bluuebunny/crossref_metadata_2025 huggingface dataset:
The Lung ART adjuvant radiotherapy phase 3 randomized trial: Impact of quality of resection in stage IIIAN2 patients.
Authors: Thomas Pascal Alexandre , Edwards John G. , Rami-Porta Ramón , Van Schil Paul , Mercier Olaf , Le Rochais Jean Philippe , Falcoz Pierre-Emmanuel , Meunier Jean-Pierre , Gkika Eleni , Kheira Hireche , Riesterer Oliver , Ghigna Maria Rosa , Bardet Aurelie , Le Pechoux Cecile ,   On behalf of LungART investigators (IFCT 0503, UK Lung ART Group, SAKK)
Published: June 2022

8522

Background: Lung ART is an international phase 3 trial whose main objective was to evaluate the impact of post-operative conformal radiotherapy (PORT) on disease-free survival (DFS) in patients with completely resected pathologically proven N2 non-small cell lung cancer (NSCLC), with or without neo- or adjuvant chemotherapy. Previously communicated results showed no impact of PORT on DFS. However, as quality of surgical resection and extent of lymph node dissection were expected to be critically important in the interpretation of results, surgical and pathological reports were centrally reviewed by a surgical committee. Methods: A surgical advisory committee composed of 4 expert thoracic surgeons reviewed anonymized surgical and pathological reports of all included patients. Pre-defined classification rules were defined using published guidelines from the International Association for the Study of Lung Cancer and the European Society of Thoracic Surgeons. Tumor resection was defined as complete (no residual tumor and adequate lymph node assessment), uncertain (highest mediastinal nodal station involved, incomplete nodal exploration, involved N2 removed in fragments) or incomplete (presence of residual tumor). Nodal exploration was classified as sampling, selective dissection or extensive dissection. Results: 501 patients were included in the Lung ART trial. Before surgical committee review intervention, all patients except 2 had complete resection. 496 patients’ reports were analyzed by the surgical advisory committee. The basic characteristics are specified in the following table: Conclusions: Monitoring of the quality of nodal exploration and of resection should be implemented in randomized studies evaluating peri-operative strategies in NSCLC in order to provide reliable and generalizable results. Clinical trial information: NCT00410683. [Table: see text]
Racial disparities in the clinical use of durvalumab for patients with stage III unresectable non–small cell lung cancer treated at Veterans Health Administration facilities.
Authors: Moore Amanda , Nooruddin Zohra , Reveles Kelly R , Datta Paromita , Brannman Lance , Cotarla Ion , Frankart Andrew , Mulrooney Tiernan , Jones Xavier , Frei Christopher R
Published: June 2022

