bluuebunny/crossref_metadata_2025 huggingface dataset:
Early pulmonary function changes associated with brigatinib initiation.
Authors: Ng Terry L. , Johnson Amber , Osypuk Andrea Abeyta , Smith Derek , Jordan Kimberly R. , Nguyen Anna Tram Anh , Conti Nicole , van Bokhoven Adrie , Hsieh Elena , Camidge D. Ross , Schenk Erin Lynn
Published: May 2020

9538

Background: Phase I-III studies reported symptomatic pulmonary toxicity within the first week of initiating brigatinib in 6% patients post-crizotinib and 3% in TKI naive patients with standard dosing (90mg QD for 7 days then 180mg QD as tolerated). A prospective observational study of pulmonary function testing (PFT) on initiating brigatinib was conducted. Methods: Patients PS≤2, with resting O2 sats on RA ≥90% and Hg ≥10 g/dL, without significant heart/lung disease or steroid use initiating brigatinib 90 mg QD were eligible. PFT with DLCO, Borg dyspnea and 6-minute walk tests were performed at baseline (prior to brigatinib), and on day 2 (D2), 8 (D8), and 15 (D15) of brigatinib. D15 analyses were initially as clinically indicated but became mandatory if DLCO had not returned to baseline by D8. Peripheral blood was collected at baseline, D2 and D8 for CyTOF analysis. The primary endpoint was the incidence of Early Onset Pulmonary Events (EOPEs), defined as a DLCO reduction of ≥ 20% from baseline. An interim analysis was performed on the first 10 patients due to a higher than expected incidence of DLCO reduction. Results: D2 and D8 measurements were captured in all 10 patients, D15 in 7 patients. Ninety percent (9/10) of patients experienced DLCO reduction with nadir occurring on D2 in 4/9 and on D8 in 5/9 patients. Median DLCO nadir was −13.33% from baseline (range: −34.44 to −5.00). Three patients (30%) met EOPE criteria, all on D8, all without symptoms. Brigatinib was not held and all 10 patients escalated to 180mg on D8. Despite continued dosing, 4/9 patients recovered DLCO to baseline or above by D15 (2/3 EOPEs cases), 2/9 recovered above nadir but below baseline by D15 (1/3 EOPE case), and 3/9 did not have improvement from nadir values but no D15 assessment was performed. Dyspnea and 6-minute walk test did not correlate with DLCO changes. Patients who experienced an EOPE had significantly higher levels of activated neutrophils (pERKhi) at baseline. On the day of the EOPE event, patients who met EOPE criteria had significantly higher levels of activated neutrophils and fewer activated CD4+ effector memory T cells. Conclusions: Modest DLCO reduction occurred in 90% (9/10) patients during the first 8 days of brigatinib-dosing without associated symptoms. When rechecked on D15, DLCO improved in 100% patients (6/6) despite continued dosing and standard dose escalation at D8. Patients unlikely to tolerate even this modest, short-lived change should consider shallower step-up dosing or alternative drugs. CyTOF analysis suggests levels of pretreatment neutrophils may be a biomarker for developing EOPEs. Clinical trial information: NCT03389399 .
SRC-homology 2 domain-containing phosphatase 2 (SHP2) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD).
Authors: Rosell Rafael , Ito Masaoki , Codony-Servat Jordi , Giménez-Capitán Ana , Serra-Mitjans Mireia , Pérez-Ochoa Francisco , Llige David , Chaib Imane , Rami-Porta Ramón , Obiols Carme , Call Sergi , Belda-Sanchis José , Tarroch-Sarasa Xavier , Karachaliou Niki , Molina Vila Miguel Angel , Okada Morihito
Published: May 2020

9540

Background: Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts). Methods: We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2. Results: Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio = 1.83 and 2.28, respectively. p = 0.03 and p = 0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocalizes SHP2 into the cytoplasm membrane, limiting AKT and ERK activation. Conclusions: High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.
Circulating and tumor-associated neutrophil subtypes discriminate hyperprogressive disease (HPD) from conventional progression (PD) upon immune checkpoint inhibitors (ICI) in advanced non-small cell lung cancer (NSCLC) patients (pts) and in vivo models.
Authors: Ferrara Roberto , Lo Russo Giuseppe , Signorelli Diego , Proto Claudia , Prelaj Arsela , Galli Giulia , De Toma Alessandro , Viscardi Giuseppe , Lobefaro Riccardo , Brambilla Marta , Talarico Giovanna , Bassani Barbara , Spanò Sestina Maria , Molino Giuliano , Zilembo Nicoletta , Ganzinelli Monica , Vitale Stefania , Colombo Mario Paolo , Garassino Marina Chiara , Sangaletti Sabina
Published: May 2020

