bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib study of BI 836880, a VEGF/Ang2-blocking nanobody, in combination with BI 754091, an anti-PD-1 antibody: Initial results in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Girard Nicolas , Wermke Martin , Barlesi Fabrice , Landsteiner Harald Timotheus , Jayadeva Girish , Alt Juergen , Hackanson Björn 
Published: May 2020

9566 Background: Preclinical studies show that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Each has shown manageable safety and preliminary activity as monotherapy. Here, we report initial results from a Phase Ib study assessing BI 836880 in combination with BI 754091. Methods: In Part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) were enrolled. Pts received BI 836880 (cohorts of 360, 500 and 720 mg intravenously [iv] 3-weekly [q3w]) plus fixed-dose BI 754091 (240 mg iv q3w). Dose escalation was guided by Bayesian logistic regression models with overdose control. Primary endpoint in Part 1 was maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), based on dose-limiting toxicities (DLTs) in Cycle 1. Initial safety and efficacy results of Part 1 are reported here. Part 2 will assess safety and efficacy in 6 expansion cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1st-line CT; and hepatocellular carcinoma after prior sorafenib or lenvatinib ± subsequent CPI. Results: 12 pts received BI 836880 plus BI 754091 (8 male; median age 59.5 years; 8 had received prior CPI). 4 pts remain on treatment (including 1 treated for 15 cycles). 1 pt had a DLT during Cycle 1 (360 mg; G3 pulmonary embolism). All pts experienced an adverse event (AE; any-cause; safety data cut-off Nov 2019), most commonly (all%/G3%) hypertension (58/25), vomiting (42/0), nausea (33/0), and asthenia (33/0). Hypertension was transient. No G4 AEs were reported; one G5 AE occurred (general physical health deterioration). 5 pts had immune-related AEs (G2 hypothyroidism in 2 pts; G2 pruritus, G1 papular rash, and G2 vomiting). To date (Jan 2020), 2 pts have achieved partial response; 1 pt (500 mg dose; CPI-naïve) had 58% target lesion reduction, and 1 (720 mg; prior CPI) had 35% target lesion reduction. 8 pts had stable disease. Conclusions: MTD/RP2D was BI 836880 720 mg plus BI 754091 240 mg q3w. The combination had a manageable safety profile, and preliminary anti-tumor activity was observed. Expansion cohorts are ongoing. Equal contribution: JA and BH Clinical trial information: NCT03468426 .
Tepotinib in patients (pts) with NSCLC with MET exon 14 (METex14) skipping: Health-related quality of life (HRQoL).
Authors: Paik Paul K. , Horn Leora , Kowalski Dariusz M. , Patel Jyoti D. , Griesinger Frank , Han Ji-Youn , Smit Egbert F. , Kato Terufumi , Le Xiuning , Scheele Jürgen , Bruns Rolf , Vioix Helene , Pfeiffer Boris M , Cho Byoung Chul 
Published: May 2020

9575 Background: In the phase II VISION study (NCT02864992) tepotinib had promising efficacy (response rate of 40–50% & median duration of response >1 y) and tolerable safety in pts with advanced NSCLC with METex14 skipping (3–4% of NSCLC), who are typically elderly with poor prognosis. Pt reported outcomes (PROs) of HRQoL are described here. Methods: Pts with advanced NSCLC positive for METex14 skipping by tissue or liquid biopsy received oral tepotinib 500 mg once daily; PROs were assessed using QLQ-LC13 (lung cancer symptoms), EORTC QLQ-C30 (Global health status [GHS] & 5 functional scales), and EQ-5D-5L (VAS). Questionnaires were completed at baseline (BL) and every 6 weeks (Wk); results were scored from 0–100 (minimal clinically important difference [MCID] ≥10 points). Mean change from BL was analyzed at Wk 12 (predefined analyses). Results: By 19 Jul 19 cut-off, 130 pts across treatment lines were enrolled (median age 74.2 y), with PROs available for 129. Questionnaire completion rates were 90.1% at Wk 12. Symptom burden at BL was moderate for advanced NSCLC; mean change from BL for PROs are shown in the table (better functioning: lower QLQ-LC13 or higher QLQ-C30 scores). For the QLQ-LC13 symptoms, mean changes from BL indicated a meaningful improvement in coughing, with a median time to improvement (2.8 months) paralleling the onset of objective response (within first 3 months), and a numerical improvement in dyspnea (–2.3 at Wk 12) and chest pain (–4.2 at Wk 12). QLQ-C30 values remained stable over treatment as did EQ-5D-5L scores (higher=better): mean (standard deviation, SD) change from BL score (60 [20.4]) was 6 (18.6) at Wk 6 and 5 (20.9) at Wk 12. Conclusions: In this first analysis of PROs in pts with advanced NSCLC with METex14 skipping with a moderate symptom burden, treatment with tepotinib led to a clinically meaningful improvement in coughing symptoms, while maintaining HRQoL. Coupled with the efficacy and safety profile, the predefined HRQoL analysis from the VISION study supports tepotinib as a promising treatment option for this elderly population with METex14+ NSCLC. Clinical trial information: NCT02864992 . [Table: see text]
Clinicopathologic characteristics and immunotherapy outcomes in SMARCA4-mutant (mut) non-small cell lung cancer (NSCLC).