8526

Background: Evidence from the PACIFIC study and real-world data highlight the benefit of durvalumab in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC). However, limited literature exists regarding disparities in durvalumab treatment patterns such as treatment initiation delays (TID), treatment interruptions (TI), number of doses, duration of therapy (DOT), adverse effects (AEs), and treatment discontinuation (TD) in minority populations. Methods: Patients with stage III UR-NSCLC and a self-reported racial identity of Black or White treated with durvalumab following chemoradiotherapy (CRT) at any Veterans Health Administration (VHA) facility from January 1, 2017 to June 30, 2020 were included. Patients were followed from their date of durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or end of the study; therefore, all patients had the opportunity to be treated for 12 months. Patients were excluded if durvalumab therapy was ongoing at the end of the study. Patient charts were retrospectively reviewed for baseline characteristics and durvalumab treatment patterns including TID (>42 days from end of CRT to durvalumab start), TI (>28 days between doses), number of doses, DOT, AEs, and TD. Nominal variables were compared using chi-square/Fisher’s exact tests. Continuous variables were compared using Student’s t-tests/Wilcoxon Rank Sum tests. Results: Among 924 patients, Black patients were younger than White patients (median age 67 years [IQR, 63-71] vs. 70 years [IQR, 65-73]; p<0.01), more likely to be current smokers (54% vs. 45%; p=0.03), with more chronic liver disease (22% vs. 9%; p<0.01), but less COPD (63% vs. 72%; p=0.01). Black patients experienced more TI (25% vs. 18%; p=0.03) but TID, number of doses, DOT, and TD were similar between the groups. Black patients were less likely to have an immune-related AE (irAE) (28% vs. 36%; p=0.03) (and less pneumonitis (7% vs. 14%; p<0.01)). Toxicity was the reason for TD in 12% of Black patients vs. 20% of White patients (p=0.01), with no other significant (α < 0.05) differences in reported reasons for TID, TI, or TD between the groups. Conclusions: In this real-world study, Black patients experienced similar TID, number of doses, and DOT as White patients. Black patients were less likely to experience an irAE (including pneumonitis) but experienced more TI; TD were similar but more likely to be from toxicity for White patients. Future research is needed to validate these findings.[Table: see text]
Pre-existing interstitial lung abnormalities are independent risk factors for interstitial lung disease during durvalumab treatment after chemoradiotherapy in patients with locally advanced non–small lung cancer.
Authors: Daido Wakako , Masuda Takeshi , Imano Nobuki , Matsumoto Naoko , Shoda Hiroyasu , Hamai Kosuke , Iwamoto Yasuo , Takayama Yusuke , Mishima Shohei , Masuda Ken , Kawase Shigeo , Awaya Yoshikazu , Nishimura Yoshifumi , Shiota Naoki , Ishikawa Nobuhisa , Yamasaki Masahiro , Kitaguchi Soichi , Fujitaka Kazunori , Nagata Yasushi , Hattori Noboru
Published: June 2022

8528

Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by treatment of durvalumab, one of immune checkpoint inhibitors (ICI). Interstitial lung disease (ILD) is a clinically life-threatening toxicity of CRT or durvalumab. The patient-characteristics or dose-volume histogram parameters of radiotherapy have been reported to be the risk factors for radiation-induced pneumonitis. However, the risk factors for ILD during durvalumab therapy has not been established. Interstitial lung abnormalities (ILA) are generated by aging or smoking, and manifest as minor interstitial shadow on lung computed tomography (CT). We previously reported that ILA were risk factors for ICI-induced ILD in patients with advanced NSCLC, as well as non-lung cancer. Therefore, we investigated whether ILA could be risk factors for ILD during the durvalumab therapy. Methods: We retrospectively enrolled NSCLC patients who received durvalumab after CRT at 10 institutions from July 2018 to June 2021. Patient-information, patient-characteristics, dose-volume histogram parameters, chest CT findings, and laboratory data, were obtained. CT findings were examined using CT obtained after CRT and prior to durvalumab therapy. Results: A total of 153 patients were enrolled, and the prevalence of ILA was 37.8% (56 patients) before durvalumab treatment. Among the enrolled patients, 94 (63.5%) developed ILD during durvalumab therapy. The proportion of patients with grade 1, grade 2, or grade 3 ILD was observed to be 29.7% (44 patients), 25.7% (38 patients), and 8% (12 patients), respectively. Univariate logistic regression analysis revealed that higher age, higher dose volume histogram parameters (V5, V20, mean lung dose), and the presence of ILA were significant risk factors for grade 2 or more ILD. Multivariate logistic regression analysis showed that ILA, especially ground grass attenuation in ILA, was an independent risk factor for grade 2 or more ILD (odds ratio: 7.02, 95% CI: 2.95-16.69, p < 0.0001). Conclusions: Pre-existing ILA are risk factors for ILD during durvalumab treatment after CRT. This observation is consistent with previously reported findings in patients with advanced lung cancer and non-lung cancer. Therefore, we should pay more attention to the development of grade 2 or more ILD during durvalumab treatment in patients with ILA.
Observer performance study to examine the feasibility of the AI-powered PD-L1 analyzer to assist pathologists’ assessment of PD-L1 expression using tumor proportion score in non–small cell lung cancer.
Authors: Kim Seokhwi , Kim Hyojin , Jung Wonkyung , Cho Soo Ick , Bentz Joel , Clingan Warren , Golden Kevin , Arcega Ramir , Bae Hyunsik , Butler Dawn L. , Choi Sangjoon , Farinola Maryam , Harrison Daniel , Hwang Soohyun , Jung Minsun , Kashikar Nilesh , Kim Hyunsung , Manny Julia , Winters Carmen , Hughes Jonathan H.
Published: June 2022