9547

Background: HPD occurs in ≃10-25% of NSCLC pts upon single-agent ICI and correlates with poor prognosis. High circulating neutrophil count and neutrophils/lymphocytes ratio have been associated with shorter survival and HPD in NSCLC pts. In mouse lung cancer models, interleukin-17 (IL-17) promoted tumour growth upon ICI increasing intratumoral neutrophils. The role of specific circulating and/or tumour-associated neutrophils in driving HPD is currently unknown. Methods: NSCLC pts treated with single agent ICI were assessed for HPD and circulating neutrophils’ phenotype. Conventional PD was defined by RECIST 1.1. HPD required 3 tumour assessments (2 before ICI, 1 upon ICI) and was defined as delta tumour growth rate (TGR) (TGR upon ICI – TGR before ICI) > 50% and/or TGR ratio (TGR upon ICI/ TGR before ICI) ≥2. Correlations with continuous variables were performed by Mann-Whitney test. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry (FC) on peripheral blood mononuclear cells (PBMCs) from fresh blood samples. LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10− and CD10−CD16− LDNs. The occurrence of HPD upon anti-PD-1 treatment was tested in C57BL/6 immune competent mice bearing Lewis Lung Carcinoma and treated with anti-murine PD-1. Tumour associated neutrophils’ phenotype was assessed by FC. Results: Of 52 NSCLC, 65% were > 65 years, 83% had stage IV, 25% PD-L1 on tumour cells ≥50%, 67% received 1st line ICI. PD and HPD occurred in 21 (40%) and 5 (10%) pts, respectively. Before ICI start, HPD pts had higher circulating immature neutrophils measured as median percentage of CD10− LDNs [41.9 (min 26.7; max 83.5) vs 10.1 (min 0.69; max 79.3), p = 0.01] and of CD16− cells among CD10− LDNs [93 (min 89.5; max 98.4) vs 86.3 (min 24.2; max 99), p = 0.03] compared to conventional PD pts. PD and HPD occurred in 17 (71%) and 3 (12.5%) of 24 immune competent mice treated with anti-murine PD-1. The median percentage of IL-17+ tumour associated neutrophils (Gr1highLy6Clow) was significantly higher in HPD compared to PD mice [0.25 (min 0.14; max 0.63) vs 0.06 (min 0.02; max 0.32), p = 0.02]. Conclusions: Circulating immature (CD10− and CD10− CD16−) LDNs and IL-17+ tumour associated neutrophils discriminate HPD from conventional PD upon ICI in NSCLC pts and in vivo models, respectively. Functional characterization of specific neutrophil subsets is ongoing.
Radiotherapy to augment pembrolizumab responses and outcomes in metastatic non-small cell lung cancer: Pooled analysis of two randomized trials.
Authors: Welsh James William , Chen Dawei , Baas Paul , Chang Joe Y. , Verma Vivek , Comeaux Nathan , Skoulidis Ferdinandos , Lin Steven H. , Heymach John , Theelen W.
Published: May 2020

9548

Background: In metastatic non-small cell lung cancer (mNSCLC), the clinical trials NCT02492568 and NCT02444741 are the only known randomized comparisons of pembrolizumab alone versus pembrolizumab combined with radiation therapy (RT). When the trials were analyzed individually, some potential benefit was observed in the combination therapy group, but the relatively small sample size of each trial limited the detection of potential differences in response rates and outcomes. Hence, we perform a pooled analysis of these two randomized trials to validate and explore whether RT improves mNSCLC patient responses to immunotherapy. Methods: This was a pooled analysis of two randomized trials (NCT02492568 and NCT02444741) of pembrolizumab with or without RT for mNSCLC. Endpoints included the out-of-field overall response rate (ORR) and disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and subgroup analysis of the different RT schemes. Results: In all, 131 patients were analyzed (n = 66 pembrolizumab; n = 65 pembrolizumab/RT (iRT)). ORR was 21% in the pembrolizumab arm vs. 38% in the iRT arm (p = 0.01); DCR was 53% in the pembrolizumab arm vs. 67% in the iRT arm (p = 0.0009); PFS was 4.4 m vs 8.3 m (p = 0.046); and OS was 9.2 m vs 19.2 m (HR 0.66; p = 0.040). Ablative RT (24Gy/3 fractions and 50Gy/4 fractions) had better ORRs of 48% and 54%, respectively, compared to 18% for non-ablative RT (45Gy/15 fractions) and 20% for pembrolizumab alone (p < 0.05, respectively). Conclusions: The addition of RT to immunotherapy significantly increased the ORR of unirradiated lesions and was additionally associated with significant improvements in PFS and OS. Ablative RT was associated with response rates significantly higher than those of non-ablative RT, possibly due to a detrimental effect of non-ablative RT on ALC. These hypothesis-generating findings require dedicated, large-volume, and randomized studies for corroboration. Clinical trial information: NCT02492568 and NCT02444741 .
Clinical performance of a comprehensive novel liquid biopsy test for identifying non-small cell lung cancer (NSCLC) patients for treatment with osimertinib.
Authors: Gray Jhanelle Elaine , Han Ji-Youn , Telaranta-Keerie Aino , Huang Xiangning , Kohlmann Alexander , Hodge Rachel , Rukazenkov Yuri , Chmielecki Juliann , Espenschied Carin R. , Wu Yi-Long , Ramalingam Suresh S. , Barrett J Carl , Odegaard Justin Iver
Published: May 2020