Authors: Alessi Joao Victor Machado , Glass Carolyn , Ricciuti Biagio , Spurr Liam F. , Sholl Lynette M. , Awad Mark M. 
Published: May 2020

9577 Background: The catalytic unit of the SWI/SNF chromatin remodeling complex is encoded by the SMARCA4 gene, which is mutated in ~10% of NSCLCs. We sought to characterize the clinicopathologic characteristics and outcomes to immune checkpoint inhibition in SMARCA4-mutant NSCLC. Methods: We collected clinicopathologic and genomic data from patients with NSCLC that had undergone targeted next generation sequencing (NGS) by OncoPanel at the Dana-Farber Cancer Institute. SMARCA4 frameshift, nonsense, and splice-site mutations were considered pathogenic, as were missense mutations if predicted to be pathogenic by Mutation Assessor and Polyphen-2. Clinical outcomes to immune checkpoint inhibition among SMARCA4-mutant NSCLCs were retrospectively assessed. Results: Of 2690 patients with NSCLC, 8% (N = 211) harbored SMARCA4 mutations. Clinicopathological characteristics were balanced between SMARCA4 mut and SMARCA4 wild-type (wt) in terms of age, histology, and PD-L1 expression. We observed a male predominance (P = 0.03), greater use of tobacco (P < 0.001), a higher tumor mutational burden (TMB) (P < 0.001), a higher prevalence of advanced disease (P < 0.001), and a lower prevalence of concurrent targetable driver mutations (P < 0.001) in SMARCA4mut vs SMARCA4wt NSCLCs. Among 513 patients with nonsquamous NSCLC who received immune checkpoint inhibitors, 11% (N = 57) harbored SMARCA4 mutations. From the start of immunotherapy, we observed no difference in overall response rate (ORR 21.5% vs 19.3%; P = 0.3), median progression free survival (mPFS 3.2 months vs 2.1 months; P = 0.4), or median overall survival (mOS 12.0 months vs 8.2 months; P = 0.09) in SMARCA4wt vs SMARCA4mut NSCLC, respectively. However, among KRASmut NSCLC, a concurrent SMARCA4 mut conferred a significantly lower ORR (23.1% vs 0.0%; P = 0.02), a significantly shorter mPFS (4.8 months vs 1.7 month; HR: 0.31 [95% CI: 0.15-0.61]; P < 0.001), and a significantly shorter mOS (15.6 months vs 2.7 months; HR: 0.25 [95%CI: 0.12-0.49]; P < 0.001). The deleterious effect of SMARCA4 mut on immunotherapy outcomes in KRAS mut NSCLC was maintained when controlling for concurrent STK11 mut. Conclusions: SMARCA4 mutations define a genomic subset of NSCLC with unique clinicopathologic characteristics, and confer worse outcomes to immunotherapy in KRAS mut NSCLC.
A phase I, dose-escalation and expansion study of TQ-B3139, a novel ALK TKI, in Chinese ALK or ROS1 positive advanced non-small cell lung cancer (NSCLC).