8529

Background: Programmed death ligand 1 (PD-L1) expression is the standard biomarker for PD-L1 inhibitors in advanced non-small cell lung cancer (NSCLC). However, evaluation of PD-L1 tumor proportion score (TPS) by pathologists causes inter-observer variation and demands time to interpret. This study aimed to evaluate the benefit of the artificial intelligence (AI) algorithm in assisting pathologists to determine TPS on PD-L1 immunohistochemistry (IHC) whole-slide images (WSIs) in NSCLC. Methods: Lunit SCOPE PD-L1, an AI-powered PD-L1 TPS analyzer, was developed from 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 WSIs stained by 22C3 pharmDx IHC. The AI model was developed based on a region-based convolutional neural network, and the model can detect and count PD-L1 positive or negative tumor cells from WSIs to calculate TPS. Seven independent board-certified pathologists scored ground truth (GT) of PD-L1 TPS from 199 WSI of NSCLC stained by 22C3 pharmDx IHC. TPS from each GT reader was grouped as negative (< 1%), low (1% to 49%), or high (≥ 50%). The GT of each slide was determined by the consensus of GT readers. Another twelve independent board-certified pathologists scored PD-L1 TPS from the same WSIs as observer performance testers (OPT). They scored TPS twice with a washout interval of 4 weeks, with or without AI assistance. TPS accuracy change and reading time of OPT reader according to the presence or absence of AI assistance were analyzed. Results: The standalone accuracy of the AI model was 0.809 (95% CI: 0.690–0.941). With AI assistance, the overall accuracy of TPS had been changed from 0.799 (95% confidence interval [CI]: 0.764–0.836) to 0.832 (95% CI: 0.796–0.869) (P = 0.004). AI assistance increased the accuracy rate in 11 out of 12 OPT readers. The result of the generalized linear mixed model revealed that AI assistance and specimen type affected the probability of correct answer, while the order of reading did not (Table). The mean time to read with AI was 195.4±506.5 (mean±standard deviation) seconds, which was significantly shorter than the mean time to read without AI (285.1±1578.4, P <0.001). Conclusions: This study demonstrates that an AI-powered PD-L1 TPS analyzer can assist board-certified pathologists in evaluating TPS of NSCLC by improving the accuracy of TPS group evaluation and reducing the time to read slides.[Table: see text]
Equity for under-served populations in lung cancer screening and treatment: Does mobile low-dose CT scanning lead to stage shift and diagnosis with potential cures at 4 years of follow-up?
Authors: Raghavan Derek , Doege Darcy L. , Dungan Kia , Wheeler Mellisa S , Doty John , Hickman Glenn , Mileham Kathryn Finch , Carrizosa Daniel R.
Published: June 2022