9553

Background: Genotyping is required to identify cancer patients (pts) eligible for targeted therapy; however, many do not receive biomarker testing, in part due to limitations associated with tissue-only genotyping practices and the growing list of biomarkers recommended to be tested. Liquid biopsy overcomes many of these limitations but is not yet fully adopted. We report here the clinical performance of a comprehensive liquid biopsy test based on next generation sequencing (NGS) of circulating tumor DNA (ctDNA) for the identification of NSCLC patients with EGFR exon 19 deletions (ex19del) or L858R mutations ( EGFRm) or EGFR T790M, eligible for treatment with osimertinib. Methods: 441 (79%) of 556 pts randomized in FLAURA (NCT02296125; first-line osimertinib vs comparator EGFR TKI in EGFRm NSCLC) and 300 (72%) of 419 pts from AURA3 (NCT012151981; osimertinib vs chemotherapy in NSCLC pts with T790M at progression on EGFR TKI) were retrospectively tested with Guardant360 (G360), a 74-gene ctDNA NGS assay assessing single nucleotide variants, insertion-deletions, amplifications, and fusions in genes relevant to targeted therapy selection as well as microsatellite instability. Progression-free survival (PFS) of pts with EGFRm or T790M detected by G360 was compared to pts detected by the cobas EGFR Mutation Test (cobas) using tissue or plasma with an unadjusted cox model. Results: Treatment with osimertinib was associated with a significant PFS benefit relative to control therapy in NSCLC pts with EGFRm (FLAURA) and T790M (AURA3) detected using G360 (Table). Observed clinical benefit for pts with EGFRm or T790M detected by G360 was similar to that for pts with EGFRm or T790M identified by cobas using tissue or plasma specimens. Conclusions: This analysis demonstrates that G360 accurately identifies pts for osimertinib therapy while simultaneously providing comprehensive genotyping for other therapeutic molecular targets. The application of NGS liquid biopsy has the potential to increase rates of pts genotyped and access to precision medicine. [Table: see text]
Genetic profiling and the response to RET inhibitors in RET fusion positive non-small cell lung cancer (NSCLC) identified by international genomic screening project (LC-SCRUM-Asia).
Authors: Nosaki Kaname , Matsumoto Shingo , Yoh Kiyotaka , Ikeda Takaya , Ohe Yuichiro , Kodani Masahiro , Yanagitani Noriko , Nishino Kazumi , Shingyoji Masato , Takeuchi Shinji , Zenke Yoshitaka , Udagawa Hibiki , Kirita Keisuke , Niho Seiji , Goto Koichi
Published: May 2020

9557

Background: RET fusions are targetable oncogenic drivers in 1 – 2 % of NSCLC, yet no RET inhibitors are approved. Selective RET inhibitors, such as LOXO-292 and BLU-667, are currently in development. The impact of co-occurring mutation on outcome in RET-TKI therapy remains largely unknown. Methods: In an international genome screening project in Asia (LC-SCRUM-Asia), 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of RET fusion+ NSCLC were evaluated using a large-scale clinicogenomic database in the LC-SCRUM-Japan. Results: From Feb 2013 to Dec 2019, a total of 7177 patients with non-squamous NSCLC were enrolled. RET fusion were detected in 167 patients (2.3 %). Median age was 61 years (range: 29 - 85), 60 % were female, 61 % were never-smokers, 99 % had adenocarcinoma, and 78 % had stage IIIB/IV disease. Based on our database, the median overall survival was 37 months. 62 patients received RET inhibitor therapy. RET fusions was identified by NGS assay (KIF5B-RET: 75, CCDC6-RET: 30, Others: 2) in 107 patients. Co-occurring genomic alterations were detected in 62 (58 %) patients, the median number of co-mutations was 1 (range 0 - 4). The most common co-occurring mutations in tumor involved TP53 (31; 29 %), STK11 (6; 6 %), CDKN2A (5; 5 %) and TSC2 (5; 5 %). In 23 patients treated with RET inhibitor (unapproved drugs), there was a strong association between co-occurring mutation and time to treatment discontinuation (TTD) in RET inhibitor therapy; HR 2.75 (95%CI 1.71 - 15.6, P = 0.0096). Conclusions: RET rearrangements continue to represent a rare but high unmet need disease. Co-occurring mutation was significantly associated with shorter TTD. Our data is the largest cohort of advanced-stage RET fusion+ NSCLC profiled by NGS to date. Co-occurring mutation should be evaluated in the development of novel targeted therapies for RET fusion+ NSCLC.
Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC).
Authors: Saltos Andreas Nicholas , Tanvetyanon Tawee , Creelan Ben C. , Shafique Michael Rahman , Antonia Scott Joseph , Haura Eric B. , Zheng Hong , Barlow Margaret , Saller James , Castellano-Fornelli Anna , Richards Antoine , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A , Gray Jhanelle Elaine
Published: May 2020

