the CROWN trial. Methods: Pts were randomized 1:1 to receive oral lorlatinib 100 mg daily or crizotinib 250 mg twice daily. The primary endpoint was PFS assessed per blinded independent central review, and secondary endpoints included time from randomization to the date of progression of disease on first subsequent systemic anticancer therapy or death (PFS2). Results: As of September 20, 2021, 91 of 149 patients (61.1%) vs 12 of 147 patients (8.2%) were still receiving lorlatinib vs crizotinib, respectively. In the lorlatinib arm, 33 of 149 patients (22.1%) received ≥1 subsequent systemic anticancer therapy vs 103 of 147 patients (70.1%) in the crizotinib arm. Among the patients who received subsequent systemic anticancer therapy, most patients in both treatment arms received ALK TKIs as first subsequent treatment: 63.6% and 93.2% in the lorlatinib and crizotinib arms. Chemotherapy was administered as first subsequent therapy to 36.3% and 2.9% of the patients, respectively. Median duration of treatment on first subsequent anticancer therapy was 9.6 months (IQR, 2.9-18.1 months) for lorlatinib arm and 13.3 months (IQR, 4.8-21.2 months) for crizotinib arm. Median PFS2 was not reached (NR; 95% CI, NR-NR) in the lorlatinib arm and was 39.6 months (95% CI, 27.4-NR) in the crizotinib arm, with a hazard ratio for lorlatinib vs crizotinib of 0.45 (95% CI, 0.30-0.67). Conclusions: While subsequent anticancer therapies offered clinical benefit in both treatment arms, PFS2 results indicated that clinical benefit was prolonged with lorlatinib vs crizotinib. Clinical trial information: NCT03052608.
Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC.
Authors: Bhalla Sheena , Fattah Farjana J. , Williams Jessica N. , Macchiaroli Alyssa , Padro Jonathan , Pogue Meredith , Dowell Jonathan , Brekken Rolf A. , Putnam William C. , McCracken Nigel William , Micklem David , D'Costa Zenobia , Gerber David E. 
Published: June 2022

9081 Background: AXL, a transmembrane receptor tyrosine kinase, is overexpressed and associated with poor prognosis and treatment resistance in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324) is a selective orally bioavailable small molecule inhibitor of AXL, currently in phase 2 clinical development, that has demonstrated synergistic activity with docetaxel in in vivo models of NSCLC. This phase I dose escalation and expansion trial assessed the safety, tolerability, and preliminary efficacy of bemcentinib in combination with docetaxel in previously treated advanced NSCLC. Methods: Dose escalation of daily bemcentinib in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a standard 3+3 design. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic effects alone and in combination. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) pre-dose (C1D-7), C1D1, and C2D1. Results: A total of 21 patients (pts) were enrolled with median age 62 (range 39-84) and 67% male. A median of 3 (range 1-13) cycles of therapy were administered. Principal treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (52%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever ≥G3 occurred in 7 (33%) pts. The maximum tolerated dose was 60 mg/m2 docetaxel plus 200 mg bemcentinib daily with prophylactic G-CSF support. Pharmacokinetics of bemcentinib alone and in combination with docetaxel were highly similar. Among 15 evaluable pts, 4 (27%) pts had partial response and 9 (60%) pts had stable disease as the best radiographic response. Bemcentinib treatment resulted in changes in plasma levels of proteins associated with regulation of sterol synthesis and AKT signaling. Conclusions: Bemcentinib in combination with docetaxel and prophylactic G-CSF support has a manageable safety profile, leads to decreases in systemic factors associated with tumor growth and metastasis, and demonstrates evidence of anti-tumor activity in previously treated, advanced NSCLC. Further studies to identify the patient population most likely to benefit from this regimen are warranted. Clinical trial information: NCT02922777.
DUBLIN-3 results on quality of life (QoL) in second/third-line EGFR-wild type NSCLC patients (pts) receiving docetaxel (Doc) with or without plinabulin (Plin) using the validated EORTC QLQ C30 and QLQ LC13 questionnaires.
Authors: Feinstein Trevor , Ogenstad Stephan , Mitchell Dominic , Huang Lan , Mohanlal Ramon W. 
Published: June 2022

9091 Background: Plin, a novel immune-enhancing small molecule, enhances dendritic cell maturation and T-cell proliferation. In the ITT population, the Plin/Doc combination had superior Efficacy (mOS; p = 0.0399), Safety (Gr3/4 AE rate/pt/year; p = 0.038) and QTWiST (p = 0.026) vs standard of care (SoC) Doc alone in NSCLC pts in DUBLIN-3 (Han, ESMO 2021). Here we report DUBLIN-3 QoL results. Methods: DUBLIN-3(NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR wt NSCLC pts with a measurable lesion (RECIST 1.1) in the lung, and ECOG ≤ 2, conducted in US, Australia, and China. Pts (n = 559) were randomized 1:1 to Plin/Doc or Doc/Placebo (21-day (D) cycle). Doc (75 mg/m2 on D1 and Plin 30 mg/m2 on D1 and D8 were given by IV infusion. QoL was evaluated by the validated questionnaires EORTC QLQ C30 and QLQ LC13 (which is specific for Lung Cancer), and patient-reported scores were collected at baseline and D1, D8 of each cycle (C). Results: Baseline characteristics and QLQ C30 and LC13 scores were comparable between both groups. Plin/Doc was well tolerated. Cumulative C30 sand LC13 scores were calculated for each patient. Mean (SEM) change from baseline in cumulative C30 and LC13 scores were comparable for Plin/Doc and Doc in the first 10 cycles, however separated after C10 in favor of Plin/Doc (table). LC13 items in favor of Plin/Doc vs Doc alone, were items 31 (Coughing; p < 0.05), 36 (Sore Mouth; p < 0.01), 37 (Dysphagia; p < 0.01). Conclusions: We previously reported an OS, Safety, and QTWiST benefit with Plin/Doc vs Doc alone (ESMO 2021) in EGFR wild type 2nd/3rd line NSCLC pts from DUBLIN-3. Here, we report statistically significant QoL benefits with Plin/Doc vs Doc alone, as assessed with EORTC QLQ C30 and LC13, which may be relevant to guide treatment decisions in this generally sick patient population. Clinical trial information: NCT02504489. [Table: see text]
Gefitinib plus chemotherapy versus gefitinib alone in untreated patients with EGFR-mutated non–small cell lung cancer and brain metastases (GAP Brain): An open-label, randomized, multicenter, phase 3 study.
Authors: Chen Likun , Hou Xue , Li Meichen , Wu Guowu , Feng Weineng , Su Jin , Jiang Honghua , Jiang Guanming , Zhang Baishen , Chen Jing , You Zhixuan 
Published: June 2022

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P < 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P < 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.