8551

Background: Randomized trials proved that screening high-risk patients with LDCT of chest reduces lung cancer mortality. Under-served patients have missed this benefit in most studies through access issues. We showed that mobile LDCT improves access and now assess if this translates to equity of survival. Methods: We used two coaches with BodyTom © portable 32 slice low-dose CT scanners (Samsung) to screen uninsured and under-served heavy smokers for lung cancer (Oncologist, 2019). All films were reviewed by central panel using LUNG RADS technique. Protocol was approved by Advarra IRB. Medicare pts were excluded as insurance covered them for LDCT (causing negative bias for diagnosis as the elderly are at high risk). Results: We initially screened 1200 uninsured/under-insured subjects, mean age 61 years (range 55-64), with average pack year history of 47.8 (30-150); 61% male; 18% Black, 3% Hispanic/Latino; 78% rural. We found 97 pts with LUNG RADS 4 (high risk) lesions, 30 lung cancers (2.5%), including 18 at stage I-III treated with curative intent (60%); 5 incidental non-lung cancers (renal CA 2, head & neck CA 1, pancreas CA 2); > 50% with intercurrent cardiovascular disease and COPD seen on LDCT. Of eligible first-screen subjects, 51% attended 12 month repeat LDCT and 27% attended third LDCT. One pt (6%) treated with curative intent has relapsed to date (median follow up 2.5 years, with 25% beyond 3 years). An additional 288 screened pts revealed 9 lung cancers (5 stage I-III), confirming shift to early stage disease at diagnosis. Conclusions: Mobile LDCT yields higher screening rate for under-served pts than prior hallmark trials, with shift to early-stage detection of lung cancer, with sustained treatment-induced remissions beyond 4 years. This approach could be applied to improve national lung cancer survival in the under-served.
Clinical activity of pembrolizumab monotherapy in diffuse malignant peritoneal mesothelioma.
Authors: Wang Xiao , Offin Michael , Roshkovan Leonid , Miura John , Ginsberg Michelle S. , Ciunci Christine Agnes , Egger Jacklynn V. , Walker Suzanne , Cercek Andrea , Litzky Leslie , Nash Garrett Michael , Haas Andrew , Karakousis Giorgos , Cengel Keith A. , Katz Sharyn I. , Zauderer Marjorie Glass , Langer Corey J. , Marmarelis Melina Elpi
Published: June 2022

8557

Background: Among patients with malignant mesothelioma, pembrolizumab has demonstrated activity in diffuse pleural mesothelioma (DPM), with limited data available for those with diffuse malignant peritoneal mesothelioma (DMPM). DMPM represents a clinically distinct entity from DPM and disease specific outcomes data is needed. We present real world data on the efficacy of pembrolizumab in DMPM. Methods: In this retrospective study, we identified patients with DMPM treated with pembrolizumab at two tertiary care cancer centers between 1/1/2009 and 1/1/2021. Clinicopathologic features were annotated. Median progression free survival (mPFS) and median overall survival (mOS) were calculated using Kaplan-Meier curves. Best overall response rate (BOR) was determined using RECIST 1.1 criteria. Association of partial response with disease characteristics was evaluated using Fisher’s exact test. Results: We identified 24 patients with DMPM who received pembrolizumab (median age 62 years, 63% never smokers, 58% female, 75% had epithelioid histology). All patients received systemic chemotherapy prior to pembrolizumab (median prior lines of therapy: 3). BOR was 17% (3 partial responses, 10 stable disease, 5 progressive disease, 6 lost to follow-up). With a median follow up time of 29.2 months, mPFS was 4.9 months and mOS 20.9 months from pembrolizumab initiation. Three patients experienced PFS of > 2 years. Among the 14 patients who underwent next generation sequencing of tumor tissue, there were 8 somatic BAP1 alterations. Among the 17 patients tested for PDL1, 6 had positive PDL1 expression (1-80%). There was no association between partial response and presence of a BAP1 somatic alteration (p = 0.453), PDL1 positivity (p = 0.7) or non-epithelioid histology (p = 0.55). Conclusions: Pembrolizumab is active in a PDL1 unselected cohort of patients with DMPM. The overall response rate of 17% and mPFS of 4.9 months in this 75% epithelioid histology cohort warrants further investigation to identify those most likely to respond to immunotherapy, especially among epithelioid histology.
A phase 1/2 trial of lurbinectedin (L) in combination with pembrolizumab (P) in relapsed small cell lung cancer (SCLC): The LUPER study.
Authors: Calles Antonio , Navarro Alejandro , Doger Bernard , de Miguel Maria J. , Alvarez Alvarez Rosa Maria , Moreno Victor , Ramón Jorge , Galera López María del Mar , Hernandez-Guerrero Tatiana , Corral Elena , Calvo Emiliano
Published: June 2022