Authors: Ma Yuxiang , Yang Nong , Li Su , Zhao Hongyun , Li Liu , Yang Haiyan , Fang Wenfeng , Zhang Yang , Hong Shaodong , Xiong Yi , Zhou Chunhua , Zhang Yongchang , Zeng Liang , Zhang Li 
Published: May 2020

9585 Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. Methods: Patients with advanced NSCLC and failed at least one systemic anti-cancer treatment were enrolled. TQ-B3139 was administered orally from 50mg~100mg qd and 200, 300, 400, 500, 600 and 800mg bid, using a PK-guided modified Fibonacci 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles, dose limited toxicities (DLTs) was observed at first cycle. Dose-expansion phase started at dose level which objective response occurs. Treatment was continued until disease progression, death or unacceptable toxicity. Results: Between July 2017 and May 2019, totally 63 patients (59 ALK+, 4 ROS1+) were enrolled. Sixteen patients had prior ALK inhibitor therapy (11 Crizotinib, 5 Ensartinib), and 23 (36.5%) with baseline brain metastasis. Totally, 62 (98.4%) patients experienced treatment-related adverse events (TRAEs), grade 3-4 TRAEs were observed in 21 (33.3%) patients. One DLT occurred in the 800mg bid dose cohort (grade 3 nausea and vomiting). Top 3 common TRAEs were nausea (all grade 87.3%; grade 3-4 3.2%), diarrhea (84.1%, 6.4%), transaminase elevation (65.1%, 4.8%). AUC and Ctrough at steady state increased proportionally from 200mg to 600mg bid. Absorption saturation was observed in 800mg bid. Base on the safety and PK results, PR2D was decided at 600mg bid. Overall ORR was 73.0% (2 CR, 44 PR); DCR was 85.7% (8 SD). Objective response was observed from dose level 200mg bid cohort, ORR and DCR at ≥200mg bid was 78.0% and 89.8%. For ALK TKI-naïve and -resistant patients, the ORR was 78.7% (37/47) and 56.3% (9/16) respectively. For patients with measurable baseline brain metastasis, the ORR for brain lesions was 80.0% (8/10). At data cut-off (23 Jan 2020), 32 events (50.8%) occurred, the median PFS for all patients was 12.1 months (95%CI 8.5-15.6), for patients at ≥200mg bid dose was 12.2 months. The median PFS was not reached for -naive patients (6 months PFS rate 74.5%, 95%CI 68.1-80.9), and 5.6months (95%CI 1.6-9.5) for ALK TKI-resistant patients. Conclusions: TQ-B3139 was well tolerated in Chinese NSCLC patients with high antitumor activity. RP2D was established at 600mg bid. A randomized phase III trial of TQ-B3139 versus Crizotinib in advanced ALK-TKI naïve NSCLC patients is underway. Clinical trial information: NCT03099330 .
Plasma-derived cfDNA to reveal potential biomarkers of response prediction and monitoring in non-small cell lung cancer (NSCLC) patients on immunotherapy.
Authors: Vallania Francesco , Assayag Karen , Ulz Peter , Drake Adam , Warsinske Hayley , St John John , Putcha Girish , Cabel Luc , Beaucaire-Danel Sophie , Girard Nicolas , Bidard Francois-Clement 
Published: May 2020

9588 Background: Immune checkpoint inhibitors have shown promising results in many advanced cancers, but the response rate remains low. Various molecular and cellular biomarkers, such as elevated tumor-infiltrating cytotoxic T cells and Natural Killer (NK) cells at baseline, are associated with response. Blood-based biomarkers to predict or monitor response remain challenging to develop. Here we investigate the potential of cell-free DNA (cfDNA) biomarkers to predict response to the PD-1 immune checkpoint inhibitor nivolumab in patients with refractory metastatic non-small cell lung cancer (NSCLC). Methods: Plasma from stage IV NSCLC patients enrolled in ALCINA (NCT02866149) was collected before (baseline, BL, n = 30) and at week 8 (W8, n = 17) of nivolumab therapy. Response was determined using RECIST 1.1 (responders n = 5; non-responders n = 25). Whole-genome sequencing was performed to characterize cfDNA fragments. Tumor fraction (TF) was assessed using ichorCNA. Cellular composition was estimated by deconvolution of cfDNA co-fragmentation patterns, and transcription factor activity was estimated by measuring binding site accessibility across the genome. Results: Although estimated TF at baseline did not predict response to nivolumab, NK cell levels estimated by cell-mixture deconvolution were significantly higher in responders at BL (p < 0.05). Furthermore, estimated monocyte levels at W8 strongly correlated with overall survival (r = 0.75, p < 0.0005, HR = 15.02) and were significantly higher in responders (p < 0.05). By evaluating changes in transcription factor binding activity, we identified factors with greater accessibility in non-responders at baseline (DEAF1, THAP11) and W8 (DUX4, PDX-1). Conclusions: Plasma cfDNA signatures may be useful for response prediction and monitoring in NSCLC patients on immunotherapy. Our results suggest that changes in the immune system, as reflected by cellular composition and transcriptional activity inferred from cfDNA, may provide biological insights beyond TF alone that may benefit biomarker discovery and drug target identification.