9567

Background: Histone deacetylase inhibitors may enhance tumor immunogenicity through various mechanisms including induced expression of T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in mNSCLC was well tolerated with signals of activity in ICI-pretreated pts. We initiated a randomized trial in the first-line setting with the primary objective to determine if the combination had superior ORR compared to pembrolizumab monotherapy. Methods: Pts with treatment-naïve mNSCLC and PD-L1 expression ≥ 1% were eligible. Pts were randomized open-label 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] or P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for analysis of CD8+ TIL, scored using a 0-3 scale in tumor beds. Here we report results after a preplanned interim analysis for efficacy, with accrual ongoing to a planned total of 39 patients per arm. Results: Between 7/2017 – 1/2019, 49 pts were enrolled, with 47 pts evaluable for response (24 in Arm A and 23 in Arm B). Median age was 69 (range 47 - 87), 49% female, ECOG PS 0/1 in 11%/89%. PD-L1 TPS was ≥50% in 13/24 (54%) of pts in Arm A, and in 13/23 (57%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (13%), fatigue (8%), and pruritus (8%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included anorexia (43%), fatigue (43%), nausea (35%) and increased creatinine (35%). 1 pt in Arm B experienced grade ≥ 3 irAE (1 grade 3 pneumonitis). Pre-treatment CD8+ TIL were not significantly different between Arm A and Arm B (p = 0.85) with the majority of tumors in both arms having a low TIL score of 1 (65% Arm A and 73.7% Arm B). A significant increase from pre-treatment to on-treatment TIL scores was seen in both Arm A (p = 0.001) and Arm B (p = 0.002). The ORR in Arm B pts with low pre-treatment TIL (score = 1) pts was substantially higher (66.7%) than in Arm A (33.3%), suggesting the combination may be especially beneficial against low TIL tumors. Conclusions: The combination arm had a considerably higher ORR compared to pembrolizumab monotherapy, with a manageable toxicity profile. The combination of pembrolizumab plus vorinostat in mNSCLC warrants further investigation. Clinical trial information: NCT02638090 . [Table: see text]
IMpower150: Exploratory analysis of brain metastases development.
Authors: Cappuzzo Federico , Reck Martin , Socinski Mark A. , Mok Tony S. K. , Jotte Robert M. , Finley Gene Grant , Rodriguez-Abreu Delvys , Aerts Joachim , West Howard , Nishio Makoto , Villaruz Liza C , Coleman Shelly , Lee Anthony , Vollan Hans Kristian , Yu Wei , Sufan Roxana Ioana , Bara Ilze , Barlesi Fabrice
Published: May 2020

9587

Background: In the global phase III IMpower150 study (NCT02366143), atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP] (ABCP) showed significant improvements in PFS and OS vs BCP in patients with chemotherapy-naive metastatic NSCLC (Socinski et al. N Engl J Med 2018). Because bev has been shown to delay or prevent brain metastases progression in NSCLC (Fu et al. J Chemother 2016; Ilhan-Mutlu et al. Mol Can Ther 2016), exploratory analyses were conducted to assess the development of brain metastases in patients treated with ABCP, BCP and atezo + CP (ACP) in IMpower150. Methods: A total of 1202 patients (intention-to-treat [ITT] population) were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were given every 3 weeks: atezo 1200 mg, bev 15 mg/kg, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2. Co-primary endpoints were investigator-assessed PFS and OS in ITT–wild-type (no EGFR or ALK alterations) patients. Exploratory analyses included the rate and time to development (TTD) of new brain metastases in the ITT population, regardless of the presence of baseline brain metastases, as well as safety. Brain scans were performed as clinically indicated, and analyses were based on investigator assessments. Results: With a minimum follow-up of 32.4 months in the ITT population (data cutoff: September 13, 2019), 100 patients had developed brain metastases, with the highest rate of new brain lesions seen in the ACP (11.9%) vs the ABCP (7.0%) and BCP (6.0%) arms (table). Median TTD was not reached in any arm; a trend toward delayed TTD was seen in the ABCP vs BCP arm (HR, 0.68 [95% CI: 0.39, 1.19]). Among patients with and without brain metastases, 17 (35.4%) and 155 (44.0%) in the ACP arm, 18 (64.3%) and 207 (56.7%) in the ABCP arm and 10 (41.7%) and 183 (49.5%) in the BCP arm had Grade 3-4 treatment-related adverse events, respectively. Conclusions: The ACP arm had the highest rate of new brain lesions, whereas the ABCP and BCP arms had similar, lower rates. Taken together with the trend toward delayed development of new brain lesions with ABCP, the data suggest that adding atezo to BCP may not reduce the rate of new brain lesion development but may delay the time to new lesion development. No new safety signals were observed in this exploratory analysis. Clinical trial information: NCT02366143 . [Table: see text]
Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).
Authors: Tamiya Yutaro , Zenke Yoshitaka , Matsumoto Shingo , Furuya Naoki , Sakamoto Tomohiro , Kato Terufumi , Nishino Kazumi , Shingyoji Masato , Miyamoto Shingo , Shirakawa Chigusa , Toyozawa Ryo , Ohashi Kadoaki , Ikeda Takaya , Nosaki Kaname , Udagawa Hibiki , Kirita Keisuke , Yoh Kiyotaka , Niho Seiji , Goto Koichi
Published: May 2020

9589

Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p < 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.
Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with BRAF V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC).
Authors: Planchard David , Besse Benjamin , Groen Harry , Hashemi Sayed MS , Mazieres Julien , Kim Tae Min , Quoix Elisabeth A. , Souquet Pierre Jean , Barlesi Fabrice , Baik Christina S , Villaruz Liza C , Kelly Ronan Joseph , Zhang Shirong , Tan Monique , Gasal Eduard , Santarpia Libero , Johnson Bruce E.
Published: May 2020