8581

Background: L is a novel anticancer agent that inhibits trans-activated transcription and modulates the tumor microenvironment. L is approved by the FDA for metastatic SCLC patients (pts) with progressive disease (PD) on or after platinum-based chemotherapy (CT). The LUPER study is assessing the safety, tolerability, and preliminary efficacy of L+P as second-line regimen for SCLC pts after failure of platinum-based CT. Phase 1 data are presented here. Methods: In this phase 1/2 trial (NCT04358237), adult pts with histologically confirmed SCLC, PD to a previous CT-containing regimen (≥4 weeks before study initiation), no prior exposure to immunotherapy, ECOG PS of 0-1, and measurable disease as per RECIST 1.1 are eligible. Pts with treated, stable, and asymptomatic brain metastases (BMs) are allowed. A 3+3 dose-escalation was done to determine the recommended phase 2 dose (RP2D) of L+P. L was dosed at 2.4 mg/m2 and 3.2 mg/m2 IV Q3W in the dose level (DL)1 and 2, respectively, in combination with fixed dose of P (200 mg IV Q3W). The RP2D was the highest DL at which 0/3 pts or ≤1/6 pts experienced dose-limiting toxicities (DLTs) during the first cycle. Treatment was administered until PD, unacceptable toxicity, or consent withdrawal. Secondary endpoints include safety as per CTCAE 5.0, preliminary efficacy, and pharmacokinetics. Results: Thirteen pts were enrolled across 3 hospitals in Spain (DL1, n = 7; DL2, n = 6). Median age was 66 (range 43–78) years, 46.2% were female, 61.5% had ECOG PS of 1, 38.5% had platinum-free interval < 90 days, 30.8% had LDH > upper normal limit, and 15.4% had BMs. One DLT (G3 asthenia) and one G4 neutropenia lasting > 3 days (controlled with G-CSF prophylaxis upon C2, without requiring dose delay or modification) occurred in the DL1. No DLT were reported in the DL2. The RP2D was identified as 3.2 mg/m2 L and 200 mg P IV Q3W. At data cutoff (Jan 21, 2022), 5 (38.4%) pts remained on treatment (1 pt in DL1 discontinued due to COVID-19 in cycle 1). Median duration of treatment was 2.1 (0–11.8) months, 5 (38.5%) pts had ≥8 cycles, and median relative dose intensity of L and P were 91.1% and 95.7%, respectively. Immune-related AEs (G2 pneumonitis; G3 ALT increased) led to P discontinuation in 2 (15.4%) pts. Responses were shown in both DLs, with ORR of 30.8% (1 confirmed complete response and 3 partial responses); 3 pts had stable disease (SD; including 1 patient with SD > 12 weeks) and 5 (38.5%) pts experienced PD. Conclusions: This is the first report to demonstrate a manageable safety profile and preliminary efficacy of second-line L+P for relapsed SCLC pts. This combination warrants further confirmation in the ongoing expansion phase 2. Clinical trial information: NCT04358237.
Circulating tumor DNA (ctDNA) mutations associate with response in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with talazoparib (TALA) and temozolomide (TMZ).
Authors: Velez Maria A , Cummings Amy Lauren , Mulroy Matthew C , Garon Edward B. , Slamon Dennis J. , Goldman Jonathan W.
Published: June 2022