Real-world (RW) outcomes for advanced non-small cell lung cancer (aNSCLC) patients (pts) with EGFR exon 19 deletions (x19del) stratified by deletion size.
Authors: Ou Sai-Hong Ignatius , Madison Russell , Snow Tamara , Snider Jeremy , McCusker Margaret Elizabeth , Singal Gaurav , Alexander Brian Michael , Venstrom Jeffrey , Castellanos Emily , Schrock Alexa Betzig 
Published: May 2020

9591 Background: EGFR x19dels are well-established targetable drivers in NSCLC. Historically x19dels have been treated as a single group, but it’s unclear whether responses vary for distinct subtypes. We compared demographic, clinical and genomic characteristics as well as outcomes to EGFR tyrosine kinase inhibitors (TKIs) for aNSCLC pts with x19dels of varying lengths using a RW Clinico-Genomic Database (CGDB). Methods: Eligible pts had a diagnosis of aNSCLC, received care within the Flatiron Health network between 1/2011-9/2019, and had comprehensive genomic profiling (CGP) by Foundation Medicine. Clinical characteristics, treatment history and RW progression were obtained via technology-enabled abstraction as previously described (Singal G, JAMA 2019). x19del length was evaluated for association with overall survival (OS) and RW progression-free survival (rwPFS) with Kaplan-Meier analysis and unadjusted/adjusted (practice type, gender, age at TKI start, EGFR TKI type, race) hazard ratios (HR/aHR) from Cox proportional hazards models adjusted for survival bias. Results: Among 6,577 aNSCLC pts, EGFR x19dels were detected in 336 cases (5%). E746_A750del was the most frequent (214; 64%) and generally 5 amino acid (aa) deletions (x19del-5) were the most common (241; 72%). Other deletions (x19del-other) of 6 (61; 18%), 3 (20; 6%), 4 (11; 3%) or 8 aa (3; 1%) were also observed. Among pts treated with 1st-line EGFR TKI monotherapy after CGP, the x19del-5 (n = 70) cohort was more frequently female compared to x19del-other (n = 27) (90% vs 59%, p = 0.001). No statistically significant differences in the frequency of co-occurring alterations were observed, specifically for genes associated with response to EGFR TKI response such as CTNNB1 (14% vs 19%) and PIK3CA (10% vs 15%). 1st line EGFR TKIs used were similar for x19del-5 vs x19del-other (43% vs 41% osimertinib, 30% vs 37% erlotinib, 24% vs 22% afatinib, 3% vs 0% gefitinib). x19del-5 pts had similar median rwPFS (10.6 vs 10.6 months, HR: 0.73 [0.41-1.28], aHR:0.78 [0.38-1.59]) and median OS (29.2 vs 24.9 months, HR: 0.64 [0.32- 1.29], aHR: 0.75 [0.32-1.75]) compared to x19del-other. Conclusions: In a RW CGDB of 336 aNSCLC pts with EGFR x19dels, 5 aa x19dels were most common (71%) and 29% of cases had 3, 4, 6 or 8 aa x19dels . For pts included in the treatment cohort, no significant differences in rwPFS or OS were observed. These results suggest that x19del length does not significantly impact clinical outcomes to 1st-line EGFR TKIs.
Clinical characteristics and anti-PD-(L)1 treatment outcomes of KRAS-G12C mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung cancer.
Authors: Arbour Kathryn Cecilia , Rizvi Hira , Plodkowski Andrew J. , Halpenny Darragh , Hellmann Matthew David , Heller Glenn , Knezevic Andrea , Yu Helena Alexandra , Ladanyi Marc , Kris Mark G. , Arcila Maria E. , Rudin Charles M. , Lito Piro , Riely Gregory J. 