9593

Background: The phase II multicenter, open label study, which evaluated efficacy and safety of D+T in pretreated (cohort B) and treatment (tx)-naive (cohort C) pts with BRAF V600E mut metastatic NSCLC. The results of the primary analysis have been reported. Here, we present an updated survival and genomic analysis data for cohorts B and C. Methods: Tx-naïve (n=36) and pretreated (n=57) pts received D 150 mg twice daily + T 2 mg daily. Primary objective: ORR, secondary objectives: PFS, DOR, OS, safety, tolerability and PK of D+T. Tumor samples were centrally tested using a NGS cancer targeted panel (Oncomine Dx Target test, ThermoFisher Scientific). KM curves and Cox regression models were used to evaluate potential associations between baseline genomic landscape and pt efficacy endpoints. Results: As of June 22, 2019, median (m) follow-up was 16.3 mo in tx-naïve pts and 16.6 mo in pretreated pts. mOS was 17.3 mo (95% CI: 12.3, 40.2; 3 yr OS: 40%) and 18.2 mo (95% CI: 14.3, 28.6; 3 yr OS: 33%) with 14/36 and 11/57 pts alive in tx naïve and pretreated pts respectively. Detailed efficacy results are presented in table. 57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. Eleven pts (18%) had concomitant somatic mutations and/or genetic alterations in addition to BRAF V600E mut: 4 had alterations within PI3K pathway4 had concomitant mutations at IDH1 R132X, and 3 pts had additional mutations at BRAF G466V, KRAS G13C and a cMET exon 14 skipping, respectively. Pts whose tumors had concomitant genetic alterations, particularly in PI3K pathway, showed a trend towards decreased PFS and OS. Safety profile was similar to previous reported results. Conclusions: This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings. Clinical trial information: NCT01336634 . [Table: see text]
A phase II study of lorlatinib in patients (pts) with ALK-positive (ALK+) lung cancer with brain-only progression.
Authors: Dagogo-Jack Ibiayi , Oxnard Geoffrey R. , Fink Jessica , Diubaldi Gianluca , Helms Caitlyn , Gainor Justin F. , Rabin Michael S. , Heist Rebecca Suk , Lin Jessica Jiyeong , Ackil Jennifer , Muzikansky Alona , Shaw Alice Tsang
Published: May 2020

9595

Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease. Methods: Between 11/2016 and 1/2019, 22 pts with IC progression on an ALK TKI with no other sites of measurable disease were enrolled at 2 institutions. Pts received lorlatinib at a starting dose of 100 mg QD. The primary endpoint was the IC disease control rate (DCR) at 12 weeks per modified RECIST v1.1. Secondary endpoints were IC objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: Of the 22 pts enrolled, 21 (95%) had progressed on a 2nd-gen ALK TKI and 14 (64%) had previously received CNS radiation (median 21.1 months between radiation and lorlatinib). Median number of prior ALK TKIs was 2 (range 1-4). As of the data cutoff of 12/15/19, median follow-up was 14 months. At 12 weeks, the IC-DCR was 95%, including 8 pts with stable disease. Best IC ORR was 59% with 6 complete and 7 partial responses. Nine (41%) pts relapsed on study, including 3 IC-only, 5 EC-only, and 1 combined relapse. Four pts continued treatment beyond EC-only progression. Although median IC DOR and PFS were not estimable due to few progression events, the IC progression-free rate at 12 months was 81% (95% CI: 53%-94%). Twelve pts have discontinued study treatment due to progression (n = 6), edema (n = 1), pulmonary hypertension (n = 1), or transition to commercial lorlatinib (n = 4). Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 .
Nintedanib + docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Updated efficacy and safety results of the ongoing non-interventional study (NIS) VARGADO (NCT02392455).
Authors: Grohé Christian , Blau Wolfgang , Gleiber Wolfgang , Haas Siegfried , Krüger Stefan , Mueller-Huesmann Harald , Schulze Mathias , Atz Judith , Kaiser Rolf
Published: May 2020

9604

Background: Nintedanib (Vargatef) is an oral triple angiokinase inhibitor targeting VEGF-, PDGF- and FGF receptor pathways. It is approved in the EU and other countries in combination with docetaxel for treatment of locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1st line chemotherapy. ICI +/- chemotherapy has changed the standard of care for 1st line treatment of metastatic non-mutated NSCLC. However, currently, only limited clinical data are available to help guide treatment decisions after prior ICI therapy in subsequent lines. Methods: This updated analysis is part of the ongoing NIS VARGADO (cohort B), a prospective non-interventional study of nintedanib + docetaxel after 1st line chemotherapy for adenocarcinoma NSCLC. The analysis includes 57 pts who had previously received both chemotherapy and ICI treatment. Results: Median age was 61 years (range: 45 – 80), 32/57 pts (56.1%) were men, and 41/57 pts (71.9%) were ECOG PS 0/1. 12/57 pts (21.1%) had brain metastases, and 46/57 pts (80.7 %) were current or former smokers. 1st line chemotherapy treatments included pemetrexed (36/57 pts, 63.2%), cisplatin (29/57 pts, 50.9%), carboplatin (33/57 pts, 57.9%), bevacizumab (14/57 pts, 24.6%), vinorelbine (13/57 pts, 22.8%), paclitaxel (8/57 pts, 14.0%), and docetaxel (1/57 pts, 1.8%). 2nd line treatments included nivolumab (34/57 pts, 59.7%), pembrolizumab (14/57 pts, 24.6%), and atezolizumab (7/57 pts, 12.3%). Under nintedanib and docetaxel, ORR was 50% (20/40 pts); DCR was 85.0% (34/40 pts). Median PFS was 6.5 months (95%CI 4.8 – 8.7), median OS was 12.4 months (95%CI 11.4 – 14.1). Treatment emergent adverse events (TEAEs) grade ≥3, serious TEAEs, and TEAEs leading to discontinuation were observed in 30/57 pts (52.6%), 30/57 pts (52.6%), and 17/57 pts (29.8%), respectively. Conclusions: This updated analysis of the VARGADO study continues to show the clinical benefit and manageable safety profile of nintedanib plus docetaxel in patients who had previously received both chemotherapy and ICI treatment. These data add to the real-world evidence that can inform clinical decision-making after prior ICI therapy. Clinical trial information: NCT02392455 .
Outcomes in patients with advanced non-small cell lung cancer (aNSCLC) and high PD-L1 expression treated with immune checkpoint inhibitor monotherapy: An FDA-pooled analysis.
Authors: Shah Sujay Yogesh , Vallejo Jonathon Joseph , Gong Yutao , Brown Thomas D. , Zhang Chenan , Hirsch Jonathan , Tang Shenghui , Blumenthal Gideon Michael , Singh Harpreet , Kluetz Paul Gustav , Theoret Marc Robert , Beaver Julia A. , Pazdur Richard
Published: May 2020