8582

Background: Poly (ADP-ribose) polymerase (PARP) inhibition in combination with TMZ is a promising treatment strategy for ES-SCLC. In SCLC models, TALA, a potent PARP inhibitor, exhibits cytotoxic effects by impairing PARP proteins 1/2 and trapping PARP on DNA while TMZ potentiates antitumor response by contributing to genomic instability (Wainberg 2016). A prior analysis of ctDNA in 15 pts treated on trial with TALA and TMZ suggested that mutations in DNA damage repair (DDR) genes occurred with this combination and may associate with response (Mulroy ASCO 2021). Methods: Pts with relapsed or refractory ES-SCLC were treated with TALA 0.75 mg po daily with TMZ 37.5 mg/m2 po on days 1-5 of 28-day cycles in a phase 2 clinical trial (UCLA/TRIO-US L-07, NCT03672773). ctDNA was collected and assessed based on allele frequency and plasma copy number at baseline and every 8 weeks during treatment with the Guardant360 assay (Redwood City, CA). DDR status was defined as a mutation known or likely to result in aberrant expression of ATM or BRCA1/2 (other DDR genes not detected by assay) (Pearl 2015). Germline DDR mutations were evaluated with matched-normal (PBMC) whole exome sequencing (WES) with archival specimens by Tempus (Chicago, IL). Response to treatment was defined by RECIST 1.1 criteria. Fishers exact tests were used to compare proportions of patients, with P-values <0.05 considered statistically significant ( www.r-project.org , Vienna, AU). Results: For 27 pts with evaluable response, 78 ctDNA samples were collected. The most common baseline somatic alterations were mutations in TP53 (23 pts), RB1 (8 pts), ATM (5 pts), and BRCA2 (5 pts). There were no patients with germline DDR mutations. Overall, 22/27 (81.5%) had disease control (DC), including 11 with confirmed partial responses (PR) and 11 with stable disease while 5 had progressive disease. All those with PRs and ctDNA burden >0.2% at baseline experienced a ctDNA decrease at 8 weeks of treatment. DDR mutations were found in 18/27 (66.7%) pts. Of those with ≥ 1 follow-up ctDNA time point collected, 13/17 (76.4%) pts had at least one new mutation detected while on treatment, most commonly in ATM (6 pts). The appearance of new mutations associated with DC (P=0.042) and with a trend towards improved progression free survival (PFS, 5.9 m vs 3.6 m, P=0.099). All 5 pts with DDR mutations present at baseline had DC with TALA and TMZ, and 9/11 (81.8%) of those with PR had DDR mutations detected at some point during the trial, although the trend toward DC enrichment with DDR mutations did not maintain statistical significance (P=0.24). Conclusions: Mutations in DDR genes occur on treatment with TALA and TMZ and may associate with disease control. Validation in a larger cohort will be pursued.
Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis.
Authors: Nakajima Erica C. , Ren Yi , Vallejo Jonathon Joseph , Akinboro Oladimeji , Mishra-Kalyani Pallavi Shruti , Larkins Erin A. , Drezner Nicole Lauren , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Singh Harpreet
Published: June 2022

9001

Background: While existing data suggest a detriment of immune checkpoint inhibitors (ICI) in other targetable mutations in non-small cell lung cancer (NSCLC), limited retrospective analyses suggest patients with Kirsten rat sarcoma oncogene ( KRAS)-mutated NSCLC benefit from ICI in the front-line (1L). To better define this benefit, pooled data from 12 registrational clinical trials investigating 1L ICI with or without chemotherapy (chemo) in patients with documented KRAS status (mutant or wildtype) was evaluated for efficacy of ICI+chemo, ICI alone, and chemo alone. Methods: Pooled data was evaluated for objective response rate (ORR) and overall survival (OS) by KRAS status (mutant, G12C, or wildtype). ORR and 95% confidence intervals (CI) were estimated using Clopper-Pearson method; median OS was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS status and PD-L1 status (Positive (combined positive score (CPS) ≥1), Negative (CPS<1), High (CPS≥50), Low (CPS<50)). Results: KRAS mutational status was reported in 1430 patients (61% wildtype, 39% mutated). KRAS G12C was reported in 11% of patients with a KRAS mutation (157/555). Demographics were similar between KRAS mutated, G12C, and wildtype patients. Amongst all patients, 60% were male, 89% white, 60% positive PD-L1, 67% former or current smokers. Table 1 shows outcomes of chemo+ICI, ICI alone, and chemo alone in each population. Conclusions: This retrospective, pooled analysis suggests that patients with KRAS-mutated NSCLC benefit from 1L chemo-ICI similarly to those with KRAS wild-type NSCLC, and should receive combination therapy upfront. Patients with KRAS-mutated NSCLC derived the greatest benefit from the combination of chemo-ICI as compared to ICI or chemo alone. The small number of patients with documented KRAS G12C mutation limits interpretation of the data for this subgroup. Clinical trials investigating targeted therapies for KRAS-mutated NSCLC in the 1L should include a chemo-ICI comparator arm. [Table: see text]
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.