Published: May 2020

9596 Background: KRAS mutations are identified in approximately 30% of NSCLC. There are no FDA approved targeted therapies for patients with KRAS-mutant non-small cell lung cancer (NSCLC) but novel direct inhibitors of KRAS G12C have shown some activity in early phase clinical trials. We hypothesized that patients with KRAS-G12C mutations may have distinct clinical characteristics and responses to systemic therapies compared to patients with non-G12C subtypes. Methods: We identified patients with KRAS-mutant lung cancers who underwent next-generation sequencing with MSK-IMPACT, between January 2014 and December 2018. Baseline characteristics were compared with the Chi-square and Fisher’s exact test for categorical data and Wilcoxon rank-rum test for continuous data. Overall survival was calculated from time of diagnosis of metastatic/recurrent disease to date of death or last follow up, with left truncation to account for time of MSK-IMPACT. Overall survival was compared between groups using the Cox proportional-hazards model. Response evaluations where performed by independent thoracic radiologists according to RECIST 1. and compared between group with the Fisher’s exact test. Results: We identified 1194 patients with KRAS -mutant NSCLC, 772 with recurrent or metastatic disease. Of patients with advanced disease, 46% (352/772) had mutations in KRAS-G12C and 54% harbored non-G12C mutations (15% G12D, 16% G12V, 8% G12A, 4% G13D). Co-mutation patterns were similar with respect to KEAP1 (p=0.9) and STK11 (p=1.0). Patients with non-G12C mutations had a higher proportion of never smokers (10% vs 1.4% p<0.001). The median OS from diagnosis was 13 months for G12C and non-G12C patients (p=0.99). 45% (347/772) received 1L or 2L line treatment with PD-(L)1 inhibitor. RECIST measurements were available for 290/347 cases (84%). ORR with anti-PD-(L)1 treatment was 24% vs 28% in G12C vs non-G12C patients (p=0.5). In patients with PD-L1 50% (n=103), ORR was 39% for G12C vs 58% non-G12C patients (p=0.06). Conclusions: KRAS G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development. Baseline characteristics including co-mutation patterns are similar between patients with G12C and non-G12C, except for smoking history. The efficacy of KRAS G12C direct inhibitors will need to be compared to other available therapies for KRAS mutant NSCLC (chemotherapy and PD-(L)1 inhibitors) to identify most effective therapeutic strategy.
Biomarker utilization in non-small cell lung cancer, are we treating after testing?
Authors: Makhoul Elias , Kim Jong Taek , Zhang Wenjuan , Lopategui Jean Raphael , Balmanoukian Ani Sarkis , Vail Eric 
Published: May 2020

9609 Background: Targeted therapy in EGFR and ALK mutated non-small cell lung cancer (NSCLC) has been the standard of care for nearly a decade with subsequent FDA approvals for ROS1 and BRAF V600 mutated NSCLC occurring in 2016 and 2017. However, recent studies have shown suboptimal utilization of genomic profiling results in these patients. In 1 recent study of community oncologists, ~70% of EGFR/ALK+ patients received appropriate targeted therapy, while patients with other gene mutations (including BRAF and ROS1) only received targeted therapy ~30% of the time. Left unanswered was what patients were receiving instead and why. Additionally, it is unknown if this finding is generalizable to the academic setting. We aimed to investigate whether in our patient population, NSCLC patients with actionable mutations received associated FDA approved therapies and if not why. Methods: The pathology database was queried for all NSCLC with molecular testing (including qPCR, FISH and NGS) from 2009 to 2019. Patients with sensitizing EGFR, ALK, ROS1 or BRAF mutations that were detected after the first FDA approval for their respective targeted therapies were included for analysis with those lost to follow up subsequently excluded. Basic demographic and clinical variables were collected as well as treatment records. Results: 2160 NSCLC patients were evaluated (2160 EGFR, 1417 ALK, 810 ROS1, 589 BRAF). 468 patients were identified with targetable mutations (411 EGFR, 46 ALK, 5 ROS1, 6 BRAF). No patient had more than 1 targetable mutation. Of those patients, 248 were at an advanced stage and had clinical follow up (202 EGFR, 37 ALK, 4 ROS1, 5 BRAF). Of those patients 197/202 (97.5%), 33/37 (89.2%), 3/4 (75%) and 1/5 (20%) received EGFR, ALK, ROS1 or BRAF targeted therapy respectively. Across biomarkers 14/248 patients (5.6%) did not receive subsequent targeted therapy. 10 patients (5 EGFR, 3 ALK, 1 ROS1 and 1 BRAF) passed away before targeted therapy could be initiated. Physician choice and missed findings accounted for the remaining four cases. Conclusions: The vast majority of advanced NSCLC patients analyzed in this study received appropriate targeted therapy matched to genomic findings. The main reason (~4% of total cases) that patients did not receive therapy was due to rapidly progressive disease and death before it could be initiated. These findings are at odds with those published from the community setting. This may be due to multiple factors, including clinician education, ease of access to targeted therapies across patient populations and incomplete data in the previous study populations.