9606

Background: Higher PD-L1 score ≥ 50% predicts for greater benefit to immune checkpoint inhibitor (ICI) therapy in first line (1L) treatment of aNSCLC. It has recently been reported that PD-L1 score ≥ 90% predicts for even greater benefit to 1L ICI monotherapy (Aguilar et al., 2019). We examined pooled clinical trial databases to examine the relationship between high PD-L1 expression across multiple ICI monotherapies in 1L and second line (2L) treatment of aNSCLC. Methods: Data was pooled from trials (five 1L and five 2L) of ICI for the treatment of patients with aNSCLC. We defined PD-L1 score as the proportion of tumor cell stained by the assay (total of four assays identified) and included patients in the analysis with PD-L1 score ≥ 50%. Tumor-infiltrating immune cell staining was not considered. Progression-free survival (PFS) and overall survival (OS) by line of therapy for patients with PD-L1 score ≥ 90% and patients with PD-L1 score 50-89% was analyzed. Results: A total of 1320 patients treated with ICI monotherapy were identified, 873 in 1L and 447 in 2L. Median follow-up was 9.6 months in 2L patients and 13.3 months in 1L patients. Patients receiving 2L ICI therapy with PD-L1 score ≥ 90% (N = 208) had longer PFS and OS compared to patients with PD-L1 score 50-89% (N = 239), with mPFS 7.1 vs. 4.2 months (HR = 0.66 [95% CI: 0.52-0.83]) and mOS NR vs. 15.8 months (HR = 0.66 [95% CI: 0.49-0.89]). 1L ICI therapy analysis revealed similar trends, as patients with PD-L1 score ≥ 90% (N = 405) had longer PFS and OS compared to patients with a PD-L1 score 50-89% (N = 468), with mPFS 8.3 vs. 5.4 months (HR = 0.78 [95% CI: 0.66-0.92]) and mOS 22.9 vs. 16.4 months (HR = 0.74 [95% CI: 0.61-0.90]). Conclusions: This analysis showed the potential of an enhanced clinical benefit in patients with aNSCLC and PD-L1 score ≥90% across ICI monotherapies in both the 1L and 2L treatment setting. These data will be further analyzed in real world populations.
Cabozantinib in combination with atezolizumab in non-small cell lung cancer (NSCLC) patients previously treated with an immune checkpoint inhibitor: Results from cohort 7 of the COSMIC-021 study.
Authors: Neal Joel W. , Lim Farah Louise , Felip Enriqueta , Gentzler Ryan D. , Patel Shiven B. , Baranda Joaquina , Fang Bruno , Squillante Christian Michael , Simonelli Matteo , Werneke Scott , Curran Dominic , Ponce Aix Santiago
Published: May 2020

9610

Background: First-line immunotherapy with/without chemotherapy is standard of care for patients (pts) with advanced NSCLC; however, there is a need for effective treatment options after progression on a prior immune checkpoint inhibitor (ICI). Cabozantinib (C) may augment response to ICI by inhibiting kinases implicated in suppressing immune cell responses and has shown encouraging clinical activity in combination with ICI in other tumor types including RCC and HCC. COSMIC-021, a multicenter phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from cohort 7 in NSCLC pts after prior ICI therapy. Methods: Eligible pts had ECOG performance status (PS) 0-1 and radiographic progression after one prior anti-PD-1/PD-L1 ICI given alone or in combination with chemotherapy for metastatic non-squamous NSCLC. Up to 2 lines of prior systemic anticancer therapies were permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Primary endpoint is ORR per RECIST 1.1 by investigator. Other endpoints include safety, duration of response (DOR), progression-free survival, and overall survival. Results: Thirty pts with advanced NSCLC were enrolled. Median age was 67 yrs (range 41, 81), 43% were male, 57% had ECOG PS 1, and 23% had liver metastases. Median duration of prior ICI therapy was 4.8 months (mo; range 0.8, 29), and 15 (50%) pts were refractory to prior ICI (progressive disease as best response). As of December 20, 2019, the median follow-up was 8.9 mo (range 5, 20) with 9 (30%) pts continuing study treatment. The most common treatment related adverse events (TRAEs) of any grade were diarrhea (53%), fatigue (37%), nausea (23%), decreased appetite (20%), palmar-plantar erythrodysesthesia (20%) and vomiting (20%). Grade 3/4 TRAEs occurred in 14 (47%) pts, and 1 (3.3%) had grade 5 TRAEs of myocarditis and pneumonitis. Confirmed ORR per RECIST 1.1 was 23% (7 of 30 pts; all partial responses including 3 pts refractory to prior ICI). Time to response was 1.4 mo (range 1, 3), and median DOR was 5.6 mo (range 2.6, 6.9). DCR (CR+PR+SD) was 83%. Conclusions: The combination of C and A had an acceptable safety profile and showed encouraging clinical activity in pts with advanced NSCLC who had progressed after prior ICI therapy. The response rate was greater than previously observed with C monotherapy. Due to the promising data, enrollment in this cohort has been expanded and is ongoing. Clinical trial information: NCT03170960 .
Adjuvant chemotherapy with or without an anthracycline in older adults with node-negative triple-negative breast cancer (TNBC): A SEER Medicare study.
Authors: Schreiber Anna R , Kagihara Jodi , Eguchi Megan , Kabos Peter , Meyer Elisabeth , Kondapalli Lavanya , Fisher Christine M. , Bradley Cathy J , Diamond Jennifer Robinson
Published: May 2020

e12505

Background: TNBC is an aggressive breast cancer subtype comprising approximately 15% of breast cancers. Adjuvant chemotherapy reduces the risk of recurrence, particularly in patients with tumors > 1 cm or node positive disease. Anthracycline (A) + taxane (T)-containing regimens are more efficacious than T-based regimens, however, the risk of cardiac toxicity is greater in older patients. We investigated the use of AT and T-containing regimens in patients ≥ 66 years old with node negative TNBC and evaluated clinical outcomes and cardiac risk factors. Methods: We identified female patients ≥ 66 diagnosed between 2010-2015 with TNBC node negative disease in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. Baseline characteristics, including age, tumor size, cardiac history, and adjuvant chemotherapy administration (AT vs. T) were collected. A logistic regression analysis was performed to estimate independent predictors of AT vs. T chemotherapy. Overall survival (OS) was estimated at 3 years. Results: We identified 3348 patients, including 1679 (50.2%) who received chemotherapy for T1a/bN0 (32.5%), T1cN0 (55.5%), T2N0 (57.0%) and T3/T4N0 (49.6%) disease. Of those, 984 (58.6%) received T, 420 (25.0%) received AT and 275 (16.4%) received other chemotherapy. AT use was associated with larger tumor size; T1a/bN0 (13.6%), T1cN0 (21.3%), T2N0 (31.6%) and T3/T4N0 (34.9%). In a multivariate analysis, independent predictors of AT vs. T were age, region treated in the USA, tumor size and presence of prior cardiac risk factors or pre-existing cardiac disease. OS at 3 years was 91% for T and 86% for AT (p 0.03). Conclusions: Approximately half of older patients diagnosed with node negative TNBC received adjuvant chemotherapy. T-based regimens were more commonly used than AT regimens. Younger age, higher stage and lack of cardiac comorbidities correlated with use of AT compared to T. Continued investigation of the benefit of adjuvant chemotherapy in older patients may assist in clinical decision making.
Endocrine therapy adherence of premenopausal Mexican breast cancer patients.
Authors: Villarreal-Garza Cynthia , Mesa-Chavez Fernanda , Ferrigno Ana Sofia , De la Garza-Ramos Cynthia , Villanueva-Tamez Karen , Fonseca Alan , Campos-Salgado Jose Yair , Pineda Claudia , García-García Marisol , Rodriguez David Omar , Cruz-Ramos Marlid , Cabrera-Galeana Paula
Published: May 2020

e12510

Background: Among premenopausal women with breast cancer (BC), adherence to endocrine therapy (ET) has often been reported suboptimal due to age-related adverse effects, lack of understandable information and inadequate social support. The current increased use of ovarian function suppression (OFS) may lead to even lower adherence rates in this group due to its high adverse effects profile. This study aims to assess the extent to which premenopausal patients comply with ET and to identify factors that hinder optimal adherence in Mexico. Methods: Women aged ≤50 years with primary stage I-III hormone receptor-positive BC receiving adjuvant ET for ≥1year were invited to fill a survey regarding their attitude towards ET and self-reported adherence. Fisher’s exact test was used to explore associations between categorical variables. This study was funded by AstraZeneca Mexico. Results: From Sep 2019 to Jan 2020, 127 patients with a median age of 45 years (range: 25-50) were included. Most had at least high school education (64%) and were unemployed (61%). ET distribution was: 69% tamoxifen (TMX) alone; 2% TMX switch to aromatase inhibitor (AI); 29% OFS plus TMX/AI. All patients recognized ET as a necessary part of their treatment and 97% believed it reduced their recurrence risk, yet 14% considered they had not received enough information about ET. Adverse effects were reported by 98%, predominantly hot flashes (82%), arthralgias (59%) and fatigue (58%). A statistically significant higher proportion of patients treated with a switch strategy or OFS experienced hot flashes, headache, insomnia, decreased libido and dyspareunia than those with TMX alone. Only 59% claimed their physician had taken measures to reduce these symptoms. Overall, 93% reported complete ET adherence. Nonetheless, 22% of them subsequently acknowledged missing 1-6 doses in the last month, the most common reasons being forgetfulness (78%), adverse effects (27%) and unwillingness to take the medication (11%). Unemployed patients were more likely to report daily compliance than students/employees (79% vs 60%; p = 0.02). No significant differences in adherence were found according to other factors, including type of ET. Conclusions: Premenopausal Mexican women self-report remarkably high rates of ET adherence. However, a considerable proportion misses ≥1 doses/month, with forgetfulness as the most common cause particularly in students/employees. Interventions aimed at reminding this group to take their ET and managing adverse effects could be crucial to improve adherence and, consequently, disease outcomes.
SEER-Medicare study of early-stage triple-negative breast cancer: Real-world treatment patterns, survival, and expenditures 2010 to 2016.
Authors: Sieluk Jan , Haiderali Amin , Huang Min , Yang Lingfeng , Tryfonidis Konstantinos , Hirshfield Kim M.
Published: May 2020

e12512

Background: In the US, triple-negative breast cancer (TNBC) represents about 10–20% of breast cancers. Current information about the clinical and economic burden of early-stage TNBC in elderly patients is lacking. Methods: We used the SEER-Medicare database to identify patients with continuous Medicare Parts A/B enrollment, ≥66 years old, newly diagnosed between 2010 - 2015 (followed until 2016) with stage II-III TNBC, who initiated systemic neoadjuvant and/or adjuvant (including chemotherapy and radiation) therapy. Overall survival (OS) and event-free survival (EFS) from diagnosis were estimated using Kaplan-Meier (KM). Healthcare costs were determined during neoadjuvant and adjuvant periods. Results: Of 1569 patients ( > 99% women), 94 (6%) received neoadjuvant therapy, 1162 (74%) received adjuvant therapy, and 313 (20%) received both (neo/adj; Table). Age and race/ethnicity distributions were comparable in the three cohorts. Primary tumor T stage was T1c/T2 for 43%, 83%, and 58% in neoadjuvant, adjuvant, and neo/adj, respectively, and T3 for 14%, 10%, and 15%, respectively. The most common systemic regimens in both neoadjuvant and adjuvant periods were a taxane +/- anthracycline; 21% and 67% of patients in adjuvant and neo/adj cohorts received radiation therapy after surgery. Most claims were for outpatient treatment; hospitalizations were uncommon. The total mean expenditures per patient per month were US$10,620 and $24,408 during neoadjuvant and adjuvant periods, respectively. Conclusions: This study provides insights into patient characteristics, as well as clinical and economic outcomes for elderly patients with early-stage TNBC, treated from 2010-2016 in the US, highlighting the high monetary burden of TNBC and poor outcomes associated with stage III patients. [Table: see text]
RelB silencing to reverse tamoxifen resistance by regulating GPx4 and ferroptosis in breast cancer.
Authors: Xu Zhi , Tang Jinhai
Published: May 2020

e12513

Background: Tamoxifen(Tam), as an essential therapeutic treatment of estrogen receptor(ER)-positive breast cancer(BCa), has been available for the past three decades. However, the induction of Tam resistance during therapy has indicated a significant challenge with regards to this agent. Tam could increase oxidative stress and induce cell death by regulating reactive oxygen species(ROS). Ferroptosis, a cell death process driven by the accumulation of iron-dependent lipid peroxides, has been induced by inactivation/depletion of glutathione peroxidases(GPxs). Our previous studies found that the expression level of RelB gene, a member of NF-κB family, is negatively correlated with ER targeted by Tam in BCa. Methods: The RelB level of BCa tumor tissues and the corresponding cell lines were examined by immunoblotting and western blot. The effects of Tam on cell viability were determined using colony survival and MTT assay. The ROS and oxygen consumption rates(OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. The lipid peroxidation level of cells was analyzed by immunofluorescence assay. The morphological changes of mitochondria were observed by transmission electron microscope. RelB binding to the NF-κB intronic enhancer region of the human GPx4 gene was determined using a ChIP assay. Accordingly, the effect of RelB on BCa Tam resistance was further validated using BCa mice xenograft models. Results: RelB was uniquely expressed at the high level in Tam resistance BCa tissues and cell lines. Down-regulation of RelB based on a CRISPR/Cas9 system remarkably sensitized resistance BCa cells to Tam. Treatment with SN52, a RelB inhibitor, illuminated the role of RelB in Tam-treated BCa cells. The high level of ROS and declination of mitochondrial respiration which induced by Tam were inhibited in resistance cells. Tam enhanced lipid peroxidation with concomitant non-apoptotic cell death, which are negatively regulated by GPx4 activity. In addition to GPx4 knockdown, deferoxamine was able to rescue Tam-induced cell death in BCa cells, verifying that Tam induces cell death partially through ferroptosis. Importantly, RelB upregulates GPx4 expression through binding to an NF-κB enhancer element located at the 5’-flanking region. Consistently, in vivo functional validation confirmed that RelB inhibition not only impairs tumor growth, but also inhibits Tam resistance in nude mice. Conclusions: RelB could inhibit ferroptosis which induced by hydroxyl radicals accumulation through upregulating GPx4 in BCa.